Author: "Région Pays de la Loire" / Topic: animals - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Région Pays de la Loire"' showing total 68 results

Start Over Author "Région Pays de la Loire" Topic animals

68 results on '"Région Pays de la Loire"'

1. Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization

Author: Yannick Jacques, Monique Mathé-Allainmat, Laurence Arzel, Mike Maillasson, Erwan Mortier, Jacques Lebreton, Romy Vomiandry, Didier Dubreuil, Agnès Quéméner, Benoit Sicard, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), This work was funded by the programs CIMATH2 (Ciblage Moléculaire et Applications Thérapeutiques 2) and PIRAMID (Protein‐protein Interactions in Rational Approaches for Medicinal Innovative Drugs) supported by La Région Pays de la Loire. R.V. was supported by a fellowship from La Région Pays de la Loire. We thank CHEM)Symbiose and IMPACT facilities for technical assistance., Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, 01 natural sciences, Cell Line, Small Molecule Libraries, Mice, Structure-Activity Relationship, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Discovery, medicine, Animals, Humans, Receptor, Cell Proliferation, Interleukin-15, Virtual screening, 010405 organic chemistry, Chemistry, Interleukin, Stereoisomerism, Triazoles, Small molecule, 0104 chemical sciences, 3. Good health, Cell biology, Interleukin-2 Receptor beta Subunit, Molecular Docking Simulation, 030104 developmental biology, Cytokine, Interleukin 15, Immunology, Phthalazines, Molecular Medicine, Pharmacophore, Databases, Chemical, CD8
Abstract: International audience; Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 β and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL- 15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rβ chain and/or the proliferation of IL-15-dependent cells. One of them was selected as a hit, optimized by a structure-activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.
Published: 2017

2. Diuron exposure and Akt overexpression promote glioma formation through DNA hypomethylation

Author: Briand, Joséphine, Nadaradjane, Arulraj, Bougras-Cartron, Gwenola, Olivier, Christophe, Vallette, François M., Cartron, Pierre-François, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire de Biologie des Cancers et de Théranostic [St Herblain, Nantes] (LabCT), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Réseau Epigénétique du Cancéropôle Grand-Ouest [Nantes] (REpiCGO), Cancéropôle Grand Ouest [Nantes]-Maison de la Recherche en Santé [Nantes], Epigénétique - Santé - AgroAlimentaire - Végétal - Mer - Environnement - Nutrition [Nantes] (EpiSAVMEN), Consortium de la Recherche en Epigénétique de la Région Pays de la Loire [Nantes], Service de pharmacologie et de Toxicologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), LabEX IGO Immunothérapie Grand Ouest, JB was supported by a fellowship from EpiSAVMEN/Région Pays de la Loire (Programme Dynamique Scientifique 2016). We also thank 'En Avant la Vie' (an association supporting the patients suffering from gliomas and their family, and the research on glioma field) for the partial funding of the JB’s fellowship., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), and Bernardo, Elizabeth
Subjects: PD-L1, DNA methylation, Brain Neoplasms, Research, Receptors, Cell Surface, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Glioma, B7-H1 Antigen, Up-Regulation, Gene Expression Regulation, Neoplastic, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Diuron, 5-Methylcytosine, Animals, Humans, Lectins, C-Type, Gliomagenesis, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt, Neoplasm Transplantation
Abstract: International audience; Background: Diuron is an environmental component listed as a likely human carcinogen. Several other studies report that diuron can be oncogenic for bladder, urothelial, skin, and mammary cells. No study mentions the putative effect of diuron on the glioma occurrence. Objectives: We here wanted to investigate the effects of diuron exposure on the glioma occurrence while wishing to incriminate a putative implication of DNA methylation modulation in this process. Methods: In in vivo model of glioma, diuron exposure was firstly compared or combined with oncogenic overexpressions already known to promote gliomagenesis. ELISA quantifying the 5-methylcytosine level on DNA was performed to examine the global DNA methylation level. Quantitative real-time polymerase chain reaction and proximity ligation in situ assay were performed to identify the molecular causes of the diuron-induced changes of DNA methylation. The signatures diuron-induced changes of DNA methylation were analyzed in a cohort of 23 GBM patients. Results: Diuron exposure is not sufficient to promote glioma, such as the oncogenic overexpression of Akt or Ras. However, the combination of diuron exposure and Akt overexpression promotes glioma. We observed that the diuron/Akt-induced glioma is characterized by three phenotypic signatures characterizing cancer cells: a global DNA hypomethylation, a loss of sensitivity to cell death induction, and a gain of signals of immune escape. Our data associated these phenotypes with three aberrant DNA methylation signatures: the LLT1, PD-L1, and Bcl-w hypomethylations. Strikingly, we observed that these three concomitant hypomethylations were only observed in GBM patients having a potential exposure to diuron via their professional activity. Conclusions: As single player, diuron is not an oncogenic of glioma, but it can participate to the glioma formation in association with other events (also devoid of oncogenic property as single player) such as Akt overexpression.
Published: 2019

3. In vivo analysis of human immune responses in immunodeficient rats

Author: Menoret, Séverine, Ouisse, Laure-Hélène, Tesson, Laurent, Remy, Severine, Usal, Claire, Guiffes, Aude, Chenouard, Vanessa, Royer, Pierre-Joseph, Evanno, Gwénaëlle, Vanhove, Bernard, Piaggio, Eliane, Anegon, Ignacio, Le Bihan, Sylvie, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Laboratoires communs organismes de recherche publics – PME/ETI - Nouveaux outils pour la création de rongeurs génétiquement modifiés - - SOURIRAT2014 - ANR-14-LAB5-0008 - LABCOM - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Xenothera [Nantes, France], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was performed in the context of different programs: Biogenouest by Région Pays de la Loire, IBiSA program, TEFOR (Investissements d’Avenir French Government program, ANRII-INSB-0014), LabCom SOURIRAT project (ANR-14-LAB5-0008), Labex IGO project (Investissements d’Avenir French Government program, ANR-11-LABX-0016-01), IHU-Cesti project (Investissements d’Avenir French Government program, ANR-10-IBHU-005, Nantes Métropole and Région Pays de la Loire) and Fondation Progreffe. TransImm team (E.P.) is supported by LabEx DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043), SIRIC INCa-DGOS-Inserm_12554, Center of Clinical Investigation (CIC IGR-Curie 1428)., ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-14-LAB5-0008,SOURIRAT,Nouveaux outils pour la création de rongeurs génétiquement modifiés(2014), and ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011)
Subjects: Homeodomain Proteins, Immunoglobulin gamma-Chains, [SDV]Life Sciences [q-bio], Immunologic Deficiency Syndromes, Graft vs Host Disease, Breast Neoplasms, Antigens, Differentiation, Xenograft Model Antitumor Assays, Rats, Sprague-Dawley, [SDV] Life Sciences [q-bio], Disease Models, Animal, Immunocompromised Host, Original Basic Science—General, Cell Line, Tumor, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Leukocytes, Mononuclear, Animals, Heterografts, Humans, Female, Rats, Transgenic, Receptors, Immunologic, Antilymphocyte Serum
Abstract: Supplemental Digital Content is available in the text., Background. Humanized immune system immunodeficient mice have been extremely useful for the in vivo analyses of immune responses in a variety of models, including organ transplantation and graft versus host disease (GVHD) but they have limitations. Rat models are interesting complementary alternatives presenting advantages over mice, such as their size and their active complement compartment. Immunodeficient rats have been generated but human immune responses have not yet been described. Methods. We generated immunodeficient Rat Rag−/− Gamma chain−/− human signal regulatory protein alpha-positive (RRGS) rats combining Rag1 and Il2rg deficiency with the expression of human signal regulatory protein alpha, a negative regulator of macrophage phagocytosis allowing repression of rat macrophages by human CD47-positive cells. We then immune humanized RRGS animals with human peripheral blood mononuclear cells (hPBMCs) to set up a human acute GVHD model. Treatment of GVHD was done with a new porcine antihuman lymphocyte serum active through complement-dependent cytotoxicity. We also established a tumor xenograft rejection model in these hPBMCs immune system RRGS animals by subcutaneous implantation of a human tumor cell line. Results. RRGS animals receiving hPBMCs showed robust and reproducible reconstitution, mainly by T and B cells. A dose-dependent acute GVHD process was observed with progressive weight loss, tissue damage, and death censoring. Antihuman lymphocyte serum (L1S1) antibody completely prevented acute GVHD. In the human tumor xenograft model, detectable tumors were rejected upon hPBMCs injection. Conclusions. hPBMC can be implanted in RRGS animals and elicit acute GVHD or rejection of human tumor cells and these are useful models to test new immunotherapies.
Published: 2019

4. CD9+ Regulatory B Cells Induce T Cell Apoptosis via IL-10 and Are Reduced in Severe Asthmatic Patients

Author: Bousseau, Carole, Durand, Maxim, Colas, Luc, Durand, Eugenie, Foureau, Aurore, Cheminant, Marie-Aude, Bouchaud, Grégory, Castan, Laure, Klein, Martin, Magnan, Antoine, Brouard, Sophie, Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Immunoregulation And Immunointervention in Transplantation and Autoimmunity (Team 4 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), INRA Centre Angers-Nantes [Nantes, France], CIC biothérapies CBT 0503 [Nantes], Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by a grant from l’Institut de Recherche en Santé Respiratoire-Pays de la Loire. This work was achieved in the context of the BASAL project financed by Région Pays de la Loire and the IHU-Cesti project, the DHU Oncogreffe and the LabEX IGO thanks to French government financial support managed by the National Research Agency via the Investment into the Future program (ANR-10-IBHU-005 and ANR-11-LABX-0016-01). The IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire., ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Le Bihan, Sylvie, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Unité de recherche de l'institut du thorax (ITX-lab), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), and Institut National de la Recherche Agronomique (INRA)
Subjects: Adult, Male, severe asthma, [SDV.IMM] Life Sciences [q-bio]/Immunology, MAP Kinase Signaling System, Immunology, Cell Communication, Mitochondrial Dynamics, Severity of Illness Index, Tetraspanin 29, Mice, effector T cells, T-Lymphocyte Subsets, regulatory B cells, CD9(+) B cells, apoptosis, Animals, Humans, Prospective Studies, Lung, Original Research, Aged, B-Lymphocytes, Regulatory, CD9+ B cells, Middle Aged, G1 Phase Cell Cycle Checkpoints, Asthma, Interleukin-10, Disease Models, Animal, embryonic structures, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, CD9 + B cells
Abstract: International audience; CD9 was recently identified as a marker of murine IL-10-competent regulatory B cells. Functional impairments or defects in CD9 + IL-10-secreting regulatory B cells are associated with enhanced asthma-like inflammation and airway hyperresponsiveness. In mouse models, all asthma-related features can be abrogated by CD9 + B cell adoptive transfer. We aimed herein to decipher the profiles, features, and molecular mechanisms of the regulatory properties of CD9 + B cells in human and mouse. The profile of CD9 + B cells was analyzed using blood from severe asthmatic patients and normal and asthmatic mice by flow cytometry. The regulatory effects of mouse CD9 + B cells on effector T cell death, cell cycle arrest, apoptosis, and mitochondrial depolarization were determined using yellow dye, propidium iodide, Annexin V, and JC-1 staining. MAPK phosphorylation was analyzed by western blotting. Patients with severe asthma and asthmatic mice both harbored less CD19 + CD9 + B cells, although these cells displayed no defect in their capacity to induce T cell apoptosis. Molecular mechanisms of regulation of CD9 + B cells characterized in mouse showed that they induced effector T cell cycle arrest in sub G0/G1, leading to apoptosis in an IL-10-dependent manner. This process occurred through MAPK phosphorylation and activation of both the intrinsic and extrinsic pathways. This study characterizes the molecular mechanisms underlying the regulation of CD9 + B cells to induce effector T cell apoptosis in mice and humans via IL-10 secretion. Defects in CD9 + B cells in blood from patients with severe asthma reveal new insights into the lack of regulation of inflammation in these patients.
Published: 2018

5. Loss of vascular expression of nucleoside triphosphate diphosphohydrolase-1/CD39 in hypertension

Author: Antoine Caillon, Daniel Henrion, Ludovic Martin, Julie Favre, Daniele C. Nascimento, Jean Sévigny, Julie Tabiasco, Bernhard Ryffel, Jean Mérot, Charlotte Roy, Simon C. Robson, Gilles Kauffenstein, Yves Delneste, Anne-Laure Guihot, Euromov (EuroMov), Université de Montpellier (UM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de la Recherche Agronomique (INRA), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Département de microbiologie-infectiologie et d’immunologie [Québec City, QC, Canada], Faculté de médecine de l'Université Laval [Québec] (ULaval), Biologie et physiologie moléculaire du vaisseau, Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de recherche de l'institut du thorax (ITX-lab), Division of Gastroenterology [Boston, MA, USA], Harvard University [Cambridge]-Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Centre de recherche [CHU Québec, Canada], Medical Biology, Medicine / Université de Laval-Hôtel-Dieu de Québec [Canada]-CHU de Québec–Université Laval, MitoVasc Institute was supported by INSERM, CNRS, University of Angers, CHU of Angers, Région Pays de la Loire, Angers-Loire Métropole, and Département du Maine et Loire. CR was supported by grants from INSERM and Région Pays de la Loire., Bernardo, Elizabeth, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Faculté de médecine de l'Université Laval (Québec) [Canada], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Vascular smooth muscle, Nucleotidase activity, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Myocytes, Smooth Muscle, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030204 cardiovascular system & hematology, Proinflammatory cytokine, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, CD, Internal medicine, medicine, Animals, Ectonucleotidase, Endothelial dysfunction, Molecular Biology, ComputingMilieux_MISCELLANEOUS, CD39, Chemistry, Angiotensin II, Apyrase, Endothelial Cells, Arteries, Cell Biology, medicine.disease, 3. Good health, Mice, Inbred C57BL, ATP, 030104 developmental biology, Cytokine, Endocrinology, Hypertension, Original Article, Tumor necrosis factor alpha
Abstract: International audience; Ectonucleoside triphosphate diphosphohydrolase-1, the major vascular/immune ectonucleotidase, exerts anti-thrombotic and immunomodulatory actions by hydrolyzing extracellular nucleotides (danger signals). Hypertension is characterized by vascular wall remodeling, endothelial dysfunction, and immune infiltration. Here our aim was to investigate the impact of arterial hypertension on CD39 expression and activity in mice. Arterial expression of CD39 was determined by reverse transcription quantitative real-time PCR in experimental models of hypertension, including angiotensin II (AngII)-treated mice (1 mg/kg/day, 21 days), deoxycorticosterone acetate-salt mice (1% salt and uninephrectomy, 21 days), and spontaneously hypertensive rats. A decrease in CD39 expression occurred in the resistance and conductance arteries of hypertensive animals with no effect on lymphoid organs. In AngII-treated mice, a decrease in CD39 protein levels (Western blot) was corroborated by reduced arterial nucleotidase activity, as evaluated by fluorescent (etheno)-ADP hydrolysis. Moreover, serum-soluble ADPase activity, supported by CD39, was significantly decreased in AngII-treated mice. Experiments were conducted in vitro on vascular cells to determine the elements underlying this downregulation. We found that CD39 transcription was reduced by proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor alpha on vascular smooth muscle cells and by IL-6 and anti-inflammatory and profibrotic cytokine transforming growth factor beta 1 on endothelial cells. In addition, CD39 expression was downregulated by mechanical stretch on vascular cells. Arterial expression and activity of CD39 were decreased in hypertension as a result of both a proinflammatory environment and mechanical strain exerted on vascular cells. Reduced ectonucleotidase activity may alter the vascular condition, thus enhancing arterial damage, remodeling, or thrombotic events.
Published: 2018

6. Interleukin-10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection byStreptococcus pneumoniae

Author: Hernán F. Peñaloza, Pamela A. Nieto, Natalia Muñoz-Durango, María José Parga, Javiera Torres, Francisco J. Salazar-Echegarai, Manuel Álvarez-Lobos, Susan M. Bueno, Claudia A. Riedel, Alexis M. Kalergis, Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Departamento de Anatomia Patologica [Santiago, Chile] (Facultad de Medicina), Departamento de Gastroenterologıa [Santiago, Chile] (Facultad de Medicina), Departamento de Ciencias Biologicas [Santiago, Chile] (Facultad de Ciencias Biologicas y Facultad de Medicina), Universidad Andrés Bello [Santiago] (UNAB), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Departamento de Inmunologıa Clınica y Reumatologıa [Santiago, Chile] (Escuela de Medicina), This study was supported by the following grants: FONDO NACIONAL DE CIENCIA Y TECNOLOGIA DE CHILE (FONDECYT numbers 1140010, 1110604, 1100971, 1131012, 1150862 and 1110397), Millennium Institute on Immunology and Immunotherapy P09/016-F and Grant ‘Nouvelles Equipes-nouvelles thématiques’ from the La Région Pays De La Loire. HFP, PAN, NMD and MJP are supported by the Comision Nacional de Investigacion Cientıﬁca y Tecnologica (CONICYT). AMK is a Chaire De La Région Pays De La Loire, Chercheur Etranger D’excel-lence, France., and Le Bihan, Sylvie
Subjects: medicine.medical_treatment, Interleukin-1beta, Immunology, Inflammation, Biology, medicine.disease_cause, Pathogenesis, Sepsis, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, neutrophils, Streptococcus pneumoniae, medicine, Animals, Immunology and Allergy, Lung, 030304 developmental biology, Mice, Knockout, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tumor Necrosis Factor-alpha, bacterial infection, Brain, Original Articles, Pneumonia, Pneumococcal, medicine.disease, Bacterial Load, cytokines, Interleukin-10, respiratory tract diseases, 3. Good health, Mice, Inbred C57BL, Interleukin 10, Otitis, Cytokine, Neutrophil Infiltration, Pneumococcal pneumonia, systemic bacterial infection, medicine.symptom, lung inﬂammation, Spleen, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: International audience; Streptococcus pneumoniae is a major aetiological agent of pneumonia worldwide, as well as otitis media, sinusitis, meningitis and sepsis. Recent reports have suggested that inﬂammation of lungs due to S. pneumoniae infection promotes bacterial dissemination and severe disease. However, the contribution of anti-inﬂammatory molecules to the pathogenesis of S. pneumoniae remains unknown. To elucidate whether the production of the anti-inﬂammatory cytokine interleukin-10 (IL-10) is beneﬁcial or detrimental for the host during pneumococcal pneumonia, we performed S. pneumoniae infections in mice lacking IL-10 (IL-10[-/-] mice). The IL-10/[-/-] mice showed increased mortality, higher expression of proinﬂammatory cytokines, and an exacerbated recruitment of neutrophils into the lungs after S. pneumoniae infection. However, IL-10[-/-] mice showed signiﬁcantly lower bacterial loads in lungs, spleen, brain and blood, when compared with mice that produced this cytokine. Our results support the notion that production of IL-10 during S. pneumoniae infection modulates the expression of pro-inﬂammatory cytokines and the inﬁltration of neutrophils into the lungs. This feature of IL-10 is important to avoid excessive inﬂammation of tissues and to improve host survival, even though bacterial dissemination is less efﬁcient in the absence of this cytokine.
Published: 2015

7. Antigen-specific single B cell sorting and expression-cloning from immunoglobulin humanized rats: a rapid and versatile method for the generation of high affinity and discriminative human monoclonal antibodies

Author: Laetitia Gautreau-Rolland, Melinda Moyon, Laure-Hélène Ouisse, Xavier Saulquin, Jonathan Visentin, Frank Halary, Marie-Claire Devilder, Roland Buelow, Marianne Brüggemann, Ignacio Anegon, Michael J. Osborn, Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Recombinant Antibody Technology Ltd. [Cambridge, UK], Babraham Bioscience Technologies Ltd [Cambridge, UK], Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Immunologie et Immunogénétique [Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Pellegrin - Bordeaux, Ligand Pharmaceuticals, This work was financially supported by the IHU-Cesti project funded by the « Investissements d'Avenir » French Government program, managed by the French National Research Agency (ANR) (ANR-10-IBHU-005). The IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire. This work was performed in the context of the Labex IGO and TEFOR projects which are also part of the « Investissements d’Avenir » French Government program managed by the ANR (ANR-11-LABX-0016-01 and ANRI I-INSB-0014), respectively. The work was also partially funded by Région Pays de la Loire through Biogenouest and by the IBiSA program., ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Bernardo, Elizabeth, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID
Subjects: 0301 basic medicine, Tetramers, Human antibodies, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Separation, Yeast display, Protein Engineering, Monoclonal antibody, Major histocompatibility complex, Polymerase Chain Reaction, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, medicine, Animals, Humans, Cloning, Molecular, Humanized rats, B cell, B-Lymphocytes, biology, Methodology Article, Immunogenicity, pMHC, Antibodies, Monoclonal, Cytofluorimetry, Molecular biology, Rats, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Immunoglobulin G, Expression cloning, biology.protein, Antibody, Biotechnology
Abstract: Background There is an ever-increasing need of monoclonal antibodies (mAbs) for biomedical applications and fully human binders are particularly desirable due to their reduced immunogenicity in patients. We have applied a strategy for the isolation of antigen-specific B cells using tetramerized proteins and single-cell sorting followed by reconstruction of human mAbs by RT-PCR and expression cloning. Results This strategy, using human peripheral blood B cells, enabled the production of low affinity human mAbs against major histocompatibility complex molecules loaded with peptides (pMHC). We then implemented this technology using human immunoglobulin transgenic rats, which after immunization with an antigen of interest express high affinity-matured antibodies with human idiotypes. Using rapid immunization, followed by tetramer-based B-cell sorting and expression cloning, we generated several fully humanized mAbs with strong affinities, which could discriminate between highly homologous proteins (eg. different pMHC complexes). Conclusions Therefore, we describe a versatile and more effective approach as compared to hybridoma generation or phage or yeast display technologies for the generation of highly specific and discriminative fully human mAbs that could be useful both for basic research and immunotherapeutic purposes. Electronic supplementary material The online version of this article (doi:10.1186/s12896-016-0322-5) contains supplementary material, which is available to authorized users.
Published: 2017

8. RORγt+ cells selectively express redundant cation channels linked to the Golgi apparatus

Author: Gaelle Beriou, Aurélie Lemoine, Melanie Lancien, Aurélie Moreau, Arnaud Nicot, Régis Josien, Jerome Martin, Elise Chiffoleau, Laurence Bouchet-Delbos, Géraldine Bienvenu, Thierry Cens, Maria-Cristina Cuturi, Pierre Charnet, Hans Jörg Fehling, Lucile Drujont, Cédric Louvet, Flora Guillot, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institute of Immunology [Ulm], Universitätsklinikum Ulm - University Hospital of Ulm, Faculté de Médecine - Université de Nantes, Laboratoire d'Immunologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), The IHU-Cesti project is also supported by Nantes Métropole and région Pays de la Loire. Inserm-Région Pays de la Loire fellowship, Fondation Progreffe., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Le Bihan, Sylvie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, and Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID
Subjects: 0301 basic medicine, Encephalomyelitis, Autoimmune, Experimental, T cell, Biology, Article, 03 medical and health sciences, Mice, Downregulation and upregulation, RAR-related orphan receptor gamma, medicine, Animals, Humans, Psoriasis, Cells, Cultured, Orphan receptor, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Experimental autoimmune encephalomyelitis, Innate lymphoid cell, Membrane Proteins, T-Lymphocytes, Helper-Inducer, Nuclear Receptor Subfamily 1, Group F, Member 3, medicine.disease, Colitis, Cell biology, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Intracellular, Cation channel activity, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, trans-Golgi Network
Abstract: Retinoid-related orphan receptor gamma t (RORγt) is a master transcription factor central to type 17 immunity involving cells such as T helper 17, group 3 innate lymphoid cells or IL-17-producing γδ T cells. Here we show that the intracellular ion channel TMEM176B and its homologue TMEM176A are strongly expressed in these RORγt+ cells. We demonstrate that TMEM176A and B exhibit a similar cation channel activity and mainly colocalise in close proximity to the trans-Golgi network. Strikingly, in the mouse, the loss of Tmem176b is systematically associated with a strong upregulation of Tmem176a. While Tmem176b single-deficiency has no effect on the course of experimental autoimmune encephalomyelitis, T cell or DSS-induced colitis, it significantly reduces imiquimod-induced psoriasis-like skin inflammation. These findings shed light on a potentially novel specific process linked to post-Golgi trafficking for modulating the function of RORγt+ cells and indicate that both homologues should be simultaneously targeted to clearly elucidate the role of this intracellular ion flow.
Published: 2016

9. Modulation of antigen processing by haem-oxygenase 1. Implications on inflammation and tolerance

Author: Sebastián A. Riquelme, Janyra A. Espinoza, Claudia A. Riedel, Alexis M. Kalergis, Susan M. Bueno, Leandro J. Carreño, Manuel Álvarez-Lobos, Juan Pablo Mackern-Oberti, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Department of Microbiology and Immunology [Bronx, NY, USA], Albert Einstein College of Medicine [New York], Institute of Medicine and Experimental Biology of Cuyo [Mendoza, Argentina] (IMBECU), Science and Technology Center [Mendoza, Argentina] (CCT)-National Council of Scientific and Technical Research [Mendoza, Argentina], Institute of Physiology [Mendoza, Argentina] (School of Medicine), National University of Cuyo [Mendoza, Argentina], Departamento de Gastroenterologıa [Santiago, Chile] (Facultad de Medicina), Departamento de Ciencias Biologicas [Santiago, Chile] (Facultad de Ciencias Biologicas y Facultad de Medicina), Universidad Andrés Bello - UNAB (CHILE), Departamento de Endocrinología [Santiago, Chile] (Facultad de Medicina), This study was supported by the following grants: FONDO NACIONAL DE CIENCIA Y TECNOLOGIA DE CHILE (FONDECYT numbers 1110397, 1131012, 1140010 and 1110604), Millennium Institute on Immunology and Immunotherapy P09/016-F and Grant ‘Nouvelles Equipesnouvelles thématiques’ from the La Région Pays De La Loire. SAR and JAE are supported by the Comision Nacional de Investigacion Cientıfica y Tecnologica (CONICYT). LJC is a Latin American Pew Fellow. AMK is a Chaire De La Région Pays De La Loire, Chercheur Etranger D’excellence, France., Le Bihan, Sylvie, and Universidad Andrés Bello [Santiago] (UNAB)
Subjects: 0301 basic medicine, CIENCIAS MÉDICAS Y DE LA SALUD, T-Lymphocytes, Immunology, Inmunología, Priming (immunology), Inflammation, Lymphocyte Activation, DENDRITIC CELLS, HAEM-OXYGENASE 1, Immunomodulation, 03 medical and health sciences, Immune system, Immunity, ANTIGEN PRESENTATION, medicine, cytokine, Immune Tolerance, Immunology and Allergy, Animals, Humans, dendritic cells, Review Articles, haem-oxygenase 1, Antigen Presentation, Carbon Monoxide, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Graft rejection, Antigen processing, business.industry, CARBON MONOXIDE, Haem Oxygenase, 3. Good health, CYTOKINE, Medicina Básica, 030104 developmental biology, Immune System Diseases, Drug Design, medicine.symptom, Endotoxic shock, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Heme Oxygenase-1
Abstract: Haem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC- and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases. Fil: Riquelme, Sebastián A.. Pontificia Universidad Católica de Chile; Chile Fil: Carreño, Leandro J.. Pontificia Universidad Católica de Chile; Chile Fil: Espinoza, Janyra A.. Pontificia Universidad Católica de Chile; Chile Fil: Mackern Oberti, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina Fil: Alvarez Lobos, Manuel M.. Pontificia Universidad Católica de Chile; Chile Fil: Riedel, Claudia. Universidad Andrés Bello; Chile Fil: Bueno, Susan M.. Pontificia Universidad Católica de Chile; Chile Fil: Kalergis, Alexis M.. Pontificia Universidad Católica de Chile; Chile
Published: 2016

10. Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy

Author: Laurent Tesson, Helicia Goubin, Jean-Baptiste Renaud, Thibaut Larcher, Caroline Le Guiner, Yan Cherel, Carine Giovannangeli, Corinne Huchet, Maeva Dutilleul, Ignacio Anegon, Gilles Toumaniantz, Anne De Cian, Lydie Guigand, Jean-Paul Concordet, Séverine Remy, Charlotte Boix, A. Lafoux, Virginie François, Virginie Thepenier, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Atlantic Gene Therapies, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de Transplantation Urologie-Néphrologie (ITUN), Institut de Transplantation Urologie-Néphrologie ( ITUN), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Généthon, Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Région Pays de la Loire (Biogenouest), IBiSA program, Fondation Progreffe, TEFOR (Infrastructures d'Avenir du Gouvernement Français), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes (UN), APEX - Plate-forme d'expertise en anatomie pathologique pour la Recherche [Nantes] (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-INRA - Oniris (INRA UMR0703), Institut National de la Recherche Agronomique (INRA)-Institut National de la Recherche Agronomique (INRA), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Recherche et développement [Généthon, Evry] (R & D Généthon), Généthon [Evry], Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Région Pays de la Loire through Biogenouest, IBiSA program, Fondation Progreffe and TEFOR (Infrastructures d’Avenir of the French goverment), and the integrative genomic facility of Nantes for sequencing experiments., Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Unité de recherche de l'institut du thorax (ITX-lab), Le Bihan, Sylvie, and Lafoux, Aude
Subjects: Male, Pathology, Necrosis, myopathie de duchenne, Physiology, Duchenne muscular dystrophy, Gene Expression, Adipose tissue, Dystrophin, 0302 clinical medicine, Medicine and Health Sciences, Medicine, rat, Muscular dystrophy, Creatine Kinase, 0303 health sciences, Muscle Weakness, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Ventricular Remodeling, biology, Dilated cardiomyopathy, Exons, Diaphragm (structural system), Neurology, Gene Targeting, Female, medicine.symptom, Research Article, Biotechnology, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Science, Médecine humaine et pathologie, modèle d'analyse, 03 medical and health sciences, Genetics, Congenital Disorders, Animals, RNA, Messenger, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, Base Sequence, business.industry, Myocardium, Biology and Life Sciences, Muscle weakness, Cell Biology, Muscular Dystrophy, Animal, medicine.disease, Fibrosis, Rats, Muscular Dystrophy, Duchenne, Disease Models, Animal, Mutation, biology.protein, Human health and pathology, business, mutant déficient, Gene Deletion, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmd[mdx]) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmd[mdx] rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmd[mdx] rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmd[mdx] rats represent a new faithful small animal model of DMD.
Published: 2014

11. Modelling the effects of antimicrobial metaphylaxis and pen size on bovine respiratory disease in high and low risk fattening cattle

Author: Sébastien Picault, Pauline Ezanno, Kristen Smith, David Amrine, Brad White, Sébastien Assié, Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Kansas State University, Institut Carnot France Futur Élevage (F2E) — projet SEPTIME, Région Pays de la Loire (PULSAR), and European Project: 101000494,DECIDE
Subjects: MESH: Anti-Bacterial Agents / pharmacology, Farms, Epidemiological modelling, Respiratory Tract Diseases, Bovine Respiratory Disease Complex, MESH: Anti-Infective Agents / therapeutic use, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Anti-Infective Agents, Disease control, Animals, MESH: Animals, Antimicrobial usage, MESH: Bovine Respiratory Disease Complex / diagnosis, Farming practices, MESH: Farms, MESH: Bovine Respiratory Disease Complex / drug therapy, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, General Veterinary, Bovine respiratory disease, MESH: Bovine Respiratory Disease Complex* / prevention & control, MESH: Anti-Infective Agents / pharmacology, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Anti-Bacterial Agents, Stochastic models, MESH: Cattle, MESH: Respiratory Tract Diseases / veterinary, [INFO.INFO-MA]Computer Science [cs]/Multiagent Systems [cs.MA], Cattle, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Anti-Bacterial Agents / therapeutic use
Abstract: Bovine respiratory disease (BRD) dramatically affects young calves, especially in fattening facilities, and is difficult to understand, anticipate and control due to the multiplicity of factors involved in the onset and impact of this disease. In this study we aimed to compare the impact of farming practices on BRD severity and on antimicrobial usage. We designed a stochastic individual-based mechanistic BRD model which incorporates not only the infectious process, but also clinical signs, detection methods and treatment protocols. We investigated twelve contrasted scenarios which reflect farming practices in various fattening systems, based on pen sizes, risk level, and individual treatment vs. collective treatment (metaphylaxis) before or during fattening. We calibrated model parameters from existing observation data or literature and compared scenario outputs regarding disease dynamics, severity and mortality. The comparison of the trade-off between cumulative BRD duration and number of antimicrobial doses highlighted the added value of risk reduction at pen formation even in small pens, and acknowledges the interest of collective treatments for high-risk pens, with a better efficacy of treatments triggered during fattening based on the number of detected cases.
Published: 2022

12. Carbon monoxide decreases endosome-lysosome fusion andinhibits soluble antigen presentation by dendritic cells to tcells

Author: Alexis M. Kalergis, Claudia A. Riedel, Susan M. Bueno, Claudia M. Cortés, Séverine Remy, Thomas Simon, Virginie Tardif, Cédric Louvet, Leandro J. Carreño, Marcelo Hill, Jean Marie Bach, Sebastián A. Riquelme, Ignacio Anegon, Christine Chauveau, Philippe Blancou, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN), Millenium Institute of Immunology and Immunotherapy, Pontificia Universidad Católica de Chile (UC), Universidad Andrés Bello [Santiago] (UNAB), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Departamento de Reumatologia, La Région Pays de la Loire through the 'Chaire d’excellence program'., IMBIO program., Agence de la Biomédecine., Ministère de la Recherche., Fondation CENTAURE., Fondation Progreffe., Grant 'Nouvelles Equipes-nouvelles thématiques' from the La Région Pays De La Loire., INSERM CDD grant., ECOS France-Chile grant., Millennium Institute on Immunology and Immunotherapy from Chile (P09/016-F)., École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Le Bihan, Sylvie
Subjects: CD4-Positive T-Lymphocytes, Lipopolysaccharides, Endosome, Ovalbumin, Immunology, Antigen presentation, Mice, Transgenic, Endosomes, Lymphocyte Activation, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Antigen, MHC class I, Immunology and Allergy, Animals, Cells, Cultured, 030304 developmental biology, 0303 health sciences, MHC class II, Antigen Presentation, Carbon Monoxide, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cross-presentation, biology, Antigen processing, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Membrane Proteins, Dendritic Cells, Endocytosis, Cell biology, Mice, Inbred C57BL, biology.protein, Lysosomes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Heme Oxygenase-1, 030215 immunology
Abstract: International audience; Heme oxygenase-1 (HO-1) inhibits immune responses and inflammatory reactions via the catabolism of heme into carbon monoxide (CO), Fe 2+ , and biliverdin. We have previously shown that either induction of HO-1 or treatment with exogenous CO inhibits LPS-induced maturation of dendritic cells (DCs) and protects in vivo and in vitro antigen-specific inflammation. Here, we evaluated the capacity of HO-1 and CO to regulate antigen presentation on MHC class I and MHC class II molecules by LPS-treated DCs. We observed that HO-1 and CO treatment significantly inhibited the capacity of DCs to present soluble antigens to T cells. Inhibition was restricted to soluble OVA protein, as no inhibition was observed for antigenic OVA-derived peptides, bead-bound OVA protein, or OVA as an endogenous antigen. Inhibition of soluble antigen presentation was not due to reduced antigen uptake by DCs, as endocytosis remained functional after HO-1 induction and CO treatment. On the contrary, CO significantly reduced the efficiency of fusion between late endosomes and lysosomes and not by phagosomes and lysosomes. These data suggest that HO-1 and CO can inhibit the ability of LPS-treated DCs to present exogenous soluble antigens to naïve T cells by blocking antigen trafficking at the level of late endosome-lysosome fusion.
Published: 2013

13. The Internal Conduit System of the Swine Inverted Lymph Node

Author: Dubreil, Laurence, Ledevin, Mireille, Hervet, Caroline, Menard, Déborah, Philippe, Claire, Michel, François J., Larcher, Thibaut, Meurens, François, Bertho, Nicolas, Expertise en Anatomie Pathologique (APEX), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Saskatchewan [Saskatoon] (U of S), and APEX, PAnTher, INRAE, Oniris is supported by Pays de la Loire, IBISA and NeurATRIS translational research infrastructure for innovative therapies in NeuroSciences. Biogenouest (the network of technology core facilities in Western France in life sciences and the environment, and by the Conseil Régional des Pays de la Loire). APEX platform is a Center of Excellence Nikon. Reagents and equipment were purchased thanks to the establishment grant obtained by FM from the Région Pays de la Loire (RFI Food for tomorrow-Cap aliment).
Subjects: Follicle, B-Lymphocytes, Swine, Macrophages, [SDV]Life Sciences [q-bio], Immunology, Lymph Node, Second harmonic generation, Fluorescence imaging, Mice, Endothelial cell, Animals, Immunology and Allergy, Lymph Nodes, Lymphocytes, Whole organ imaging, Lymphatic Vessels, B lymphocytes
Abstract: International audience; Lymph nodes (LN) are the crossroad where naïve lymphocytes, peripheral antigens and antigen presenting cells contact together in order to mount an adaptive immune response. For this purpose, LN are highly organized convergent hubs of blood and lymphatic vessels that, in the case of B lymphocytes, lead to the B cell follicles. Herein take place the selection and maturation of B cell clones producing high affinity antibodies directed against various antigens. Whereas the knowledge on the murine and human LN distribution systems have reached an exquisite precision those last years, the organization of the antigens and cells circulation into the inverted porcine LN remains poorly described. Using up to date microscopy tools, we described the complex interconnections between afferent lymphatics and blood vessels, perifollicular macrophages, follicular B cells and efferent blood vessels. We observed that afferent lymphatic sinuses presented an asymmetric Lyve-1 expression similar to the one observed in murine LN, whereas specialized perifollicular sinuses connect the main afferent lymphatic sinus to the B cell follicles. Finally, whereas it was long though that mature B cells egress from the inverted LN in the T cell zone through HEV, our observations are in agreement with mature B cells accessing the efferent blood circulation in the efferent, subcapsular area. This understanding of the inverted porcine LN circuitry will allow a more accurate exploration of swine pathogens interactions with the immune cells inside the LN structures. Moreover, the mix between similarities and differences of porcine inverted LN circuitry with mouse and human normal LN shall enable to better apprehend the functions and malfunctions of normal LN from a new perspective.
Published: 2022

14. Lipid nanocapsules for intracellular delivery of microRNA: A first step towards intervertebral disc degeneration therapy

Author: Brian Le Moal, Élise Lepeltier, Dominique Rouleau, Catherine Le Visage, Jean-Pierre Benoit, Catherine Passirani, Jérôme Guicheux, Marion Fusellier, Johann Clouet, Lemaire, Laurent, RMeS - Regenerative Medicine of Bone Tissues (RMeS-REGOS), Université d'Angers (UA)-Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR Odontologie, Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR Odontologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Nantes Université - UFR Odontologie, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), PHU 4 OTONN [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), and grant 'Tremplin clinique vétérinaire' BIOREGATE (Région Pays de la Loire, DISCODOG project), Fondation d’entreprise Grand Ouest BPGO (grant Territoire Recherche 2020, award 'Encouragement').
Subjects: lipid nanocapsules, Sheep, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV]Life Sciences [q-bio], intradiscal delivery, Pharmaceutical Science, Down-Regulation, Intervertebral Disc Degeneration, Lipids, [SDV] Life Sciences [q-bio], MicroRNAs, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Nanocapsules, [CHIM] Chemical Sciences, nucleic acid delivery, [CHIM]Chemical Sciences, Animals, Humans
Abstract: International audience; Approximately 40% of cases of lower back pain are caused by disc degeneration disease (DDD). It is well established that microRNA (miR) dysregulation is a key player in various diseases, and its impact on DDD has recently been highlighted. RNAi (miR in particular) is increasingly being considered as a novel therapeutic tool. However, free miR is degraded rapidly in vivo, and its protection is thus a prerequisite. Nanoparticular platforms, such as lipid nanocapsules (LNC), could be specifically adapted for miR delivery, allowing the transfer and release of miR in the cell cytoplasm. The objective of the current study was to formulate and characterize miR-loaded LNC to establish their in vitro potential (cell internalization, bioactivity) as well as to determine the safety and feasibility of in situ intervertebral disc (IVD) injection of miR LNC in a healthy sheep model. Using a miR library, miR-155 was clearly identified as being involved in the DDD process and was selected for further assessment. miR-155-loaded LNC (miR-155 LNC) were successfully formulated using a phase inversion process, with the addition of lipoplexes in the cooling step. Following purification, miR-155 LNC were fully characterized, and the optimized formulation had an average diameter of 75 nm, a polydispersity index below 0.1, and a positive zeta potential. By fluorescence spectroscopy, an encapsulation efficiency (EE) of 75.6% and a drug loading (DL) of 0.6% were obtained, corresponding to a sufficient amount of miR per mL of LNC to potentially have a biological effect. The sustained release of miR-155 from LNC was demonstrated compared with free miR-155: only 22% was released after 2 h and 58% after 24 h. miR-155 protection against endonuclease degradation by LNC was confirmed by gel electrophoresis, a sine qua non condition for it to be administered in vivo. Cell viability assays were performed on human adipose stromal cells (hASCs) and ovine Nucleus pulposus cells (oNP), and a cytotoxicity of less than 30% was obtained at the considered concentrations. Additionally, miR-155 LNC cell internalization was demonstrated by flow cytometry and confocal imaging. Moreover, downregulation of total ERK1/2 in hASCs and oNP cells, after miR-155 LNC treatment, was demonstrated by Western blot and quantitative reverse-transcription PCR (qRT-PCR), thus confirming maintenance of its bioactivity after formulation and internalization. Finally, the feasibility and safety of miR-155 LNC in situ injection (compared to control groups: blank LNC and sham condition) was demonstrated in healthy sheep by imaging (MRI and T2wsi measurement) and histology (Boos’ scoring) analysis. T2wsi was measured, and no significant difference was observed three months after the injection between the different conditions. No histological impact was observed, with no significant difference in Boos’ scoring between the different conditions. All these results suggest LNC may be a potent strategy for the encapsulation and delivery of miR (particularly miR-155) and can be considered as a first step towards IVD regenerative medicine.
Published: 2022

15. Mechanistic models of Rift Valley fever virus transmission: A systematic review

Author: Hélène, Cecilia, Alex, Drouin, Raphaëlle, Métras, Thomas, Balenghien, Benoit, Durand, Véronique, Chevalier, Pauline, Ezanno, METRAS, Raphaelle, Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Surveillance et modélisation des maladies transmissibles [iPLesp] (SUMO), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), London School of Hygiene and Tropical Medicine (LSHTM), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut Agronomique et Vétérinaire Hassan II (IAV Hassan II), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), and This work was part of the FORESEE project funded by INRAE metaprogram GISA (Integrated Management of Animal Health). HC was funded by INRAE, Région Pays de la Loire, CIRAD.
Subjects: [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Rift Valley Fever, Epidemiology, Arabia, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, [MATH] Mathematics [math], Arbovirosis, MESH: Pregnancy, Pregnancy, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Africa, Rift Valley Fever Virus, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Rift Valley Fever, Animals, MESH: Rift Valley fever virus, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [MATH]Mathematics [math], MESH: Female, Ecosystem
Abstract: Code used to produce figures and summary statistics is available in Github public repository; International audience; Rift Valley fever (RVF) is a zoonotic arbovirosis which has been reported across Africa including the northernmost edge, South West Indian Ocean islands, and the Arabian Peninsula. The virus is responsible for high abortion rates and mortality in young ruminants, with economic impacts in affected countries. To date, RVF epidemiological mechanisms are not fully understood, due to the multiplicity of implicated vertebrate hosts, vectors, and ecosystems. In this context, mathematical models are useful tools to develop our understanding of complex systems, and mechanistic models are particularly suited to data-scarce settings. Here, we performed a systematic review of mechanistic models studying RVF, to explore their diversity and their contribution to the understanding of this disease epidemiology. Researching Pubmed and Scopus databases (October 2021), we eventually selected 48 papers, presenting overall 49 different models with numerical application to RVF. We categorized models as theoretical, applied, or grey, depending on whether they represented a specific geographical context or not, and whether they relied on an extensive use of data. We discussed their contributions to the understanding of RVF epidemiology, and highlighted that theoretical and applied models are used differently yet meet common objectives. Through the examination of model features, we identified research questions left unexplored across scales, such as the role of animal mobility, as well as the relative contributions of host and vector species to transmission. Importantly, we noted a substantial lack of justification when choosing a functional form for the force of infection. Overall, we showed a great diversity in RVF models, leading to important progress in our comprehension of epidemiological mechanisms. To go further, data gaps must be filled, and modelers need to improve their code accessibility.
Published: 2022

16. High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2

Author: Dominique Blanchard, Melody Paulus, Gwénaëlle Evanno, Roberto Bruzzone, Matthieu Ledure, Sophie Brouard, Irina Lagutina, Sophie Conchon, Emanuele Cozzi, Roberto Duchi, Cesare Galli, Juliette Rousse, Bernard Vanhove, Elsa Lheriteau, Laurent Vacher, Apolline Salama, Romain Oger, Pierre-Joseph Royer, Andrea Perota, Nadine Gervois, Marc Bouillet, Yannick Jacques, Odile Duvaux, Ray T.Y. So, Jean-Marie Bach, Jean-Paul Soulillou, Chris Ka Pun Mok, Carine Ciron, Philippe Delahaut, Xenothera [Nantes, France], Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN), Avantea [Cremona, Italy], CER Groupe Marloie, The University of Hong Kong (HKU), University Hospital of Padua, Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Bpifrance, Xenothera, Société d'Accélération et Transfert de Technologie Ouest Valorisation, Région Pays de la Loire, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), CER Groupe, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, pig, Swine, Spike, Antibodies, Viral, medicine.disease_cause, SARS‐CoV‐2, Epitope, Animals, Genetically Modified, chemistry.chemical_compound, 0302 clinical medicine, Neuraminic acid, Immunology and Allergy, polyclonal antibodies, Research Articles, Coronavirus, Covid-19, SARS-CoV-2, Galactosyltransferases, 3. Good health, Spike Glycoprotein, Coronavirus, Research Article|Basic, Antibody, medicine.drug_class, Immunology, Immunity to infection, Heterologous, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Monoclonal antibody, Article, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, COVID‐19, medicine, Animals, Humans, Basic, COVID-19 Serotherapy, Immunization, Passive, Antibodies, Neutralizing, Virology, HEK293 Cells, 030104 developmental biology, chemistry, Polyclonal antibodies, Sialic Acids, biology.protein, 030215 immunology
Abstract: Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma or monoclonal antibodies (mAbs) in coronavirus disease (COVID‐19) by targeting multiple antigen epitopes. However, heterologous antibodies trigger human natural xenogeneic antibody responses particularly directed against animal‐type carbohydrates, mainly the N‐glycolyl form of the neuraminic acid (Neu5Gc) and the α1,3‐galactose, potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate‐N‐acetylneuraminic acid hydroxylase and α1,3‐galactosyl‐transferase (GGTA1) double KO pigs with the Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike receptor binding domain to produce glyco‐humanized polyclonal neutralizing antibodies lacking Neu5Gc and α1,3‐galactose epitopes. Animals rapidly developed a hyperimmune response with anti‐SARS‐CoV‐2 end‐titers binding dilutions over one to a million and end‐titers neutralizing dilutions of 1:10 000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV‐19, neutralized spike/angiotensin converting enzyme‐2 interaction at a concentration, GGTA1/CMAH double KO pigs produced high titers of XAV‐19, an anti‐SARS‐Cov‐2 RBD glyco‐humanized polyclonal antibody. XAV‐19 is presented with a high complement activation and a high neutralization potency in vitro and in cell‐based neutralization assays. XAV‐19 does not interact with human Fc gamma receptors, preventing Fc‐dependent enhancement or immune cells skewing.
Published: 2021

17. Nanoparticle-containing electrospun nanofibrous scaffolds for sustained release of SDF-1α

Author: Frank Boury, Muhammad Haji Mansor, Mathie Najberg, Baya Gueza, Emmanuel Garcion, Carmen Alvarez-Lorenzo, Christine Jérôme, Rodolfo Molina-Peña, Jean-Michel Thomassin, Bernardo, Elizabeth, Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Center for Education and Research on Macromolecules - CERM [Liège, Belgium], Université de Liège-CESAM RU [Liège, Belgium], SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigación Sanitaria de Santiago de Compostela / Health Research Institute of Santiago de Compostela (IDIS), EuroNanoMed III (project GLIOSILK 'Silk-fibroin interventional nano-trap for the treatment of glioblastoma'), LabEx IRON 'Innovative Radiopharmaceuticals in Oncology and Neurology' as part of the French government 'Investissements d’Avenir' program, INCa (Institut National du Cancer) MARENGO consortium 'MicroRNA agonist and antagonist Nanomedicines for Glioblastoma treatment: from molecular programmation to preclinical validation' [Grant PL-BIO 2014-2020], French Région Pays-de-la-Loire (Bioimplants for Bone Regeneration (BILBO) part of the BIOREGATE Research-Training-Innovation consortium (RFI) and NanoFar +), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Angers, France, Agencia Estatal de Investigación (AEI) and Instituto de Salud Carlos III (ISCIII) [AC19/00067] Cofinanciado FEDER, Spain, FEDER (FMF - Prostem) for the University of Liege (Liege, Belgium), Ministère de l'Enseignement supérieur, de la Recherche et de l’Innovation (MESRI), France, and European Project: AN33.32R
Subjects: Stromal cell, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Glioblastoma cell trap, Stromal cell-derived factor-1α (SDF-1α), [SDV]Life Sciences [q-bio], Nanofibers, Pharmaceutical Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Metastasis, chemistry.chemical_compound, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, medicine, Animals, Chitosan nanofibrous scaffold, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Tissue Scaffolds, Electrospinning, Chemistry, Adhesion, medicine.disease, In vitro, Chemokine CXCL12, Cell biology, Rats, PLGA, [CHIM.POLY]Chemical Sciences/Polymers, Delayed-Action Preparations, Cancer cell, NIH 3T3 Cells, Nanoparticles, Pseudopodia, Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, Sustained release
Abstract: International audience; Chemokines such as stromal cell-derived factor-1α (SDF-1α) regulate the migration of cancer cells that can spread from their primary tumor site by migrating up an SDF-1α concentration gradient, facilitating their local invasion and metastasis. Therefore, the implantation of SDF-1α-releasing scaffolds can be a useful strategy to trap cancer cells expressing the CXCR4 receptor. In this work, SDF-1α was encapsulated into poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles and subsequently electrospun with chitosan to produce nanofibrous scaffolds of average fiber diameter of 261 ± 45 nm, intended for trapping glioblastoma (GBM) cells. The encapsulated SDF-1α maintained its biological activity after the electrospinning process as assessed by its capacity to induce the migration of cancer cells. The scaffolds could also provide sustained release of SDF-1α for at least 5 weeks. Using NIH3T3 mouse fibroblasts, human Thp-1 macrophages, and rat primary astrocytes we showed that the scaffolds possessed high cytocompatibility in vitro. Furthermore, a 7-day follow-up of Fischer rats bearing implanted scaffolds demonstrated the absence of adverse effects in vivo. In addition, the nanofibrous structure of the scaffolds provided excellent anchoring sites to support the adhesion of human GBM cells by extension of their pseudopodia. The scaffolds also demonstrated slow degradation kinetics, which may be useful in maximizing the time window for trapping GBM cells. As surgical resection does not permit a complete removal of GBM tumors, our results support the future implantation of these scaffolds into the walls of the resection cavity to evaluate their capacity to attract and trap the residual GBM cells in the brain.
Published: 2021

18. Otoferlin gene editing in sheep via CRISPR-assisted ssODN-mediated Homology Directed Repair

Author: Laurent Tesson, Vanessa Chenouard, Martina Crispo, Ignacio Anegon, F. Cuadro, Jean-Marie Heslan, P.C. dos Santos-Neto, Alejo Menchaca, M Gantier, A. P. Mulet, Aude Guiffes, M Souza-Neves, Instituto de Reproducción Animal Uruguay [Montevideo, Uruguay], Fundación IRAUy, Transgenic and Experimental Animal / Animales Transgénicos y de Experimentación [Montevideo], Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Transgenesis Rat ImmunoPhenomic facility [Nantes] (TRIP platform - Inserm U1064 - CRTI), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Plate-forme GenoCellEdit [Nantes] (PF-GCE - Inserm 1064 - CRTI), This work received support from the Uruguayan National Research Agency (ANII, Uruguay). Some activities were funded by 'TEFOR' project («Investissements d’Avenir» French Government program, managed by the French National Research Agency, ANRII-INSB-0014) and the IHU-Cesti project (ANR-10-IBHU-005) which both are part of the «Investissements d’Avenir» French Government program managed by the ANR, the IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire. Part of this work was realized in the context of the Labex IGO project (ANR-11-LABX-0016-01)., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Bihan, Sylvie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, and Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID
Subjects: Male, Microinjections, [SDV]Life Sciences [q-bio], lcsh:Medicine, Biology, Article, Homology directed repair, 03 medical and health sciences, Exon, 0302 clinical medicine, Genome editing, OTOF, Animals, CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats, lcsh:Science, Gene, 030304 developmental biology, Subgenomic mRNA, Gene Editing, Genetics, 0303 health sciences, Sheep, Multidisciplinary, Cas9, lcsh:R, Membrane Proteins, Recombinational DNA Repair, 3. Good health, Experimental models of disease, [SDV] Life Sciences [q-bio], Oligodeoxyribonucleotides, 030220 oncology & carcinogenesis, Mutation, Genetic engineering, Female, lcsh:Q, CRISPR-Cas Systems
Abstract: Different mutations of the OTOF gene, encoding for otoferlin protein expressed in the cochlear inner hair cells, induces a form of deafness that is the major cause of nonsyndromic recessive auditory neuropathy spectrum disorder in humans. We report the generation of the first large animal model of OTOF mutations using the CRISPR system associated with different Cas9 components (mRNA or protein) assisted by single strand oligodeoxynucleotides (ssODN) to induce homology-directed repair (HDR). Zygote microinjection was performed with two sgRNA targeting exon 5 and 6 associated to Cas9 mRNA or protein (RNP) at different concentrations in a mix with an ssODN template targeting HDR in exon 5 containing two STOP sequences. A total of 73 lambs were born, 13 showing indel mutations (17.8%), 8 of which (61.5%) had knock-in mutations by HDR. Higher concentrations of Cas9-RNP induced targeted mutations more effectively, but negatively affected embryo survival and pregnancy rate. This study reports by the first time the generation of OTOF disrupted sheep, which may allow better understanding and development of new therapies for human deafness related to genetic disorders. These results support the use of CRISPR/Cas system assisted by ssODN as an effective tool for gene editing in livestock.
Published: 2020

19. Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme

Author: Cheray, Mathilde, Etcheverry, Amandine, Jacques, Camille, Pacaud, Romain, Bougras-Cartron, Gwenola, Aubry, Marc, Denoual, Florent, Peterlongo, Pierre, Nadaradjane, Arulraj, Briand, Josephine, Akcha, Farida, Heymann, Dominique, Vallette, François M, Mosser, Jean, Ory, Benjamin, Cartron, Pierre-Francois, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Nantes (UN), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), LabEX IGO Immunothérapie Grand Ouest, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Epigénétique - Santé - AgroAlimentaire - Végétal - Mer - Environnement - Nutrition [Nantes] (EpiSAVMEN), Consortium de la Recherche en Epigénétique de la Région Pays de la Loire [Nantes], Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], Université de Rennes (UNIV-RENNES), Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut Français de Recherche pour l'Exploitation de la Mer - Atlantique (IFREMER Atlantique), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Nantes Université (Nantes Univ), Université de Rennes (UR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Chard-Hutchinson, Xavier
Subjects: AGO4, [SDV]Life Sciences [q-bio], Mice, Nude, Apoptosis, lcsh:RC254-282, DNA Methyltransferase 3A, Cytosine, Mice, Biomarkers, Tumor, Tumor Cells, Cultured, Animals, Humans, DNA (Cytosine-5-)-Methyltransferases, Eukaryotic Initiation Factors, Promoter Regions, Genetic, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, miRNA, Epitranscriptomics, Research, DNA Methylation, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Xenograft Model Antitumor Assays, Cytosine-methylation, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, Survival Rate, MicroRNAs, Argonaute Proteins, DNMT3A, Epigenetics, Glioblastoma
Abstract: Background Literature reports that mature microRNA (miRNA) can be methylated at adenosine, guanosine and cytosine. However, the molecular mechanisms involved in cytosine methylation of miRNAs have not yet been fully elucidated. Here we investigated the biological role and underlying mechanism of cytosine methylation in miRNAs in glioblastoma multiforme (GBM). Methods RNA immunoprecipitation with the anti-5methylcytosine (5mC) antibody followed by Array, ELISA, dot blot, incorporation of a radio-labelled methyl group in miRNA, and miRNA bisulfite sequencing were perfomred to detect the cytosine methylation in mature miRNA. Cross-Linking immunoprecipiation qPCR, transfection with methylation/unmethylated mimic miRNA, luciferase promoter reporter plasmid, Biotin-tagged 3’UTR/mRNA or miRNA experiments and in vivo assays were used to investigate the role of methylated miRNAs. Finally, the prognostic value of methylated miRNAs was analyzed in a cohorte of GBM pateints. Results Our study reveals that a significant fraction of miRNAs contains 5mC. Cellular experiments show that DNMT3A/AGO4 methylated miRNAs at cytosine residues inhibit the formation of miRNA/mRNA duplex and leading to the loss of their repressive function towards gene expression. In vivo experiments show that cytosine-methylation of miRNA abolishes the tumor suppressor function of miRNA-181a-5p miRNA for example. Our study also reveals that cytosine-methylation of miRNA-181a-5p results is associated a poor prognosis in GBM patients. Conclusion Together, our results indicate that the DNMT3A/AGO4-mediated cytosine methylation of miRNA negatively. Graphical abstract
Published: 2020

20. Der p 2.1 Peptide Abrogates House Dust Mites-Induced Asthma Features in Mice and Humanized Mice by Inhibiting DC-Mediated T Cell Polarization

Author: Klein, Martin, Colas, Luc, Cheminant, Marie-Aude, Brosseau, Carole, Sauzeau, Vincent, Magnan, Antoine, Bouchaud, Grégory, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes (UN), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Fondation du Souffle, Fond de Dotation de Recherche en Santé Respiratoire, Région Pays de la Loire., ANR: ANR-16-IDEX-0007,national agency and future investment under the program ANR-16-IDEX-0007, Unité de recherche de l'institut du thorax (ITX-lab), ANR-16-IDEX-0007,NExT (I-SITE),NExT (I-SITE)(2016), DUPRE, Olivier, and NExT (I-SITE) - - NExT (I-SITE)2016 - ANR-16-IDEX-0007 - IDEX - VALID
Subjects: Adult, Male, Immunology, Mice, SCID, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Arthropod Proteins, Mice, Th2 Cells, Mice, Inbred NOD, Animals, Humans, Antigens, Dermatophagoides, Prospective Studies, dendritic cells, Original Research, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Mice, Inbred BALB C, Pyroglyphidae, Cell Polarity, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, asthma, allergy, peptide, respiratory tract diseases, Disease Models, Animal, Treatment Outcome, Desensitization, Immunologic, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Th17 Cells, Female, T lymphocyte (T-cell), [SDV.IB]Life Sciences [q-bio]/Bioengineering, immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Peptides
Abstract: International audience; Asthma is a chronic airway disease often due to sensitization to aeroallergens, especially house dust mite allergens (HDMs). The Dermatophagoides pteronyssinus group 2 (Der p 2), is one of the most representative HDM allergens and is recognized by more than 90% of HDM-allergic patients. In mouse models, all asthma-related features can be prevented by prophylactic administration of Dermatophagoides pteronyssinus 2-derived peptide (Der p 2.1). However, it is unknown whether it is able to treat well-established asthma in mice and humans. We aimed here to evaluate the efficacy of Der p 2.1 immunotherapy in a mouse, humanized mouse, and asthmatic patients. Asthma related-features were analyzed through airway hyperresponsiveness (AHR), allergen-specific IgE, and lung histology in mice and humanized mice. Immune profile was analyzed using lung and blood from mice and severe asthmatic patients respectively. T cell and dendritic cell (DC) polarization was evaluated using co-culture of bone marrow derived cells (BMDCs) and naive T cell from naive mice. Mice and humanized mice both have a reduced AHR, lung tissue alteration, and HDM-specific IgE under Der p 2.1 treatment. Concerning the immune profile, T helper 2 cells (Th2) and T helper 17 cells (Th17) were significantly reduced in both mice and humanized mice lung and in peripheral blood mononuclear cells (PBMCs) from severe asthmatic patients after Der p 2.1 incubation. The downregulation of T cell polarization seems to be linked to an increase of IL-10-secreting DC under Der p 2.1 treatment in both mice and severe asthmatic patients. This study shows that allergen-derived peptide immunotherapy abrogates asthma-related features in mice and humanized mice by reducing Th2 and Th17 cells polarization via IL-10-secreting DC. These results suggest that Der p 2.1 peptide immunotherapy could be a promising approach to treat both Th2 and Th17 immunity in asthma.
Published: 2020

21. From 1957 to Nowadays: A Brief History of Epigenetics

Author: Eric Hervouet, Paul Peixoto, Aurélien A. Sérandour, Pierre-François Cartron, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), EPIgenetics and GENe EXPression Technical Plateform (EPIGENExp), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Apoptose et progression tumorale (ICO, Saint-Herblain), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], EpiSAVMEN Network (Région Pays de la Loire) [Saint-Herblain], LabEX IGO Immunothérapie Grand Ouest, École Centrale de Nantes (ECN), DImaCell Platform, Université Bourgogne Franche-Comté [COMUE] (UBFC), Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Dispositif Inter-régional d'Imagerie Cellulaire [Dijon] (DImaCell), Procédés Alimentaires et Microbiologiques (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ingénierie et biologie cellulaire et tissulaire (IBCT (ex IFR133)), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Agroécologie [Dijon], and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Epigenomics, History, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, History, 21st Century, Catalysis, Epigenesis, Genetic, Inorganic Chemistry, lcsh:Chemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Epitranscriptomics, histones, Animals, Humans, Epigenetics, Physical and Theoretical Chemistry, Molecular Biology, lcsh:QH301-705.5, Spectroscopy, 030304 developmental biology, Cognitive science, 0303 health sciences, DNA methylation, epigenetics, Organic Chemistry, General Medicine, History, 20th Century, Computer Science Applications, lcsh:Biology (General), lcsh:QD1-999, 030220 oncology & carcinogenesis, Identification (biology), history, epitranscriptomics, Protein Processing, Post-Translational
Abstract: International audience; Due to the spectacular number of studies focusing on epigenetics in the last few decades, and particularly for the last few years, the availability of a chronology of epigenetics appears essential. Indeed, our review places epigenetic events and the identification of the main epigenetic writers, readers and erasers on a historic scale. This review helps to understand the increasing knowledge in molecular and cellular biology, the development of new biochemical techniques and advances in epigenetics and, more importantly, the roles played by epigenetics in many physiological and pathological situations.
Published: 2020

22. Comparison of Stomaching versus Rinsing for Recovering Bacterial Communities from Rainbow Trout (Oncorhynchus mykiss) Fillets

Author: Catherine Magras, Albert Rossero, Agnès Bouju-Albert, Hervé Prévost, Nicolas Helsens, Ségolène Calvez, Sécurité des Aliments (SECALIM), Ecole Nationale Vétérinaire de Nantes-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and European Union and the 'Région Pays de la Loire' (RFI 'Food for Tomorrow' call for proposals 2016—contract 34000656—PhD grant to Nicolas Helsens
Subjects: [SDV]Life Sciences [q-bio], Microbiology, 03 medical and health sciences, Rainbow trout fillets, Recovery method, Animals, Food science, Rinsing, DNA extraction, Volume concentration, 030304 developmental biology, 0303 health sciences, biology, Bacteria, 030306 microbiology, Chemistry, Stomaching, Fish fillet, Bacterial recovery, biology.organism_classification, Bacterial communities, Fresh fish, Oncorhynchus mykiss, Rainbow trout, Brochothrix thermosphacta, Food Science, Brochothrix
Abstract: International audience; The use of high-throughput methods allows a better characterization of food-related bacterial communities. However, such methods require large amounts of high-quality bacterial DNA, which may be a challenge when dealing with a complex matrix that has a low concentration of bacteria, such as fresh fish fillets. Therefore, the choice of method used to recover bacteria from a food matrix in a cost-effective way is critical, yet little information is available on the performance of commonly used methods. We assessed the recovery capacity of two such methods: stomaching and mechanical rinsing. The efficiency of the methods was evaluated through quantitative recovery and compatibility with end-point quantitative PCR (qPCR). Fresh rainbow trout (Oncorhynchus mykiss) fillets were inoculated with a bacterial marker, Brochothrix thermosphacta, at different concentrations (7.52 to 1.52 log CFU/g). The fillets were processed by one of the two methods, and the recovery of the marker in the suspensions was assessed by plate counting and qPCR targeting B. thermosphacta-rpoC. The same analyses were performed on six noninoculated fresh fillets. Stomaching and mechanical rinsing allowed efficient and repeatable recovery of the bacterial communities from the 42 inoculated fillets. No significant differences in recovery ratios were observed between the marker enumerated in the inoculation suspensions and in the corresponding recovery suspensions after rinsing and stomaching. However, the stomaching method allowed too many particles to pass through the filters bag, making necessary a limiting supplementary filtration step. As a consequence, only the rinsing recovery method allowed proper PCR quantification of the inoculated B. thermosphacta. The mean recovered bacterial level of the fillets was approximately 3 log CFU/g. It seems more relevant and cost-effective to recover the endogenous bacterial microbiota of a fish fillet structure using the rinsing method rather than the stomaching method.
Published: 2020

23. Maternal Protein Restriction in Rats Alters the Expression of Genes Involved in Mitochondrial Metabolism and Epitranscriptomics in Fetal Hypothalamus

Author: Simon Guignard, Patricia Parnet, Isabelle Grit, Dimitri Meistermann, Valérie Amarger, Morgane Frapin, Valentine Suzanne Moullé, Vincent Paillé, Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Centre de Recherche en Nutrition Humaine Ouest [UNIV Nantes] (CRNHO), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), INRAE, Région Pays de la Loire and the Fondation pour la Recherche Médicale (ARF20170938730)., and Le Bihan, Sylvie
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Hypothalamus, lcsh:TX341-641, Biology, Mitochondrion, Energy homeostasis, Article, Transcriptome, Fetal Development, 03 medical and health sciences, transcriptomics, 0302 clinical medicine, Fetus, fetal brain, Pregnancy, Diet, Protein-Restricted, Animals, protein restriction, Gene, Progenitor, 2. Zero hunger, Nutrition and Dietetics, differentiation, Maternal Nutritional Physiological Phenomena, Cell biology, Mitochondria, Rats, [SDV] Life Sciences [q-bio], neurogenesis, 030104 developmental biology, Mitochondrial respiratory chain, Female, epitranscriptomics, lcsh:Nutrition. Foods and food supply, 030217 neurology & neurosurgery, Food Science, maternal nutrition
Abstract: International audience; Fetal brain development is closely dependent on maternal nutrition and metabolic status. Maternal protein restriction (PR) is known to be associated with alterations in the structure and function of the hypothalamus, leading to impaired control of energy homeostasis and food intake. The objective of this study was to identify the cellular and molecular systems underlying these effects during fetal development. We combined a global transcriptomic analysis on the fetal hypothalamus from a rat model of maternal PR with in vitro neurosphere culture and cellular analyses. Several genes encoding proteins from the mitochondrial respiratory chain complexes were overexpressed in the PR group and mitochondrial metabolic activity in the fetal hypothalamus was altered. The level of the N6-methyladenosine epitranscriptomic mark was reduced in the PR fetuses, and the expression of several genes involved in the writing/erasing/reading of this mark was indeed altered, as well as genes encoding several RNA-binding proteins. Additionally, we observed a higher number of neuronal-committed progenitors at embryonic day 17 (E17) in the PR fetuses. Together, these data strongly suggest a metabolic adaptation to the amino acid shortage, combined with the post-transcriptional control of protein expression, which might reflect alterations in the control of the timing of neuronal progenitor differentiation.
Published: 2020

24. Characterization of Rat ILCs Reveals ILC2 as the Dominant Intestinal Subset

Author: Ahmed Abidi, Thomas Laurent, Gaëlle Bériou, Laurence Bouchet-Delbos, Cynthia Fourgeux, Cédric Louvet, Raja Triki-Marrakchi, Jeremie Poschmann, Régis Josien, Jérôme Martin, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Tunis - El Manar II, Université de Tunis El Manar (UTM), École Centrale de Nantes (ECN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d’Immunologie, Centre d’Immunomonitorage Nantes Atlantique (CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), This work was realized in the context of IHU-CESTI project that received French government financial support managed by the National Research Agency (ANR). This work was also supported by the Région Pays de la Loire. AA was supported by a FrenchTunisian PHU-UTIQUE grant from the 2015 Hubert Curien program (CMCU N◦15G0809)., ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Bihan, Sylvie, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and University of Tunis El Manar
Subjects: Male, 0301 basic medicine, lcsh:Immunologic diseases. Allergy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, innate lymphoid cells, Cell Count, Biology, Flow cytometry, ILC2, Rats, Sprague-Dawley, Mice, 03 medical and health sciences, Th2 Cells, 0302 clinical medicine, Intestinal mucosa, medicine, Animals, Humans, Immunology and Allergy, Mesenteric lymph nodes, rat, Lymphocytes, Intestinal Mucosa, Receptor, skin and connective tissue diseases, intestine, Cells, Cultured, Original Research, medicine.diagnostic_test, Innate lymphoid cell, Flow Cytometry, Phenotype, Immunity, Innate, Lymphocyte Subsets, Rats, Cell biology, Peyer Patch, [SDV] Life Sciences [q-bio], body regions, 030104 developmental biology, medicine.anatomical_structure, Cytokine, secondary lymphoid organs, Cytokines, lcsh:RC581-607, 030215 immunology
Abstract: International audience; Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that lack antigen-specific receptors and exhibit innate effector functions such as cytokine production that play an important role in immediate responses to pathogens especially at mucosal sites. Mouse and human ILC subsets have been extensively characterized in various tissues and in blood. In this study, we present the first characterization of ILCs and ILC subsets in rat gut and secondary lymphoid organs using flow cytometry and single cell RNA sequencing. Our results show that phenotype and function of rat ILC subsets are conserved as compared to human and mouse ILCs. However, and in contrast to human and mouse, our study unexpectedly revealed that ILC2 and not ILC3 was the dominant ILC subset in the rat intestinal lamina propria. ILC2 predominance in the gut was independent of rat strain, sex or housing facility. In contrast, ILC3 was the predominant ILC subset in mesenteric lymph nodes and Peyer patches. In conclusion, our study demonstrates that in spite of highly conserved phenotype and function between mice, rat and humans, the distribution of ILC subsets in the intestinal mucosa is dependent on the species likely in response to both genetic and environmental factors.
Published: 2020

25. Anti-PD1 therapy induces lymphocyte-derived exosomal miRNA-4315 release inhibiting Bim-mediated apoptosis of tumor cells

Author: Nina Guyon, Delphine Garnier, Joséphine Briand, Arulraj Nadaradjane, Gwenola Bougras-Cartron, Judith Raimbourg, Mario Campone, Dominique Heymann, François M. Vallette, Jean-Sébastien Frenel, Pierre-François Cartron, Bernardo, Elizabeth, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], EpiSAVMEN Network (Région Pays de la Loire) [Saint-Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Sulfonamides, Aniline Compounds, Bcl-2-Like Protein 11, Cell Death, lcsh:Cytology, T-Lymphocytes, Programmed Cell Death 1 Receptor, Mice, Nude, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Exosomes, Article, MicroRNAs, Phenotype, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Resistance, Neoplasm, Cell Line, Tumor, Neoplasms, miRNAs, Biomarkers, Tumor, Temozolomide, Animals, Humans, lcsh:QH573-671, Cancer
Abstract: International audience; Anti-PD1 immunotherapy, as a single agent or in combination with standard chemotherapies, has significantly improved the outcome of many patients with cancers. However, resistance to anti-PD1 antibodies often decreases the long-term therapeutic benefits. Despite this observation in clinical practice, the molecular mechanisms associated with resistance to anti-PD1 antibody therapy have not yet been elucidated. To identify the mechanisms of resistance associated with anti-PD1 antibody therapy, we developed cellular models including purified T cells and different cancer cell lines from glioblastoma, lung adenocarcinoma, breast cancer and ovarian carcinoma. A murine model of lung cancer was also used. Longitudinal blood samples of patients treated with anti-PD1 therapy were also used to perform a proof-of-concept study of our findings. We found that anti-PD1 exposure of T-cell promotes an enrichment of exosomal miRNA-4315. We also noted that exosomal miRNA-4315 induced a phenomenon of apopto-resistance to conventional chemotherapies in cancer cells receiving exosomal miRNA-4315. At molecular level, we discern that the apopto-resistance phenomenon was associated with the miRNA-4315-mediated downregulation of Bim, a proapoptotic protein. In cellular and mice models, we observed that the BH3 mimetic agent ABT263 circumvented this resistance. A longitudinal study using patient blood showed that miRNA-4315 and cytochrome c can be used to define the time period during which the addition of ABT263 therapy may effectively increase cancer cell death and bypass anti-PD1 resistance.This work provides a blood biomarker (exosomal miRNA-4315) for patient stratification developing a phenomenon of resistance to anti-PD1 antibody therapy and also identifies a therapeutic alternative (the use of a BH3 mimetic drug) to limit this resistance phenomenon.
Published: 2020

26. Nanomedicine as a potent strategy in melanoma tumor microenvironment

Author: Vincent Pautu, Catherine Passirani, Elise Lepeltier, Daniela Leonetti, Nicolas Clere, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), The authors would like to thanks the Région Pays de la Loire and the Erasmus Mundus program for the financing of the Ph D programm of Vincent Pautu., Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Endothelium radiobiology and targeting (CRCINA - Département ONCO - Equipe 14), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0301 basic medicine, Skin Neoplasms, medicine.drug_class, [SDV.CAN]Life Sciences [q-bio]/Cancer, Drug resistance, Monoclonal antibody, Metastasis, 03 medical and health sciences, Drug Delivery Systems, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Humans, Melanoma, Pharmacology, Targeting, Tumor microenvironment, Nanotheranostics, business.industry, Antibodies, Monoclonal, medicine.disease, 3. Good health, Nanomedicine, 030104 developmental biology, Formulation, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Nanotherapies, Drug delivery, Immunology, Cancer research, Nanoparticles, Skin cancer, business
Abstract: International audience; Melanoma originated from melanocytes is the most aggressive type of skin cancer. Despite considerable progresses in clinical treatment with the discovery of BRAF or MEK inhibitors and monoclonal antibodies, the durability of response to treatment is often limited to the development of acquired resistance and systemic toxicity. The limited success of conventional treatment highlights the importance of understanding the role of melanoma tumor microenvironment in tumor developement and drug resistance. Nanoparticles represent a promising strategy for the development of new cancer treatments able to improve the bioavailability of drugs and increase their penetration by targeting specifically tumors cells and/or tumor environment. In this review, we will discuss the main influence of tumor microenvironment in melanoma growth and treatment outcome. Furthermore, third generation loaded nanotechnologies represent an exciting tool for detection, treatment, and escape from possible mechanism of resistance mediated by tumor microenvironment, and will be highlighted in this review.
Published: 2017

27. Immunophenotype of a Rat Model of Duchenne's Disease and Demonstration of Improved Muscle Strength After Anti-CD45RC Antibody Treatment

Author: Laure-Hélène Ouisse, Séverine Remy, Aude Lafoux, Thibaut Larcher, Laurent Tesson, Vanessa Chenouard, Carole Guillonneau, Lucas Brusselle, Nadège Vimond, Karl Rouger, Yann Péréon, Alexis Chenouard, Christèle Gras-Le Guen, Cécile Braudeau, Régis Josien, Corinne Huchet, Ignacio Anegon, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Unité de Biotechnologie, Biocatalyse et Biorégulation (U3B), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Recherche Agronomique (INRA), Atlantic Gene Therapies, Clinique Médicale et Service d'Urgences Pédiatriques, Hôpital Mère-Enfant, Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biogenouest and the TEFOR, Nantes Métropole and Région Pays de la Loire, Anegon, Ignacio, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Le Bihan, Sylvie, and Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)
Subjects: 0301 basic medicine, T-Lymphocytes, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Immune tolerance, Treg, tolerance, muscle injury, dystrophin, immunosuppression, knockout rats, nucleases, 0302 clinical medicine, Immunophenotyping, TALEN, Immunology and Allergy, Medicine, Muscular dystrophy, Original Research, biology, Antibodies, Monoclonal, Immunosuppression, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Prednisolone, Cytokines, medicine.symptom, Dystrophin, medicine.drug, lcsh:Immunologic diseases. Allergy, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Immunology, Inflammation, 03 medical and health sciences, Internal medicine, Animals, Muscle Strength, Muscle, Skeletal, business.industry, Macrophages, Skeletal muscle, medicine.disease, Rats, Muscular Dystrophy, Duchenne, Disease Models, Animal, 030104 developmental biology, Endocrinology, biology.protein, Leukocyte Common Antigens, lcsh:RC581-607, business, Spleen, 030215 immunology
Abstract: International audience; Corticosteroids (CS) are standard therapy for the treatment of Duchenne's muscular dystrophy (DMD). Even though they decrease inflammation, they have limited efficacy and are associated with significant side effects. There is therefore the need for new protolerogenic treatments to replace CS. Dystrophin-deficient rats (Dmd mdx ) closely resemble the pathological phenotype of DMD patients. We performed the first Immunophenotyping of Dmd mdx rats and showed leukocyte infiltration in skeletal and cardiac muscles, which consisted mostly of macrophages and T cells including CD45RChigh T cells. Muscles of DMD patients also contain elevated CD45RChigh T cells. We treated Dmd mdx rats with an anti-CD45RC MAb used in previous studies to deplete CD45RChigh T cells and induce immune tolerance in models of organ transplantation. Treatment of young Dmd mdx rats with anti-CD45RC MAb corrected skeletal muscle strength and was associated with depletion of CD45RChigh T cells with no side effects. Treatment of young Dmd mdx rats with prednisolone resulted in increase in skeletal muscle strength but also severe growth retardation. In conclusion, anti-CD45RC MAb treatment has potential in the treatment of DMD and might eventually result in reduction or elimination of CS use.
Published: 2019

28. Early Identification of Chronic Lung Allograft Dysfunction: The Need of Biomarkers

Author: Adrien Tissot, Richard Danger, Johanna Claustre, Antoine Magnan, Sophie Brouard, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de pneumologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de transplantation urologie-néphrologie (ITUN), Service Hospitalier Universitaire Pneumologie-Physiologie [CHU Grenoble Alpes] (Pôle Thorax et Vaisseaux), Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), The IHU-Cesti project is also supported by Nantes Métropole and Région Pays de la Loire. JC was supported by Fondation du souffle and Fonds Agir pour les maladies chroniques grants., Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Unité de recherche de l'institut du thorax (ITX-lab), and Le Bihan, Sylvie
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Graft Rejection, medicine.medical_specialty, medicine.medical_treatment, Immunology, Review, 03 medical and health sciences, 0302 clinical medicine, blood, medicine, lung transplantation, Immunology and Allergy, Lung transplantation, Animals, Humans, Routine clinical practice, Respiratory function, BOS, Intensive care medicine, Lung, Lung function, chronic lung allograft dysfunction, Immunity, Cellular, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, bronchoalveolar lavage fluid, business.industry, High mortality, Allografts, 3. Good health, Immunity, Humoral, 030104 developmental biology, medicine.anatomical_structure, Biomarker (medicine), biomarker, lcsh:RC581-607, business, Airway, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers, 030215 immunology, RAS
Abstract: International audience; A growing number of patients with end-stage lung disease have benefited from lung transplantation (LT). Improvements in organ procurement, surgical techniques and intensive care management have greatly increased short-term graft survival. However, long-term outcomes remain limited, mainly due to the onset of chronic lung allograft dysfunction (CLAD), whose diagnosis is based on permanent loss of lung function after the development of irreversible lung lesions. CLAD is associated with high mortality and morbidity, and its exact physiopathology is still only partially understood. Many researchers and clinicians have searched for CLAD biomarkers to improve diagnosis, to refine the phenotypes associated with differential prognosis and to identify early biological processes that lead to CLAD to enable an early intervention that could modify the inevitable degradation of respiratory function. Donor-specific antibodies are currently the only biomarkers used in routine clinical practice, and their significance for accurately predicting CLAD is still debated. We describe here significant studies that have highlighted potential candidates for reliable and non-invasive biomarkers of CLAD in the fields of imaging and functional monitoring, humoral immunity, cell-mediated immunity, allograft injury, airway remodeling and gene expression. Such biomarkers would improve CLAD prediction and allow differential LT management regarding CLAD risk.
Published: 2019

29. Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis

Author: Nicolas Bidère, Tiphaine Douanne, Elizabeth Harford-Wright, An Thys, Ying Li, Clément Maghe, Carolina Alves Nicolau, Jean-Sebastien Frenel, Gwennan André-Grégoire, Julie Gavard, Kilian Trillet, Kathryn A Jacobs, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Integrated Center for Oncology [Angers] (ICO), School of Life Sciences [Beijing, China], Tsinghua University [Beijing] (THU), This research was funded by Fondation pour la Recherche Medicale (Equipe labellisée DEQ20180339184), Fondation ARC contre le Cancer (JG PJA20171206146), Ligue nationale contre le cancer comités de Loire-Atlantique, Maine et Loire, Vendée, Ille-et-Vilaine (JG, NB), Région Pays de la Loire et Nantes Métropole under Connect Talent Grant (JG), and SIRIC ILIAD INCa-DGOS-Inserm_12558. KAJ received PhD fellowships from Nantes Métropole and Fondation ARC, TD received PhD fellowship from Nantes Métropole, GAG and AT hold postdoctoral fellowships from Fondation de France and Fondation ARC, respectively., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Male, Apoptosis, Lymphocyte Activation, Mice, 0302 clinical medicine, glioma, Tumor Cells, Cultured, Homeostasis, 0303 health sciences, Gene knockdown, Mice, Inbred BALB C, Membranes & Traf- ficking, General Neuroscience, TOR Serine-Threonine Kinases, RNA-Binding Proteins, Articles, Paracaspase, Middle Aged, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Neoplastic Stem Cells, lysosome, mTOR, Female, Autophagy & Cell Death, Signal Transduction, Programmed cell death, protease Subject Categories Cancer, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endosomes, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, Lysosome, medicine, Biomarkers, Tumor, Animals, Humans, Molecular Biology, PI3K/AKT/mTOR pathway, 030304 developmental biology, Aged, Cell Proliferation, General Immunology and Microbiology, MALT1, Autophagy, medicine.disease, Xenograft Model Antitumor Assays, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Proteolysis, Cancer research, Lysosomes, 030217 neurology & neurosurgery
Abstract: International audience; Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-jB activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impairs autophagic flux, and culminates in lysosomal-mediated cell death, concomitantly with mTOR inactiva-tion and dispersion from endo-lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.
Published: 2019

30. Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma

Author: Hervouet, Eric, Peixoto, Paul, Delage-Mourroux, Régis, Boyer-Guittaut, Michaël, Cartron, Pierre-François, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), EPIgenetics and GENe EXPression Technical Plateform (EPIGENExp), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Réseau Epigénétique du Cancéropôle Grand-Ouest [Nantes] (REpiCGO), Cancéropôle Grand Ouest [Nantes]-Maison de la Recherche en Santé [Nantes], Epigénétique - Santé - AgroAlimentaire - Végétal - Mer - Environnement - Nutrition [Nantes] (EpiSAVMEN), Consortium de la Recherche en Epigénétique de la Région Pays de la Loire [Nantes], This work was supported by the University of Franche-Comté, 'Ministère de l’Enseignement Supérieur et de la Recherche' (MESR) and fundings from CCIR-GE 'Ligue Contre le Cancer' and 'Région de Franche-Comté'., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: DNA Replication, DNA methylation, lcsh:QH426-470, DNMT3L, lcsh:R, DNMT1, Embryonic Development, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Epigenesis, Genetic, lcsh:Genetics, [SDV.CAN] Life Sciences [q-bio]/Cancer, DNMT-including complexes, embryonic structures, Animals, Humans, DNMT3A, Epigenetics, DNMT3B, DNA (Cytosine-5-)-Methyltransferases
Abstract: International audience; Our current view of DNA methylation processes is strongly moving: First, even if it was generally admitted that DNMT3A and DNMT3B are associated with de novo methylation and DNMT1 is associated with inheritance DNA methylation, these distinctions are now not so clear. Secondly, since one decade, many partners of DNMTs have been involved in both the regulation of DNA methylation activity and DNMT recruitment on DNA. The high diversity of interactions and the combination of these interactions let us to subclass the different DNMT-including complexes. For example, the DNMT3L/DNMT3A complex is mainly related to de novo DNA methylation in embryonic states, whereas the DNMT1/PCNA/UHRF1 complex is required for maintaining global DNA methylation following DNA replication. On the opposite to these unspecific DNA methylation machineries (no preferential DNA sequence), some recently identified DNMT-including complexes are recruited on specific DNA sequences. The coexistence of both types of DNA methylation (un/specific) suggests a close cooperation and an orchestration between these systems to maintain genome and epigenome integrities. Deregulation of these systems can lead to pathologic disorders.
Published: 2018

31. Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection

Author: Jeremy Hervouet, Karine Renaudin, David Minault, Nicolas Poirier, Sabrina Pengam, Steven Nedellec, Caroline Mary, Vianney Charpy, Véronique Nerrière-Daguin, Julien Branchereau, Stéphanie Le Bas-Bernardet, Bernard Vanhove, Simon Ville, Alexis Chenouard, Gilles Blancho, Flora Coulon, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Effimune SAS [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Cellular and Tissular Imaging Core Facility of Nantes (MicroPICell), Université de Nantes (UN), IHU-Cesti, région Pays de la Loire et Nantes Métropole., ANR: ANR-10-IBHU005, Le Bihan, Sylvie, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010)
Subjects: lymphocytes, Graft Rejection, 0301 basic medicine, Regulatory T cell, medicine.medical_treatment, kidney transplantation, chemical and pharmacologic phenomena, 030230 surgery, Biology, acute rejection, Belatacept, Antibodies, immunology, Abatacept, Mice, 03 medical and health sciences, 0302 clinical medicine, CD28 Antigens, medicine, Animals, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, immunosuppression, CD28, hemic and immune systems, General Medicine, Tacrolimus, 3. Good health, Basic Research, 030104 developmental biology, Cytokine, medicine.anatomical_structure, Nephrology, Immunology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Immunosuppressive Agents, CD80, Papio, medicine.drug, Allotransplantation
Abstract: International audience; Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab9 antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preex-isting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.
Published: 2016

32. Screening of ordinary commercial varieties of apple fruits under different storage conditions for their potential vascular and metabolic protective properties

Author: Mehdi Frifra, Jean-Pierre Renou, Agnes Gacel, Marie Charlotte Guillou, Patricia Mallegol, Grégory Hilairet, Laetitia Basset, Sylvain Guyot, Pascale Pignon, Catherine Dourguia, Ramaroson Andriantsitohaina, Yves Cadot, Mathilde Orsel, Raffaella Soleti, Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), UMT Nova2Cidre [Le Rheu, France], Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), The present study was carried out with the financial support of the 'Région Pays de la Loire' INUMAMET project. This work was realized in the context of the LabEX IGO program supported by the Agence Nationale de la Recherche via the investment of the program ANR-11-LABX-0016-01., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Innate immunity and Immunotherapy (CRCINA - Département INCIT - Equipe 7), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Antioxidant, Food Handling, medicine.medical_treatment, Apoptosis, Antioxidants, Adipocytes, Food science, 2. Zero hunger, Cell Differentiation, Hep G2 Cells, General Medicine, procyanidins, domestica borkh, cold-storage, Malus, randomized controlled-trial, women, Powders, mice, Dried fruit, diet-induced obesity, Myocytes, Smooth Muscle, Food storage, Cold storage, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, insulin-resistance, 03 medical and health sciences, Nutraceutical, [SDV.CAN] Life Sciences [q-bio]/Cancer, Human Umbilical Vein Endothelial Cells, medicine, Pink lady, Animals, Humans, Cell Proliferation, 030109 nutrition & dietetics, Interleukin-6, Plant Extracts, Flesh, Polyphenols, Diet, Oxidative Stress, Freeze Drying, RAW 264.7 Cells, Food Storage, Polyphenol, inflammation, Fruit, atherosclerosis, Reactive Oxygen Species, Food Analysis, Food Science
Abstract: International audience; Epidemiological studies reported that apple consumption is associated with a decrease of cardiovascular and metabolic dysfunction, probably due to the polyphenols and fibers present in this fruit. The storage conditions and genetic origin of apples have been reported to influence their content and, as a consequence , their pharmacological properties. The present study evaluated the influence of varieties and storage conditions of traditional and highly appreciated apples including Gala, Golden Delicious, Granny Smith and Pink Lady varieties after harvest and storage under classic cold conditions, under a controlled atmosphere, or under extreme ultra-low oxygen conditions. Thus, a multi-parametric screening on cell models associated with vascular and metabolic dysfunctions-such as endothelial and smooth muscle cells, hepatocytes, adipocytes and macrophages-in relation to the apple polyphenol content has been developed. This strategy demonstrated that, overall, peeled apple samples exhibited a vascular tropism and acted mainly on proliferation and oxidative stress in endothelial and smooth muscle cells. Apple extracts appeared to be less effective on adipocytes and macrophages, but they exhibited antioxidant properties in hepatocytes. Among the varieties, Gala and Golden Delicious were the most efficient against the processes involved in the development of atherosclerosis. Concerning storage conditions, most of the apple varieties were more efficient under harvest conditions, while they could not be discriminated under all other cold conditions and the concentration used, except for the Gala samples. Interestingly, pharmacological properties were associated with the polyphenol profiles of freeze dried apple flesh powder. The present report revealed the potential use of some apple extracts as effective food supplements or nutraceuticals for the prevention and/or management of cardiovascular and metabolic diseases.
Published: 2018

33. Rabbit antithymocyte globulin–induced serum sickness disease and human kidney graft survival

Author: Gwénaëlle Evanno, Arnaud Nicot, Ludmilla Le Berre, Yohann Foucher, Stéphanie Castagnet, Jean Harb, Pavel Vesely, Sophie Brouard, Ondrej Viklicky, Juliette Rousse, Evelyn Ang, Apolline Salama, Magali Giral, Jean-Marie Bach, Hélène Perreault, Thomas Dejoie, Béatrice Charreau, Petra Hruba, Pierrick Guerif, Grégoire Couvrat-Desvergnes, Jean-Paul Soulillou, Marine Lorent, Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Société d’Accélération du Transfert de Technologies Ouest Valorisation [Rennes, France], Xenothera [Nantes, France], Department of Nephrology [Prague, Czech Republic] (Transplant Center), Institute for Clinical and Experimental Medicine (IKEM), CEITEC - Central European Institute of Technology [Brno, Czech Republic], Laboratoire de Biochimie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Department of Chemistry [Winnipeg, MB, Canada], University of Manitoba [Winnipeg], Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, PRES Université Nantes Angers Le Mans (UNAM), Etablissement Français du Sang [Nantes], Labex Transplantex, the Natural Science and Engineering Research Council of Canada (RGPIN/170241) and Canadian Foundation for Innovation (22391), the Région Pays de la Loire., ANR-11-JSV1-0008,CSM (Composite Surrogate Marker),Construction d'un marqueur composite de substitution de la survie à long terme : application à la transplantation rénale(2011), European Project: 603049,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,TRANSLINK(2013), Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] (IECM), Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Etablissement Français du Sang EFS [Nantes] (Laboratoire HLA), ANR: ANR-11-JSV1-0008-01, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Soulillou, Jean-Paul, Le Bihan, Sylvie, Jeunes Chercheuses et Jeunes Chercheurs - Construction d'un marqueur composite de substitution de la survie à long terme : application à la transplantation rénale - - CSM (Composite Surrogate Marker)2011 - ANR-11-JSV1-0008 - JCJC - VALID, and Defining the role of xeno-directed and autoimmune events in patients receiving animal-derived bioprosthetic heart valves - TRANSLINK - - EC:FP7:HEALTH2013-09-01 - 2017-08-31 - 603049 - VALID
Subjects: Adult, Graft Rejection, Male, Kidney, Isoantibodies, Serum Sickness, Antigen, medicine, Animals, Humans, lapin, Prospective Studies, Kidney transplantation, Aged, Antilymphocyte Serum, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, Graft Survival, Kidney metabolism, General Medicine, Middle Aged, medicine.disease, Kidney Transplantation, 3. Good health, Transplantation, Serum sickness, Immunology, Sialic Acids, biology.protein, Female, Rabbits, Clinical Medicine, Antibody, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Immune complex disease
Abstract: Grégoire Couvrat-Desvergnes, Apolline Salama, and Ludmilla Le Berre contributed equally to this work.; International audience; BACKGROUND: Rabbit-generated antithymocyte globulins (ATGs), which target human T cells, are widely used as immunosuppressive agents during treatment of kidney allograft recipients. However, ATGs can induce immune complex diseases, including serum sickness disease (SSD). Rabbit and human IgGs have various antigenic differences, including expression of the sialic acid Neu5Gc and α-1-3-Gal (Gal), which are not synthesized by human beings. Moreover, anti-Neu5Gc antibodies have been shown to preexist and be elicited by immunization in human subjects. This study aimed to assess the effect of SSD on long-term kidney allograft outcome and to compare the immunization status of grafted patients presenting with SSD following ATG induction treatment.METHODS: We analyzed data from a cohort of 889 first kidney graft recipients with ATG induction (86 with SSD [SSD(+)] and 803 without SSD [SSD(-)]) from the Données Informatisées et Validées en Transplantation data bank. Two subgroups of SSD(+) and SSD(-) patients that had received ATG induction treatment were then assessed for total anti-ATG, anti-Neu5Gc, and anti-Gal antibodies using ELISA assays on sera before and after transplantation.RESULTS: SSD was significantly associated with long-term graft loss (>10 years, P = 0.02). Moreover, SSD(+) patients exhibited significantly elevated titers of anti-ATG (P = 0.043) and anti-Neu5Gc (P = 0.007) IgGs in late post-graft samples compared with SSD(-) recipients.CONCLUSION: In conclusion, our data indicate that SSD is a major contributing factor of late graft loss following ATG induction and that anti-Neu5Gc antibodies increase over time in SSD(+) patients.FUNDING: This study was funded by Société d'Accélération du Transfert de Technologies Ouest Valorisation, the European FP7 "Translink" research program, the French National Agency of Research, Labex Transplantex, the Natural Science and Engineering Research Council of Canada, and the Canadian Foundation for Innovation.
Published: 2015

34. The enigmatic role of IL-38 in inflammatory diseases

Author: Mathilde Harel, T Garraud, Marie-Astrid Boutet, Frédéric Blanchard, Benoit Le Goff, maurice, sandrine, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Rhumatologie (Rhumato - HD - NANTES), Hôtel-Dieu de Nantes, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was supported by Inserm, the Arthritis Foundation, the French Society of Rheumatology, Pfizer and the Région Pays de la Loire (Bioregate)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
Subjects: 0301 basic medicine, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Immunology, Arthritis, Inflammation, Context (language use), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Psoriatic arthritis, Mice, Psoriasis, medicine, Immunology and Allergy, Animals, Humans, Spondylitis, Ankylosing, Receptors, Cytokine, Receptor, IL-1F, Ankylosing spondylitis, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Interleukins, Arthritis, Psoriatic, Toll-Like Receptors, Receptors, Interleukin-1, Cell Differentiation, Receptors, Interleukin, medicine.disease, 3. Good health, IL-38, 030104 developmental biology, Cytokine, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Th17 Cells, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Interleukin-1
Abstract: International audience; IL-38 is the most recently discovered cytokine of the IL-1 family and is considered a potential inhibitor of the IL-1 and Toll-like receptor families. IL-38 exerts anti-inflammatory properties, especially on macrophages, by inhibiting secretion of pro-inflammatory cytokines, leading to reduced T-lymphocyte TH17 maturation. IL-38 has been studied most extensively in the context of chronic inflammatory diseases, particularly arthritis, where it is considered an attractive new drug candidate. IL-38 research has entered a new phase, with the realization that IL-38 is important in the pathophysiology of TH17 dependent-diseases (psoriasis, psoriatic arthritis and anky-losing spondylitis). In this review, we provide a critical evaluation of several controversial issues concerning IL-38 function and regulation. There is effectively contrasting data regarding IL-38: it is produced in conditions such as apoptosis, necrosis or inflammation, but data is lacking regarding IL-38 processing and biological function. Furthermore, the receptor for IL-38 has yet to be identified, although three candidate receptors – IL-1R1, IL-36R and IL-1RAPL1–have been proposed. Future studies will hopefully uncover new aspects of this enigmatic cytokine.
Published: 2017

35. Immunoregulatory properties of the cytokine IL-34

Author: Séverine Bézie, Carole Guillonneau, Ignacio Anegon, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), The Fondation Progreffe. The IHU-Cesti project is also supported by Nantes Métropole and Région Pays-de-la-Loire., ANR: ANR-11-LABX-0016-01, ANR: ANR-10IBHU-005, Le Bihan, Sylvie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), and ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010)
Subjects: 0301 basic medicine, Macrophage colony-stimulating factor, medicine.medical_treatment, Inflammation, Tregs, Biology, Models, Biological, Immune tolerance, Immunomodulation, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Immune system, Mediator, medicine, Animals, Humans, Molecular Targeted Therapy, Molecular Biology, Pharmacology, Clinical Trials as Topic, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Interleukins, Macrophage Colony-Stimulating Factor, Macrophages, FOXP3, Cell Biology, 3. Good health, CSF-1(M-CSF), Transplantation, Ischemia reperfusion, 030104 developmental biology, Cytokine, 030220 oncology & carcinogenesis, Osteopetrosis, Immunology, Molecular Medicine, medicine.symptom, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Interleukin-34 is a cytokine with only partially understood functions, described for the first time in 2008. Although IL-34 shares very little homology with CSF-1 (CSF1, M-CSF), they share a common receptor CSF-1R (CSF-1R) and IL-34 has also two distinct receptors (PTP-ζ) and CD138 (syndecan-1). To make the situation more complex, IL-34 has also been shown as pairing with CSF-1 to form a heterodimer. Until now, studies have demonstrated that this cytokine is released by some tissues that differ to those where CSF-1 is expressed and is involved in the differentiation and survival of macrophages, monocytes, and dendritic cells in response to inflammation. The involvement of IL-34 has been shown in areas as diverse as neuronal protection, autoimmune diseases, infection, cancer, and transplantation. Our recent work has demonstrated a new and possible therapeutic role for IL-34 as a Foxp3+ Treg-secreted cytokine mediator of transplant tolerance. In this review, we recapitulate most recent findings on IL-34 and its controversial effects on immune responses and address its immunoregulatory properties and the potential of targeting this cytokine in human.
Published: 2017

36. Gestational Hypothyroxinemia Affects Glutamatergic Synaptic Protein Distribution and Neuronal Plasticity Through Neuron-Astrocyte Interplay

Author: Pablo Cisternas, Hélène Boudin, Antoine Louveau, Susan M. Bueno, Claudia A. Riedel, Alexis M. Kalergis, Departamento de Ciencias Biologicas [Santiago, Chile] (Facultad de Ciencias Biologicas y Facultad de Medicina), Universidad Andrés Bello [Santiago] (UNAB), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Facultad de Medicina [Santiago, Chile], Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondo Nacional de Desarrollo Científico y Tecnológico de Chile (FONDECYT Projects 1130996, 1140010, 1110604, 1100971, 1131012, and 1110397), the Millennium Institute on Immunology and Immunotherapy P09/016-F, and the La Région Pays De La Loire through the 'Nouvelles Equipes-nouvelles thématiques'., and Le Bihan, Sylvie
Subjects: 0301 basic medicine, medicine.medical_specialty, endocrine system, Long-Term Potentiation, Neuroscience (miscellaneous), Glycine, Hippocampus, Cell Count, Nerve Tissue Proteins, Cell Communication, Biology, Glutamatergic synapse, Rats, Sprague-Dawley, 03 medical and health sciences, Cellular and Molecular Neuroscience, Glutamatergic, 0302 clinical medicine, Glutamates, Pregnancy, Internal medicine, Neuroplasticity, medicine, Animals, Neurons, Neuronal Plasticity, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Long-term potentiation, Dendrites, Neuron, Coculture Techniques, Protein Transport, Thyroxine, Gestational hypothyroxinemia, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Neurology, Hypothyroxinemia, Astrocytes, Synapses, Female, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Astrocyte, Neuroscience, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Gestational hypothyroxinemia, characterized by low levels of maternal thyroxine (T4) during gestation, is closely associated with cognitive impairment in offspring. Studies in animal models have shown that this condition alters neuronal glutamatergic synapses in the hippocampus. Given that astrocytes critically contribute to the establishment and functioning of synapses, the aim of this study was to determine the effects of gestational hypothyroxinemia on the capacity of astrocytes to regulate glutamatergic synapses. In an in vitro co-culture model of astrocytes and hippocampal neurons, gestational hypothyroxinemia profoundly affected the synaptic patterns of GluN1 and CD3ζ in an astrocyte-dependent manner. These effects were associated with impaired plasticity that was dependent on both neuronal and astrocyte contributions. These results highlight the importance of neuron-astrocyte interplay in the deleterious effects of gestational hypothyroxinemia and the timely diagnosis and treatment of this condition during gestation to ensure proper central nervous system development in offspring.
Published: 2016

37. Natal departure timing from spatially varying environments is dependent of individual ontogenetic status

Author: Jean-Marc Roussel, Julien Cucherousset, Jean-Marc Paillisson, Evolution et Diversité Biologique (EDB), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes (UR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), Écologie et santé des écosystèmes (ESE), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, PnrB, FEDER, DIREN, région Pays de la Loire, Agence de l'eau Loire-Bretagne, ERG Marie Curie grant (PERG08-GA-2010-276969), Parc naturel régional de Brière, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: 0106 biological sciences, Ontogeny, Stable isotope analyses, Niche, Inter-individual variability, Environment, 010603 evolutionary biology, 01 natural sciences, Time, Temporary waters, Animals, Body Size, Juvenile, Ecology, Evolution, Behavior and Systematics, Esox, Trophic level, Pike, computer.programming_language, Carbon Isotopes, Nitrogen Isotopes, biology, Ontogenetic niche shift, Ecology, 010604 marine biology & hydrobiology, General Medicine, Dispersion, biology.organism_classification, Spatial heterogeneity, Habitat, Esocidae, Seasons, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, computer
Abstract: International audience; Natal departure timing represents one of the first crucial decisions for juveniles born in spatially varying environments that ultimately disappear, but our knowledge on its determinants is limited. The present study aimed at understanding the determinants of juvenile natal departure by releasing individually tagged juvenile pike (Esox lucius L.) with variable body size and trophic position in a temporary flooded grassland. Specifically, we investigated whether natal departure depends on individual competitive status ('competition hypothesis'), physiological tolerance to environmental conditions ('physiological hypothesis') or individual trophic position and the spatial heterogeneity of trophic resources ('trophic hypothesis'). The results indicated that departure timing was negatively correlated with body size at release, showing that the dominance status among competing individuals was not the main trigger of juvenile departure. A positive correlation between departure timing and individual body size at departure was observed, suggesting that inter-individual variability in physiological tolerance did not explain departure patterns. While individual growth performances were similar irrespective of the timing of natal departure, stable isotope analyses revealed that juveniles with higher trophic position departed significantly earlier than individuals with lower trophic position. Therefore, the trade-off driving the use of spatially varying environments was most likely dependent upon the benefits associated with energetic returns than the costs associated with inter-individual competition or physiological stress. This result highlighted how ontogeny, and particularly ontogenetic niche shift, can play a central role in juvenile's decision to depart from natal habitats in a predatory species.
Published: 2013

38. Spitting out the demons: Extracellular vesicles in glioblastoma

Author: Gwennan André-Grégoire, Julie Gavard, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Research in SOAP team was funded by: Fondation ARC pour la recherche contre le Cancer, Ligue Nationale contre le Cancer comité Pays-de-la-Loire, comité Maine-et-Loire and comité Sarthe, and Connect Talent grant from Région Pays-de-la-Loire and Nantes Métropole., Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, exosomes, Review, Biology, Diffusion, Translational Research, Biomedical, 03 medical and health sciences, Cellular and Molecular Neuroscience, angiogenesis, Extracellular Vesicles, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, glioma, microRNA, medicine, Tumor Microenvironment, Animals, Humans, Tumor microenvironment, Brain, Cell Biology, medicine.disease, Phenotype, Transmembrane protein, Microvesicles, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Cancer cell, brain tumors, permeability, signaling, Glioblastoma
Abstract: International audience; Discovered decades ago, extracellular vesicles (EVs) emerge as dedicated organelles, able to deliver protected, specific cellular cues throughout the organism. While virtually every cell can release EVs, cancer cells co-opted this feature and efficiently unleashed them both in the tumor microenvironment and towards healthy tissues. This might contribute to tumor aggressiveness and spreading. Cancer-derived EVs that contain DNA, mRNA, miRNA, and packed and transmembrane proteins can operate locally or at distance. This review will focus on the high-grade brain tumor (i.e. glioblastoma)-derived EVs, discussing recent reports on i) their phenotype and content, ii) their putative functions, and iii) their clinical potential for improving diagnosis and therapeutics.
Published: 2016

39. Comparative Analysis of piggyBac, CRISPR/Cas9 and TALEN Mediated BAC Transgenesis in the Zygote for the Generation of Humanized SIRPA Rats

Author: Laurent Tesson, Vanessa Chenouard, Lucas Brusselle, Laure-Hélène Ouisse, Claire Usal, Nicolas Poirier, Ignacio Anegon, Séverine Ménoret, Bernard Vanhove, Séverine Remy, Chris J. Jung, Pieter J. de Jong, Center for Genetics [Oakland, CA, USA], Children's Hospital Oakland Research Institute, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Plateforme 'Production de protéines recombinantes' (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), OSE Immunotherapeutics [Nantes, France], The 'TEFOR' project. The IHUCesti project is also supported by Nantes Métropole and Région Pays de la Loire., ANR-11-INBS-0014,TEFOR,Transgenèse pour les Etudes Fonctionnelles sur les Organismes modèles(2011), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Bihan, Sylvie, Infrastructures - Transgenèse pour les Etudes Fonctionnelles sur les Organismes modèles - - TEFOR2011 - ANR-11-INBS-0014 - INBS - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, ANR: ANRII-INSB-0014, ANR: ANR-11-LABX-0016-01, and ANR: ANR-10-IBHU005
Subjects: 0301 basic medicine, Chromosomes, Artificial, Bacterial, Zygote, Transgene, Mice, Transgenic, Computational biology, Biology, Article, Germline, Genome engineering, Mice, 03 medical and health sciences, Animals, Humans, CRISPR, Transgenes, Receptors, Immunologic, Gene, Genetics, Transcription activator-like effector nuclease, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Cas9, Antigens, Differentiation, Rats, Transgenesis, 030104 developmental biology, CRISPR-Cas Systems, Rats, Transgenic, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BAC transgenic mammalian systems offer an important platform for recapitulating human gene expression and disease modeling. While the larger body mass, and greater genetic and physiologic similarity to humans render rats well suited for reproducing human immune diseases and evaluating therapeutic strategies, difficulties of generating BAC transgenic rats have hindered progress. Thus, an efficient method for BAC transgenesis in rats would be valuable. Immunodeficient mice carrying a human SIRPA transgene have previously been shown to support improved human cell hematopoiesis. Here, we have generated for the first time, human SIRPA BAC transgenic rats, for which the gene is faithfully expressed, functionally active, and germline transmissible. To do this, human SIRPA BAC was modified with elements to work in coordination with genome engineering technologies-piggyBac, CRISPR/Cas9 or TALEN. Our findings show that piggyBac transposition is a more efficient approach than the classical BAC transgenesis, resulting in complete BAC integration with predictable end sequences, thereby permitting precise assessment of the integration site. Neither CRISPR/Cas9 nor TALEN increased BAC transgenesis. Therefore, an efficient generation of human SIRPA transgenic rats using piggyBac opens opportunities for expansion of humanized transgenic rat models in the future to advance biomedical research and therapeutic applications.
Published: 2016

40. A Rapid and Cost-Effective Method for Genotyping Genome-Edited Animals: A Heteroduplex Mobility Assay Using Microfluidic Capillary Electrophoresis

Author: Laurent Tesson, Vanessa Chenouard, Lucas Brusselle, Laure-Hélène Ouisse, Séverine Remy, Claire Usal, Ignacio Anegon, Tuan Huy Nguyen, Jean-Marie Heslan, Séverine Ménoret, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme 'Production de protéines recombinantes' (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), plate-forme GenoCellEdit (Inserm/ITUN/CHU Nantes-IFR Santé François Bonamy), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Transplantation Urologie-Néphrologie ( ITUN), Fundings from the Région Pays de la Loire through Biogenouest, the IBiSA Program, Fondation Progreffe., ANR: ANR-II-INSB-0014, ANR: ANR-11-LABX-001601, ANR: ANR-10-IBHU005, ANR-11-INBS-0014,TEFOR,Transgenèse pour les Etudes Fonctionnelles sur les Organismes modèles(2011), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Bihan, Sylvie, Infrastructures - Transgenèse pour les Etudes Fonctionnelles sur les Organismes modèles - - TEFOR2011 - ANR-11-INBS-0014 - INBS - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, and Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID
Subjects: 0301 basic medicine, Genotyping, Time Factors, Genotyping Techniques, Base pair, Cost-Benefit Analysis, Biology, medicine.disease_cause, Genome, Capillary electrophoresis, 03 medical and health sciences, 0302 clinical medicine, Genome editing, Lab-On-A-Chip Devices, Genetics, medicine, Animals, Molecular Biology, Gene Editing, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Electrophoresis, Capillary, Heteroduplex mobility assay, Rats, genomic DNA, 030104 developmental biology, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Heteroduplex
Abstract: International audience; The recent emergence and application of engineered endonucleases have led to the development of genome editing tools capable of rapidly implementing various targeted genome editions in a wide range of species. Moreover, these novel tools have become easier to use and have resulted in a great increase of applications. Whilst gene knockout (KO) or knockin (KI) animal models are relatively easy to achieve, there is a bottleneck in the detection and analysis of these mutations. Although several methods exist to detect these targeted mutations, we developed a heteroduplex mobility assay on an automated microfluidic capillary electrophoresis system named HMA-CE in order to accelerate the genotyping process. The HMA-CE method uses a simple PCR amplification of genomic DNA (gDNA) followed by an automated capillary electrophoresis step which reveals a heteroduplexes (HD) signature for each mutation. This allows efficient discrimination of wild-type and genome-edited animals down to the single base pair level.
Published: 2016

41. Generation of a Double KO Mouse by Simultaneous Targeting of the Neighboring Genes Tmem176a and Tmem176b Using CRISPR/Cas9: Key Steps from Design to Genotyping

Author: Gaëlle Chauveau-Le Friec, Francina Langa, Aurélie Lemoine, Cédric Louvet, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris], Nantes Métropole, Région Pays de la Loire and Fondation Progreffe., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), Le Bihan, Sylvie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Genotyping, DNA End-Joining Repair, Genotyping Techniques, C57BL/6, Locus (genetics), Biology, Deletion, Gene Knockout Techniques, Mice, 03 medical and health sciences, Genome editing, Genetics, Animals, CRISPR, Molecular Biology, Gene, CRISPR/Cas9, Double KO, NHEJ, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Base Sequence, Cas9, Mosaicism, Inversion, Membrane Proteins, Founder Effect, Off-targets, 030104 developmental biology, CRISPR-Cas Systems, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The CRISPR/Cas9 system has been tailored to a revolutionary genetic tool because of its remarkable simplicity and efficacy. While complex genome editing in the mouse since the 1990s has been dominated by the use of embryonic stem (ES) cells, CRISPR/Cas9 now offers a versatile and fast approach to precisely modify virtually any DNA regions directly in mouse zygotes. Yet, this relative simplicity does not preclude a conscientious preparatory work that is often neglected when initiating a project. Here, we describe the key steps leading to successful generation of a double knockout (KO) mouse by simultaneously targeting two homolog genes, Tmem176a and Tmem176b, which are located in the same genomic locus. Additionally, we show that similar efficiency can be obtained in a mixed genetic background or directly in the C57BL/6 inbred strain. Thus, presented as a detailed case study that should be helpful to the non-specialists, we focus on the genotyping strategy to anticipate the various possibilities.
Published: 2016

42. Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Author: Jérôme Amiaud, Lidia Rodriguez Calleja, Marc Baud'huin, Benjamin Ory, Francois Lamoureux, James E. Bradner, Robert Owen, Thibaut Quillard, Martine Berreur, Camille Jacques, Gwendolen C. Reilly, Céline Charrier, Dominique Heymann, Bénédicte Brounais-LeRoyer, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Equipe Labellisée LIGUE 2012 [Nantes], Department of Materials Science and Engineering [Sheffield], University of Sheffield [Sheffield], Department of Medical Oncology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Dana-Farber Cancer Institute [Boston], Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Camille Jacques is founded by INSERM (Institut National de la Santé et de la Recherche Médicale) and Région Pays de la Loire (grant no. 000381794)., ANR-16-CE14-0012,EPIBONE,Rôle des protéines à bromodomaines dans la physiologie osseuse normale(2016), European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), maurice, sandrine, and European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID
Subjects: 0301 basic medicine, Physiology, Endocrinology, Diabetes and Metabolism, Cellular differentiation, Bromodomain, Osteoclasts, Cell Count, Epigenesis, Genetic, 0302 clinical medicine, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Osteoblast, Epigenetic, Nuclear Proteins, Cell Differentiation, Azepines, Organ Size, Cell biology, Chromatin, Biomechanical Phenomena, RUNX2, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, Osteoclast, Female, Signal Transduction, musculoskeletal diseases, medicine.medical_specialty, BRD4, Histology, Inhibitor, Ovariectomy, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Transcription factor, Osteoblasts, Triazoles, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Osteoporosis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Histone modifications are important for maintaining the transcription program. BET proteins, an important class of " histone reading proteins " , have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis.
Published: 2016

43. IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis

Author: Michèle Heslan, Reynald Thinard, Philippe Hulin, Anne Jarry, Ahmed Abidi, Franck Halary, Ignacio Anegon, Gaelle Beriou, Jean-Christophe Renauld, Régis Josien, Céline Bossard, Arnaud Bourreille, Bernard Lardeux, Jerome Martin, Cédric Jacqueline, Séverine Ménoret, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Faculté de Médecine - Université de Nantes, Laboratoire d'Immunologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Biomarqueurs prédictifs de la progression des metaplasies et dysplasies des epitheliums (Biométadys), Université de Nantes (UN), Service d’Anatomopathologie [CHU Nantes], Plateforme MicroPicell [Nantes], Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut des Maladies de l'Appareil Digestif, Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig Institute for Cancer Research [Brussels, Belgium] (LICR - BRUSSELS), Ludwig Institute for Cancer Research, De Duve Institute [Brussels, Belgium], Université Catholique de Louvain = Catholic University of Louvain (UCL), CIC - Nantes, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), The IHU-Cesti project is also supported by Nantes Métropole and the Pays de la Loire Region. This work was also supported by a grant from CHU Nantes (Appel d’offre interne 2013 # RC14_0042), CHU de Nantes through ‘‘Année Supplémentaire d’Internat’’. Région Pays de la Loire through the IMBIO-DC network. French-tunisian UTIQUE grant from the 2015 Hubert Curien program., ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), UCL - SSS/DDUV/MEXP - Médecine expérimentale, Le Bihan, Sylvie, and Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID
Subjects: 0301 basic medicine, Adult, Male, Colon, medicine.medical_treatment, Immunology, Inflammation, Interleukin 22, Rats, Sprague-Dawley, 03 medical and health sciences, Crohn Disease, medicine, Immunology and Allergy, Animals, Humans, Colitis, Acute colitis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Interleukins, Dextran Sulfate, Interleukin, Receptors, Interleukin, Middle Aged, medicine.disease, Ulcerative colitis, digestive system diseases, 3. Good health, Rats, Eosinophils, Disease Models, Animal, 030104 developmental biology, Cytokine, Mucosal immunology, Gene Expression Regulation, Case-Control Studies, Colitis, Ulcerative, Female, medicine.symptom, Rats, Transgenic, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: International audience; Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel diseases (IBDs), are characterized by high levels of IL-22 production. Rodent studies revealed that this cytokine is protective during colitis but whether this is true in IBDs is unclear. We show here that levels of the soluble inhibitor of IL-22, interleukin 22-binding protein (IL-22BP), are significantly enhanced during IBDs owing to increased numbers of IL-22BP-producing eosinophils, that we unexpectedly identify as the most abundant source of IL-22BP protein in human gut. In addition, using IL-22BP-deficient rats, we confirm that endogenous IL-22BP is effective at blocking protective actions of IL-22 during acute colitis. In conclusion, our study provides new important insights regarding the biology of IL-22 and IL-22BP in the gut and indicates that protective actions of IL-22 are likely to be suboptimal in IBDs thus making IL-22BP a new relevant therapeutic target.
Published: 2016

44. TGF-β1 and GDF5 Act Synergistically to Drive the Differentiation of Human Adipose Stromal Cells toward Nucleus Pulposus-like Cells

Author: Julie Lesoeur, Pierre Weiss, Anne Camus, Laurent Lescaudron, Jérôme Guicheux, Maëva Ruel, Gaëlle Bonin, Borhane-Hakim Fellah, Anne Moreau, Cécile Boyer, Pauline Colombier, Johann Clouet, Université de Nantes - UFR Odontologie, Université de Nantes (UN), Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, PHU 11 Pharmacie [CHU Nantes] (Pharmacie Centrale), Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomopathologie [Nantes], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Ostéo-articulaire - Tête et cou - Odontologie - Neurochirurgie - Neurotraumatologie [CHU Nantes] (Pôle hospitalo-universitaire PHU4 - OTONN), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), This work was supported by INSERM and grants from the Fondation pour la Recherche Médicale (FRM pionnier de la recherche 'Bioingénierie'), the AO Foundation (S-12-14G), the Fondation de l’Avenir pour la Recherche Médicale Appliquée (FARMA ET3-683), the région Pays de la Loire (BIOREGOS II and BIODIV 'nouvelle équipe-nouvelle thématique' program), the Agence Nationale pour la Recherche (ANR générique 2014 REMEDIV), and doctoral grant from the AXA Research Fund (to P.C.)., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes - UFR Odontologie (UFR Odonto), Université de Rennes (UR), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Jehan, Frederic
Subjects: 0301 basic medicine, Stromal cell, Nucleus Pulposus, Cellular differentiation, [SDV]Life Sciences [q-bio], Smad-driven nucleopulpogenic differentiation, Smad Proteins, SMAD, Intervertebral Disc Degeneration, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Stem cells, Biology, Cell morphology, Mesenchymal Stem Cell Transplantation, Regenerative medicine, Transforming Growth Factor beta1, 03 medical and health sciences, Mice, Growth Differentiation Factor 5, Adipocytes, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Cell Engineering, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Mesenchymal stem cell, Growth differentiation factor, Cell Differentiation, Mesenchymal Stem Cells, Cell Biology, Anatomy, Intervertebral disc, Cell biology, Extracellular Matrix, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Molecular Medicine, Stem cell, Low Back Pain, Developmental Biology
Abstract: Degenerative disc disease (DDD) primarily affects the central part of the intervertebral disc namely the nucleus pulposus (NP). DDD explains about 40% of low back pain and is characterized by massive cellular alterations that ultimately result in the disappearance of resident NP cells. Thus, repopulating the NP with regenerative cells is a promising therapeutic approach and remains a great challenge. The objectives of this study were to evaluate the potential of growth factor-driven protocols to commit human adipose stromal cells (hASCs) toward NP-like cell phenotype and the involvement of Smad proteins in this differentiation process. Here, we demonstrate that the transforming growth factor-β1 and the growth differentiation factor 5 synergistically drive the nucleopulpogenic differentiation process. The commitment of the hASCs was robust and highly specific as attested by the expression of NP-related genes characteristic of young healthy human NP cells. In addition, the engineered NP-like cells secreted an abundant aggrecan and type II collagen rich extracellular matrix comparable with that of native NP. Furthermore, we demonstrate that these in vitro engineered cells survived, maintained their specialized phenotype and secretory activity after in vivo transplantation in nude mice subcutis. Finally, we provide evidence suggesting that the Smad 2/3 pathway mainly governed the acquisition of the NP cell molecular identity while the Smad1/5/8 pathway controlled the NP cell morphology. This study offers valuable insights for the development of biologically-inspired treatments for DDD by generating adapted and exhaustively characterized autologous regenerative cells.
Published: 2016

45. Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine

Author: Myriam Robard, Daniel Pouliquen, Philippe Hulin, Vanessa Le Martelot, Marc Grégoire, Joëlle S. Nader, Jean-François Fonteneau, David Roulois, Charly Liddell, Sophie Deshayes, Christophe Blanquart, Marie-Noëlle Guilly, Amal Ouacher, Bernardo, Elizabeth, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Cancérologie Expérimentale (LCE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Plateforme MicroPicel, Université de Nantes (UN), The research leading to these results has received funding from the National Health and Medical Research Institute (Inserm), the 'Fondation pour la Recherche Médicale' (FRM), the 'Ligue contre le Cancer' (Ligue Nationale and the Ligue inter-régionale du Grand Ouest, and comités 49, 56, 85), the 'Institut de Recherche en Santé Respiratoire des Pays de la Loire' (IRSR PdL), the 'Région Pays de la Loire', and the ARSMESO44 association.
Subjects: 0301 basic medicine, Pathology, Lung Neoplasms, Epithelium, Malignant transformation, DNA Methyltransferase 3A, Mixed Function Oxygenases, 0302 clinical medicine, CDKN2A, Cell Movement, Mesothelioma, DNA (Cytosine-5-)-Methyltransferases, TETs, Asbestos, Crocidolite, preneoplastic mesothelial cells, DNMTs, 3. Good health, Cell Transformation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, mesothelioma, 5-Methylcytosine, Immunohistochemistry, Epithelioid cell, Research Paper, medicine.medical_specialty, Karyotype, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Biomarkers, Tumor, Animals, Cyclin-Dependent Kinase Inhibitor p18, Humans, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Cell growth, Mesothelioma, Malignant, Epithelial Cells, medicine.disease, Rats, Inbred F344, Rats, 030104 developmental biology, Cell culture, Rat, Precancerous Conditions, Mesothelial Cell
Abstract: International audience; Malignant mesothelioma (MM) is one of the worst cancers in terms of clinical outcome, urging the need to establish and characterize new preclinical tools for investigation of the tumorigenic process, improvement of early diagnosis and evaluation of new therapeutic strategies. For these purposes, we characterized a collection of 27 cell lines established from F344 rats, after 136 to 415 days of induction with crocidolite asbestos administered intraperitoneally. Four mesotheliomas were distinguished from 23 preneoplastic mesothelial cell lines (PN) according to their propensity to generate tumors after orthotopic transplantation into syngeneic rats, their growth pattern, and the expression profile of three genes. PN cell lines were further discriminated into groups / subgroups according to morphology in culture and the expression profiles of 14 additional genes. This approach was completed by analysis of positive and negative immunohistochemical MM markers in the four tumors, of karyotype alterations in the most aggressive MM cell line in comparison with a PN epithelioid cell line, and of human normal mesothelial and mesothelioma cells and a tissue array. Our results showed that both the rat and human MM cell lines shared in common a dramatic decrease in the relative expression of Cdkn2a and of epigenetic regulators, in comparison with PN and normal human mesothelial cells, respectively. In particular, we identified the involvement of the relative expression of the Ten-Eleven Translocation (TET) family of dioxygenases and Dnmt3a in relation to the 5-hydroxymethylcytosine level in malignant transformation and the acquisition of metastatic potential. INTRODUCTION Malignant mesothelioma (MM) is a rare, aggressive cancer mainly related to asbestos exposure [1], the long latency time between exposure and occurrence of clinical symptoms limiting the efficacy of therapeutic interventions. Given its chemoresistance, current therapies have a negligible impact on overall survival due to a lack of understanding of the complex biology of MM [2]. Thus, a better understanding of the different steps in the development of this disease should be of great interest for the identification of early markers of MM AU 1
Published: 2016

46. Mesenchymal and neural stem cells labeled with HEDP-coated SPIO nanoparticles: In vitro characterization and migration potential in rat brain

Author: Jean Jacques Le Jeune, Laurent Lemaire, Matthieu Jacquart, Claudia N. Montero-Menei, Florence Franconi, Gaëtan J.-R. Delcroix, Laurence Sindji, Ingénierie de la vectorisation particulaire, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme d'Ingénierie et d'Analyses Moléculaires (PIAM), Université d'Angers (UA), Région Pays de la Loire, and Lemaire, Laurent
Subjects: cell migration, MESH: Etidronic Acid, Rostral migratory stream, MESH: Neurons, Contrast Media, MESH: Rats, Sprague-Dawley, MESH: Magnetic Resonance Imaging, Rats, Sprague-Dawley, 0302 clinical medicine, Cell Movement, MESH: Animals, Coloring Agents, MESH: Cell Movement, Cells, Cultured, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Cerebral Cortex, Neurons, MESH: Iron, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, General Neuroscience, subventricular zone, Brain, Cell Differentiation, Etidronic Acid, Oxides, Cell migration, Magnetic Resonance Imaging, Olfactory Bulb, Neural stem cell, Cell biology, medicine.anatomical_structure, MESH: Cell Survival, SPIO, Stem cell, MESH: Coloring Agents, MESH: Cells, Cultured, MESH: Olfactory Bulb, MESH: Cell Differentiation, MESH: Rats, Cell Survival, Iron, Subventricular zone, Biology, Mesenchymal Stem Cell Transplantation, MESH: Brain, 03 medical and health sciences, In vivo, MESH: Contrast Media, medicine, Animals, MESH: Mesenchymal Stem Cell Transplantation, Molecular Biology, 030304 developmental biology, Mesenchymal stem cell, MESH: Embryo, Mammalian, Mesenchymal Stem Cells, Embryo, Mammalian, MESH: Cerebral Cortex, Rats, Olfactory bulb, MESH: Mesenchymal Stem Cells, MESH: Oxides, Nanoparticles, Neurology (clinical), Neuroscience, MESH: Nanoparticles, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Mesenchymal stem cells (MSC) may transdifferentiate into neural cells in vitro under the influence of matrix molecules and growth factors present in neurogenic niches. However, further experiments on the behavior of such stem cells remain to be done in vivo. In this study, rat MSC (rMSC) have been grafted in a neurogenic environment of the rat brain, the subventricular zone (SVZ), in order to detect and follow their migration using superparamagnetic iron oxide (SPIO) nanoparticles. We sought to characterize the potential effect of iron loading on the behavior of rMSC as well as to address the potential of rMSC to migrate when exposed to the adequate brain microenvironment. 1-hydroxyethylidene-1.1-bisphosphonic acid (HEDP)-coated SPIO nanoparticles efficiently labeled rMSC without significant adverse effects on cell viability and on the in vitro differentiation potential. In opposition to iron-labeled rat neural stem cells (rNSC), used as a positive control, iron-labeled rMSC did not respond to the SVZ microenvironment in vivo and did not migrate, unless a mechanical lesion of the olfactory bulb was performed. This confirmed the known potential of iron-labeled rMSC to migrate toward lesions and, as far as we know, this is the first study describing such a long distance migration from the SVZ toward the olfactory bulb through the rostral migratory stream (RMS).
Published: 2009

47. [Tumor angiogenesis: when the Tree of Life turns bad]

Author: Treps, Lucas, Gavard, Julie, Bernardo, Elizabeth, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), and Les recherches reçoivent le support de la Ligue nationale contre le cancer, l’INCA, la Fondation pour la recherche médicale, la Région Pays-de-La-Loire, et Nantes-Métropole.
Subjects: Adult, Cell Fusion, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neovascularization, Pathologic, Cell Movement, Regional Blood Flow, Neoplasms, Animals, Humans, Neovascularization, Physiologic, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: International audience; Angiogenesis is a highly controlled multistep process that allows the formation of a harmonious vascular network during embryonic development and in adults. In addition, tumor progression also involves a dedicated blood vessel supply to fuel the tumor mass, pirating physiological molecular and cellular mechanisms. However, tumor angiogenesis is a quite inefficient process, as perfusion is not optimal, vessel integrity is not guaranteed, and vessel network is irrationally organized. While fundamental molecular and cellular mechanisms have been the field of intense investigation, anticancer therapies have evolved with the possibility to target tumor angiogenesis. This review presents the different steps involved in the formation of normal and tumor angiogenesis, and how tumor vasculature abnormalities could contribute to tumorigenesis and conventional therapy failure.
Published: 2015

48. Efficient Generation of Myostatin Knock-Out Sheep Using CRISPR/Cas9 Technology and Microinjection into Zygotes

Author: Ignaco Anegón, F. Cuadro, A. P. Mulet, Laurent Tesson, N. Barrera, Martina Crispo, P.C. dos Santos-Neto, Alison Creneguy, Tuan H. Nguyen, Alejo Menchaca, Lucas Brusselle, Transgenic and Experimental Animal / Animales Transgénicos y de Experimentación [Montevideo], Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Instituto de Reproducción Animal Uruguay [Montevideo, Uruguay], Fundación IRAUy, Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), IHU-CESTI, French government, National Research Agency, Région Pays de la Loire through Biogenouest, IBiSA program, Fondation Progreffe and TEFOR, the integrative genomic facility of Nantes, FOCEM (MERCOSUR Structural Convergence Fund)COF 03/11(Uruguay), PEDECIBA (UdelaR, Uruguay)., and Le Bihan, Sylvie
Subjects: Microinjections, Zygote, lcsh:Medicine, Myostatin, Biology, Animals, Genetically Modified, symbols.namesake, Gene Knockout Techniques, Pregnancy, CRISPR, Animals, Genetically modified animal, lcsh:Science, Microinjection, Sheep, Domestic, 2. Zero hunger, Sanger sequencing, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cas9, lcsh:R, Embryo, Molecular biology, symbols, biology.protein, lcsh:Q, Female, CRISPR-Cas Systems, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract: International audience; While CRISPR/Cas9 technology has proven to be a valuable system to generate gene-targeted modified animals in several species, this tool has been scarcely reported in farm animals. Myostatin is encoded by MSTN gene involved in the inhibition of muscle differentiation and growth. We determined the efficiency of the CRISPR/Cas9 system to edit MSTN in sheep and generate knockout (KO) animals with the aim to promote muscle development and body growth. We generated CRISPR/Cas9 mRNAs specific for ovine MSTN and microinjected them into the cytoplasm of ovine zygotes. When embryo development of CRISPR/Cas9 microinjected zygotes (n = 216) was compared with buffer injected embryos (n = 183) and non microinjected embryos (n = 173), cleavage rate was lower for both micro-injected groups (P
Published: 2015

49. Contribution of dendritic cells to the autoimmune pathology of systemic lupus erythematosus

Author: Claudia A. Riedel, Carolina Llanos, Alexis M. Kalergis, Juan Pablo Mackern-Oberti, Susan M. Bueno, Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Institute of Medicine and Experimental Biology of Cuyo [Mendoza, Argentina] (IMBECU), Science and Technology Center [Mendoza, Argentina] (CCT)-National Council of Scientific and Technical Research [Mendoza, Argentina], Institute of Physiology [Mendoza, Argentina] (School of Medicine), National University of Cuyo [Mendoza, Argentina], Departamento de Inmunologıa Clınica y Reumatologıa [Santiago, Chile] (Escuela de Medicina), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Departamento de Ciencias Biologicas [Santiago, Chile] (Facultad de Ciencias Biologicas y Facultad de Medicina), Universidad Andrés Bello [Santiago] (UNAB), The authors are supported by grants FONDECYT no 1110518, FONDECYT no 1070352, FONDECYT no 1085281, FONDECYT no 1100926, FONDECYT no 3070018, FONDECYT no 3100090, FONDECYT no 11075060, FONDECYT no 1100926, FONDECYT no 1110397. CONICYT Capital Humano Avanzado en la Academia no 791100015, Vicerrectorıa de Investigacion de la Pontificia Universidad Catolica de Chile No 04/2010 and Millennium Institute on Immunology and Immunotherapy (No P09/016-F). AMK is a Chaire De La Région Pays De La Loire De Chercheur Etranger D’excellence and a CDD-DR INSERM., and Le Bihan, Sylvie
Subjects: Pathology, medicine.medical_specialty, medicine.medical_treatment, T-Lymphocytes, Immunology, Inflammation, Autoimmunity, Antigen-Antibody Complex, Cell Communication, Biology, medicine.disease_cause, Immune tolerance, Immunophenotyping, Pathogenesis, Immunomodulation, Mice, Immune system, medicine, Immune Tolerance, Immunology and Allergy, Animals, Humans, Immunologic Factors, Lupus Erythematosus, Systemic, systemic autoimmunity, Review Articles, B-Lymphocytes, Systemic lupus erythematosus, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Peripheral tolerance, Interferon-alpha, Immunotherapy, lupus, Dendritic Cells, medicine.disease, 3. Good health, Disease Models, Animal, Phenotype, Receptors, Pattern Recognition, immunotherapy, medicine.symptom, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Systemic lupus erythematosus (SLE) is a heterogeneous disease in which excessive inflammation, autoantibodies and complement activation lead to multisystem tissue damage. The contribution of the individual genetic composition has been extensively studied, and several susceptibility genes related to immune pathways that participate in SLE pathogenesis have been identified. It has been proposed that SLE takes place when susceptibility factors interact with environmental stimuli leading to a deregulated immune response. Experimental evidence suggests that such events are related to the failure of T-cell and B-cell suppression mediated by defects in cell signalling, immune tolerance and apoptotic mechanism promoting autoimmunity. In addition, it has been reported that dendritic cells (DCs) from SLE patients, which are crucial in the modulation of peripheral tolerance to self-antigens, show an increased ratio of activating/inhibitory receptors on their surfaces. This phenotype and an augmented expression of co-stimulatory molecules is thought to be critical for disease pathogen-esis. Accordingly, tolerogenic DCs can be a potential strategy for developing antigen-specific therapies to reduce detrimental inflammation without causing systemic immunosuppression. In this review article we discuss the most relevant data relative to the contribution of DCs to the triggering of SLE.
Published: 2015

50. Role of dendritic cells in the initiation, progress and modulation of systemic autoimmune diseases

Author: Claudia A. Riedel, Juan Pablo Mackern-Oberti, Susan M. Bueno, Fabián Vega, Carolina Llanos, Flavio Salazar-Onfray, Alexis M. Kalergis, Departamento de Microbiologıa y Genetica Molecular [Santiago, Chile] (Facultad de Ciencias Biologicas), Pontificia Universidad Católica de Chile (UC), Departamento de Inmunologıa Clınica y Reumatologıa [Santiago, Chile] (Escuela de Medicina), Instituto de Ciencias Biomédicas [Santiago, Chile] (Facultad de Medicina), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Departamento de Ciencias Biologicas [Santiago, Chile] (Facultad de Ciencias Biologicas y Facultad de Medicina), Universidad Andrés Bello [Santiago] (UNAB), The authors are supported by grants FONDECYT no 1110518, FONDECYT no 1070352, FONDECYT no 1085281, FONDECYT no 1100926, FONDECYT no 3070018, FONDECYT no 3100090, FONDECYT no 11075060, FONDECYT no 1100926, FONDECYT no 1110397. CONICYT Capital Humano Avanzado en la Academia no 791100015, Vicerrectoría de Investigación de la Pontiﬁcia Universidad Católica de Chile No 04/2010 and Millennium Institute on Immunology and Immunotherapy (NoP09/016-F). AMK is a Chaire De La Région Pays De La Loire De Chercheur Étranger D’excellence and a CDD-DR INSERM., and Le Bihan, Sylvie
Subjects: medicine.medical_treatment, T cell, Immunology, Lupus, chemical and pharmacologic phenomena, DENDRITIC CELLS, Autoantigens, Dendritic cells, Immune tolerance, Autoimmune Diseases, Ciencias Biológicas, 03 medical and health sciences, 0302 clinical medicine, Immune system, parasitic diseases, medicine, Immunology and Allergy, Animals, Humans, LUPUS, IMMUNE TOLERANCE, IMMUNOTHERAPY, Systemic autoimmunity, B cell, 030304 developmental biology, Autoimmune disease, CD86, 0303 health sciences, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Toll-Like Receptors, Peripheral tolerance, Immunotherapy, Bioquímica y Biología Molecular, medicine.disease, 3. Good health, medicine.anatomical_structure, population characteristics, SYSTEMIC AUTOIMMUNITY, business, geographic locations, CIENCIAS NATURALES Y EXACTAS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: Dendritic cells (DCs) play a key role in the activation of the immune response against pathogens, as well as in the modulation of peripheral tolerance to self-antigens (Ags). Furthermore, an imbalance in the activating/inhibitory receptors expressed on the surface of DCs has been linked to increased susceptibility to develop autoimmune diseases underscoring their immunogenicity potential. It has been described that modulation of activating or inhibitory molecules expressed by DCs, such as CD86, TLRs, PDL-1 and FcγRs, can define the immunogenic phenotype. On the other hand, T cell tolerance can be achieved by tolerogenic DCs, which have the capacity of blocking undesired autoimmune responses in several experimental models, mainly by inducing T cell anergy, expansion of regulatory T cells and limiting B cell responses. Due to the lack of specific therapies to treat autoimmune disorders and the tolerogenic capacity of DCs shown in experimental autoimmune disease models, autologous tolDCs are a potential therapeutic strategy for fine-tuning the immune system and reestablishing tolerance in human autoimmune diseases. New advances in the role of DCs in systemic lupus erythematosus (SLE) pathogenesis and the identification of pathogenic self-Ags may favor the development of novel tolDC based therapies with a major clinical impact. In this review, we discuss recent data relative to the role of DCs in systemic autoimmune pathogenesis and their use as a therapy to restore tolerance. Fil: Mackern Oberti, Juan Pablo. Pontificia Universidad Católica de Chile; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Llanos, Carolina. Pontificia Universidad Católica de Chile; Chile Fil: Vega, Fabián. Pontificia Universidad Católica de Chile; Chile Fil: Salazar-Onfray, Flavio. Universidad de Chile; Chile Fil: Riedel, Claudia A.. Universidad Andrés Bello; Chile. Inserm; Francia Fil: Bueno, Mirian Susana. Pontificia Universidad Católica de Chile; Chile. Inserm; Francia Fil: Kalergis, Alexis. Pontificia Universidad Católica de Chile; Chile. Inserm; Francia
Published: 2015

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

68 results on '"Région Pays de la Loire"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources