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1. Clinical contribution of myositis-related antibodies detected by immunoblot to idiopathic inflammatory myositis: A one-year retrospective study

Author

Régis Josien, Claire Toquet, Marie Lecouffe-Desprets, Caroline Hémont, Mohamed Hamidou, Antoine Néel, Agathe Masseau, Jerome Martin, Degauque, Nicolas, 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), Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomo-pathologie, Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Centre hospitalier universitaire de Nantes (CHU Nantes), and Laboratoire d’Immunologie, Centre d’Immunomonitorage Nantes Atlantique (CIMNA)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunoblotting, Immunology, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, Team4, Team1, Humans, Immunology and Allergy, Medicine, Myositis specific antibodies, CRTI, ComputingMilieux_MISCELLANEOUS, Myositis, Autoantibodies, Retrospective Studies, 030203 arthritis & rheumatology, Muscle biopsy, biology, medicine.diagnostic_test, business.industry, Retrospective cohort study, Prognosis, medicine.disease, 030104 developmental biology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Idiopathic inflammatory myositis, Antibody, business
Abstract

In this study, we aimed at evaluating the contribution of an extended myositis-related antibodies (Abs) determination by immunoblot to the diagnosis, classification, and prognosis of idiopathic inflammatory myositis (IIM). Medical records of all the patients (n = 237) with myositis-related Ab requests addressed to our department over a one-year period were retrospectively analyzed. Patients were classified as IIM, auto-immune disease (AID) other than IIM, and other diagnosis, and examined for their Ab profiles as determined by immunoblot. Ab positivity was qualified semi-quantitatively as low or strong according to the manufacturer’s recommendations. Among the 45 Ab-positive patients, 49% were diagnosed an IIM, 22% another AID, and 29% another diagnosis. The clinico-serological patterns of the myositis-related Ab+ patients fully recapitulated those described in the literature. Among non-IIM patients, anti-PM-Scl was the most frequently detected Ab (38%), followed by anti-Mi-2 (15%), and anti-OJ (12%). Importantly, strong Ab positivity was significantly more detected in IIM vs. non-IIM patients (82% vs. 35%; p = .002). This difference was further increased when comparing MSAs only (95% vs. 36%; p = .0004). Accordingly, strong Ab positivity associated with high specificity (96%) and positive likelihood ratio (pLR =12) for IIM. Our data suggest that while myositis-related Ab, including MSA, can be detected by immunoblot in non-IIM patients, strong positivity is nevertheless highly predictive of IIM. In conclusion, this work suggests that relevant clinical contribution to IIM is provided by the immunoblot determination of myositis-related Ab, more especially when considering strong positive detection of MSA.

Published
2018

2. Apprentissage de l\textquoterightanatomo-cyto-pathologie par les étudiants en médecine~: comprendre le rôle de la motivation

Author

Toquet, Claire, Normand, Adeline, Guihard, Gilles, Service d'Anatomo-pathologie, Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], 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), and Degauque, Nicolas

Subjects
Team4, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, CRTI, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

3. Increased degradation of ATP is driven by memory~regulatory T cells in kidney transplantation tolerance

Author

Carole Brosseau, Eugénie Durand, Magali Giral, Maxim Durand, Pierrick Guerif, Nathalie Bonnefoy, Florian Dubois, Jean-François Eliaou, Cécile Dejou, Nicolas Degauque, Sophie Brouard, Richard Danger, Jean-Paul Soulillou, Mélanie Chesneau, 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), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Degauque, Nicolas

Subjects
0301 basic medicine, Adult, Graft Rejection, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Lymphocyte, chemical and pharmacologic phenomena, 030230 surgery, T-Lymphocytes, Regulatory, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Adenosine Triphosphate, Team4, medicine, Humans, Ectonucleotidase, CRTI, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Aged, Kidney, business.industry, Hydrolysis, Apyrase, Graft Survival, FOXP3, hemic and immune systems, Immunosuppression, Middle Aged, Kidney Transplantation, Transplantation, Calcineurin, Adenosine Diphosphate, 030104 developmental biology, Immunosuppressive drug, medicine.anatomical_structure, Nephrology, Case-Control Studies, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Transplantation Tolerance, business, Energy Metabolism, Immunologic Memory, Immunosuppressive Agents
Abstract

Regulatory T cells were recently proposed as the central actor in operational tolerance after renal transplantation. Tolerant patients harbor increased FoxP3hi memory Treg frequency and increased demethylation in the Foxp3 Treg-specific demethylated region when compared to stable kidney recipients and exhibit greater memory Treg suppressive capacities and higher expression of the ectonucleotidase CD39. However, in this particular and unique situation the mechanisms of action of Tregs were not identified. Thus, we analyzed the ability of memory Tregs to degrade extracellular ATP in tolerant patients, healthy volunteers, and patients with stable graft function under immunosuppression and determined the role of immunosuppressive drugs on this process. The conserved proportion of memory Tregs leads to the establishment of a pro-tolerogenic balance in operationally tolerant patients. Memory Tregs in tolerant patients display normal capacity to degrade extracellular ATP/ADP. In contrast, memory Tregs from patients with stable graft function do not have this ability. Finally, in vitro, immunosuppressive drugs may favor the lower proportion of memory Tregs in stable patients, but they have no effect on CD39-dependent ATP degradation and do not explain memory Treg lack of extracellular ATP/ADP degradation ability. Thus, intrinsic active regulatory mechanisms may act long after immunosuppressive drug arrest in operationally tolerant patients and may contribute to kidney allograft tolerance via the maintenance of CD39 Treg function.

Published
2018

4. Regulation of the Immune Response by the Inflammatory Metabolic Microenvironment in the Context of Allotransplantation

Author

Degauque, Nicolas, Brosseau, Carole, Brouard, Sophie, 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), and Degauque, Nicolas

Subjects
B cells, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, immunometabolism, T lymphocytes, lactic acid, adenosine triphosphatases, Review, allotransplantation, Team4, inflammation, [SDV.IMM]Life Sciences [q-bio]/Immunology, acetate, CRTI
Abstract

International audience; Antigen challenge induced by allotransplantation results in the activation of T and B cells, followed by their differentiation and proliferation to mount an effective immune response. Metabolic fitness has been shown to be crucial for supporting the major shift from quiescent to active immune cells and for tuning the immune response. Metabolic reprogramming includes regulation of the balance between glycolysis and mitochondrial respiration processes. Recent research has shed new light on the functions served by the end products of metabolism such as lactate, acetate, and ATP. At enhanced local concentrations, these metabolites have complex effects in which they not only induce T and B cell responses, cell mobility, and cytokine secretion but also favor the resolution of inflammation by promoting regulatory functions. Such mechanisms are instrumental in the context of the immune response in transplantation, not only to protect the graft and/or eliminate cells targeting it but also to maintain cell homeostasis per se. Metabolic adaptation thus plays an instrumental role on the outcome of the cellular and humoral responses. This, of course, raises the possibility of drugs that would interfere in these metabolic pathways to control the immune response but also highlights the risk that some drugs may perturb this metabolism and cell homeostasis and be deleterious for graft outcome. This review focuses on how metabolic alterations of the local immune microenvironment regulate the immune response and the impact of metabolic manipulation in allotransplantation.

Published
2018

5. Poor Patient and Graft Outcome After Induction Treatment by Antithymocyte Globulin in Recipients of a Kidney Graft After Nonrenal Organ Transplantation

Author

Thi Van Ha Nguyen, Jean-Paul Soulillou, Antoine Sicard, Pauline Houssel-Debry, Stéphanie Malard-Castagnet, Katy Trébern-Launay, Valérie Garrigue, Julie Laurent, Vered Padler-Karavani, Christophe Legendre, Magali Giral, Sophie Brouard, Michèle Treilhaud, Anne Cesbron, Hélène Perreault, Xi Chen, Michèle Kessler, Lionel Rostaing, Shani Leviatan Ben-Arye, Hoa Le Mai, Georges Karam, Emmanuel Morelon, Sophie Girerd, Evelyn Ang, Hai Yu, 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 hospitalier universitaire de Nantes (CHU Nantes), Department of Cell Research and Immunology, Tel Aviv University (TAU), Department of Chemistry [Univ California Davis] (Chemistry - UC Davis), University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Department of Chemistry [Winnipeg, MB, Canada], University of Manitoba [Winnipeg], Manitoba Centre for Proteomics and Systems Biology [Winnipeg, MB, Canada], Methodomics, Etablissement Français du Sang [Nantes], Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], Service Néphrologie et transplantation rénale Adultes [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Transplantation, Néphrologie et Immunologie Clinique [Hôpital Edouard Herriot, HCL], Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'urologie, Hôtel-Dieu, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Degauque, Nicolas, Tel Aviv University [Tel Aviv], Department of Chemistry Davis, University of California-University of California, Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Chirurgie Hépatobiliaire et Digestive [Rennes], Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Kidney Disease, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Renal and urogenital, lcsh:Surgery, 030230 surgery, Organ transplantation, 03 medical and health sciences, Team2, 0302 clinical medicine, Team4, Internal medicine, medicine, CRTI, Kidney transplantation, Transplantation, Kidney, biology, business.industry, Proportional hazards model, Prevention, Immunosuppression, Organ Transplantation, lcsh:RD1-811, medicine.disease, Kidney Transplantation, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Propensity score matching, biology.protein, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, business
Abstract

Supplemental digital content is available in the text., Background End-stage renal failure occurs in a substantial number of patients having received a nonrenal transplantation (NRT), for whom a kidney transplantation is needed. The medical strategy regarding the use of immunosuppression (IS) for a kidney graft in patients after an NRT is not well established. The prekidney grafts long-term IS advocates for a mild induction, such as using anti-IL-2R antibodies, whereas addition of new incompatibilities and anti-HLA preimmunization may suggest using stronger IS such as induction by polyclonal antithymocyte globulins (ATG). Methods We performed Cox multivariate and propensity score analysis of our validated transplant database to study the impact of the type of induction therapy on kidney graft survival of recipients of a kidney graft after NRT. Results We report here that kidney transplantation after NRT treated with an ATG induction has a poorer outcome (kidney and recipient survival) than that with an anti–IL-2R induction. After accounting for potential baseline differences with a multivariate Cox model, or by adjusting on a propensity score, we found that despite patients having received ATG cumulate more risk factors, ATG appears independently involved. As animal-derived biotherapeutics induce antiglycan antibodies and particularly anti–N-glycolylneuraminic acid (Neu5Gc) IgGs which may activate endothelial cells in patients and grafts, we also investigated the magnitude and the nature of the anti-Neu5Gc elicited by the induction and showed that induction was associated with a shift in anti-Neu5Gc IgG repertoire. Possible reasons and mechanisms of a deleterious ATG usage in these patients are discussed. Conclusions Our study suggests that ATG induction after a kidney transplantation in recipients already under maintenance IS for a NRT should be used cautiously.

Published
2018

6. HCMV triggers frequent and persistent UL40- specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition

Author

Jouand, Nicolas, Bressollette-Bodin, Céline, Gérard, Nathalie, Giral, Magali, Guérif, Pierrick, Rodallec, Audrey, Oger, Romain, Parrot, Tiphaine, Allard, Mathilde, Cesbron-Gautier, Anne, Gervois, Nadine, Charreau, Béatrice, Anti-tumor immunosurveillances and immunotherapy ( CRCINA - Département INCIT - Equipe 3 ), Centre de recherche de Cancérologie et d'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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre de Recherche en Transplantation et Immunologie ( CRTI ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de transplantation urologie-néphrologie ( ITUN ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], Laboratoire de Virologie [CHU Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Etablissement Français du Sang [Pays de la Loire] ( EFS Pays de la Loire ), EFS, Centre européen des sciences de la transplantation et de l'immunologie [CHU Nantes] ( IHU CESTI ), Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Institut de transplantation urologie-néphrologie ( ITUN ), This study was funded by: Thesis fellowship from the Ministère de l'enseignement supérieur, de la Recherche et de l'Innovation to NJ (http://www.enseignementsup-recherche.gouv.fr/), Agence Nationale de la Recherche (http://www.agence-nationale-recherche.fr/) to NG and BC (Award number: ANR-11-LABX-016-01) and BC (Award number: ANR-RC12-0465-16), Agence de la Biomédecine (https://www.agence-biomedecine.fr/) to BC (Appel d'offre Recherche et Greffe 2013), and Région Pays de la Loire (http://www.paysdelaloire.fr/) to BC (Award name: Pari Scientifique HYPROTEC RN14044)., ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest ( 2011 ), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), 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), 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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang [Pays de la Loire] (EFS Pays de la Loire), Centre européen des sciences de la transplantation et de l'immunologie [CHU Nantes] (IHU CESTI), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut de transplantation urologie-néphrologie (ITUN), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, 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
Cytomegalovirus Infection, Male, Viral Diseases, Cytomegalovirus, CD8-Positive T-Lymphocytes, Pathology and Laboratory Medicine, Biochemistry, Immune Receptors, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, White Blood Cells, Team4, Animal Cells, Team1, Medicine and Health Sciences, Renal Transplantation, Biology (General), Post-Translational Modification, CRTI, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Antigen Presentation, Immune System Proteins, T Cells, Middle Aged, Infectious Diseases, Medical Microbiology, Viral Pathogens, Viruses, Cytomegalovirus Infections, Human Cytomegalovirus, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Cellular Types, Pathogens, Signal Peptides, Research Article, Signal Transduction, Adult, Herpesviruses, QH301-705.5, Immune Cells, Immunology, Cytotoxic T cells, Surgical and Invasive Medical Procedures, [SDV.CAN]Life Sciences [q-bio]/Cancer, Research and Analysis Methods, Microbiology, Transplantation, Autologous, Urinary System Procedures, Viral Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Aged, Retrospective Studies, Transplantation, Blood Cells, Histocompatibility Antigens Class I, Organisms, Biology and Life Sciences, Proteins, Cell Biology, Organ Transplantation, RC581-607, Kidney Transplantation, Peptide Fragments, T Cell Receptors, Case-Control Studies, Immunologic diseases. Allergy, DNA viruses, Cloning, T-Lymphocytes, Cytotoxic
Abstract

Immune response against human cytomegalovirus (HCMV) includes a set of persistent cytotoxic NK and CD8 T cells devoted to eliminate infected cells and to prevent reactivation. CD8 T cells against HCMV antigens (pp65, IE1) presented by HLA class-I molecules are well characterized and they associate with efficient virus control. HLA-E-restricted CD8 T cells targeting HCMV UL40 signal peptides (HLA-EUL40) have recently emerged as a non-conventional T-cell response also observed in some hosts. The occurrence, specificity and features of HLA-EUL40 CD8 T-cell responses remain mostly unknown. Here, we detected and quantified these responses in blood samples from healthy blood donors (n = 25) and kidney transplant recipients (n = 121) and we investigated the biological determinants involved in their occurrence. Longitudinal and phenotype ex vivo analyses were performed in comparison to HLA-A*02/pp65-specific CD8 T cells. Using a set of 11 HLA-E/UL40 peptide tetramers we demonstrated the presence of HLA-EUL40 CD8 αβT cells in up to 32% of seropositive HCMV+ hosts that may represent up to 38% of total circulating CD8 T-cells at a time point suggesting a strong expansion post-infection. Host’s HLA-A*02 allele, HLA-E *01:01/*01:03 genotype and sequence of the UL40 peptide from the infecting strain are major factors affecting the incidence of HLA-EUL40 CD8 T cells. These cells are effector memory CD8 (CD45RAhighROlow, CCR7-, CD27-, CD28-) characterized by a low level of PD-1 expression. HLA-EUL40 responses appear early post-infection and display a broad, unbiased, Vβ repertoire. Although induced in HCMV strain-dependent, UL4015-23-specific manner, HLA-EUL40 CD8 T cells are reactive toward a broader set of nonapeptides varying in 1–3 residues including most HLA-I signal peptides. Thus, HCMV induces strong and life-long lasting HLA-EUL40 CD8 T cells with potential allogeneic or/and autologous reactivity that take place selectively in at least a third of infections according to virus strain and host HLA concordance., Author summary Understanding the mechanisms of immune control of viral infection is crucial to improve diagnosis and to design efficient immunotherapies. CD8 T lymphocytes are key components of the cellular immunity against human cytomegalovirus (HCMV), a widespread pathogen that cause severe illness and poor outcome in immunocompromised hosts such as transplant recipients and HIV-infected patients. In this study we characterized a population of non-conventional CD8 T lymphocytes directed against the viral protein UL40 and presented by the non-classical HLA-E molecules in blood samples from HCMV seropositive hosts. This immune response was detectable in around 30% of hosts, may represent up to 38% of total blood CD8 T lymphocytes, persists for life and thus seems to belong to the common immune arsenal against HCMV. Genetic factors related to the host and to the different strains of HCMV are critical parameters for the existence of this immune subset. Although specifically induced in response to HCMV infection, a key feature of these cells is their potential ability to be also responsive against multiple HLA molecules. In conclusion, HCMV infection frequently leads to the long-term persistence of a large subset of lymphocytes with potential side effect requiring attention in contexts such as autoimmunity and transplantation.

Published
2018

7. Vasculitides induced by cocaine and/or levamisole

Author

Christian Agard, Antoine Néel, Mohamed Hamidou, Degauque, Nicolas, Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), and Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Adult, Male, Vasculitis, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, Global Health, 030207 dermatology & venereal diseases, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Rheumatology, Cocaine, Team4, medicine, Humans, 030212 general & internal medicine, Antineutrophil cytoplasm antibodies, CRTI, ComputingMilieux_MISCELLANEOUS, business.industry, Incidence, Levamisole, medicine.disease, Antirheumatic Agents, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, medicine.drug
Abstract

International audience

Published
2018

8. Renal cortical volume: High correlation with pre- and post-operative renal function in living kidney donors

Author

Sophie Limou, Christophe Perret, Pierre-Antoine Gourraud, Pierre-Marie Heudes, Lola Jacquemont, Eric Frampas, Maryvonne Hourmant, Edouard Gardan, Degauque, Nicolas, 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), and Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Male, medicine.medical_treatment, 030232 urology & nephrology, Kidney, Kidney Function Tests, Scintigraphy, Nephrectomy, 030218 nuclear medicine & medical imaging, Cohort Studies, 0302 clinical medicine, Team5, Team4, Living Donors, Medicine, CRTI, ComputingMilieux_MISCELLANEOUS, education.field_of_study, medicine.diagnostic_test, Organ Size, General Medicine, Cone-Beam Computed Tomography, Middle Aged, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Glomerular Filtration Rate, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Population, Urology, Renal function, Kidney Volume, Transplant Donor Site, Young Adult, 03 medical and health sciences, Multidetector Computed Tomography, Preoperative Care, Humans, Radiology, Nuclear Medicine and imaging, Radionuclide Imaging, education, Aged, Retrospective Studies, Postoperative Care, Receiver operating characteristic, business.industry, medicine.disease, Kidney Transplantation, business, Kidney disease
Abstract

Background CT volumetry has previously been proposed as an alternative to scintigraphy for the evaluation of pre-donation split renal function and the prediction of post-donation renal function in living kidney donors. The aim of our study was to retrospectively assess the relevance of three CT volumetry techniques for estimating pre-donation kidney function and predicting the risk for chronic kidney disease (CKD) at 1-year post-nephrectomy in a French cohort of living donors using isotopic measures of kidney function. Methods Kidney volume was quantified pre-donation for 105 donors using three methods total parenchymal three-dimensional renal volume (3DRV), total parenchymal renal volume contouring (RVCt), and renal cortical volume (RCoV). Subjects also had a 51Cr-EDTA scintigraphy to measure glomerular filtration rate (mGFR) pre-donation and 1-year after donation. For each volume, we tested for association with mGFR using univariate regression models, and computed receiver operating characteristics analyses to assess their predictive potential of post-donation CKD. Results Our population was composed of healthy subjects, who were predominantly female (69%) with a median age at donation of 51yo. Median mGFR was 102 mL/min/1.73 m2 at pre-donation and 66 mL/min/1.73 m2 1-year after nephrectomy. The pre-donation median volume of the preserved kidney was 156 cm3, 163 cm3 and 99 cm3 for the 3DRV, RVCt and RCoV methods respectively, with a high correlation observed between each technique (R > 0.84). For all methods, total kidney volume was significantly associated with pre-donation mGFR (P Conclusions In our cohort of healthy donors with measured kidney function, cortical volumetry (RCoV) appears as the best volumetric technique to use as a surrogate to scintigraphy for estimating pre-donation split renal function and predicting post-donation renal outcomes.

Published
2018

9. MD1003 (High-Dose Pharmaceutical-Grade Biotin) for the Treatment of Chronic Visual Loss Related to Optic Neuritis in Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Study

Author

Véronique Deburghgraeve, Alain Vighetto, Olivier Gout, Jean Pelletier, Thibault Moreau, Marc Debouverie, Pierre Clavelou, David Brassat, Carl Arndt, Pierre Labauge, Frédéric Sedel, Olivier Heinzlef, Caroline Papeix, Gilles Defer, Ahmed T. Toosy, Ayman Tourbah, Olivier Outteryck, Christine Lebrun-Frenay, Jérôme De Seze, David-Axel Laplaud, Le Bihan, Sylvie, Université de Reims Champagne-Ardenne (URCA), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), CHU Pontchaillou [Rennes], Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Universitaire de Nice (CHU Nice), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Neurologie vasculaire, pathologie neuro-dégénérative et explorations fonctionnelles du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UPS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de compétence de la Sclérose Latérale Amyotrophique [CHU Clermont-Ferrand] (SLA CHU Clermont-Ferrand), CHU Clermont-Ferrand, Service de Neurologie [CHU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), CHU Strasbourg, CHU Caen, Normandie Université (NU), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), MedDay Pharmaceuticals, Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de Psychopathologie et Neuropsychologie (LPN), Université Paris 8 Vincennes-Saint-Denis (UP8), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon, Departement de Neurologie (HCL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), University College of London [London] (UCL), Centre hospitalier universitaire de Nantes (CHU Nantes), Immunoregulation And Immunointervention in Transplantation and Autoimmunity (Team 4 - U1064 Inserm - 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), CHU Dijon, CHI Poissy-Saint-Germain, CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), MedDay Pharmaceuticals., Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), 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), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, medicine.medical_specialty, Visual acuity, Multiple Sclerosis, Optic Neuritis, genetic structures, Placebo-controlled study, Vision Disorders, Visual Acuity, Biotin, Placebo, law.invention, Optic neuropathy, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, Team4, law, Ophthalmology, medicine, Clinical endpoint, Humans, Pharmacology (medical), Optic neuritis, Original Research Article, CRTI, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dose-Response Relationship, Drug, business.industry, medicine.disease, eye diseases, 3. Good health, Visual field, Psychiatry and Mental health, Treatment Outcome, Vitamin B Complex, 030221 ophthalmology & optometry, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Chronic visual loss is a disabling feature in patients with multiple sclerosis (MS). It was recently shown that MD1003 (high-dose pharmaceutical-grade biotin or hdPB) may improve disability in patients with progressive MS. Objective The aim of this study was to evaluate whether MD1003 improves vision compared with placebo in MS patients with chronic visual loss. Methods The MS-ON was a 6-month, randomized, double-blind, placebo-controlled study with a 6-month open-label extension phase. Adult patients with MS-related chronic visual loss of at least one eye [visual acuity (VA) below 0.5 decimal chart] were randomized 2:1 to oral MD1003 300 mg/day or placebo. The selected eye had to show worsening of VA within the past 3 years following either acute optic neuritis (AON) or slowly progressive optic neuropathy (PON). The primary endpoint was the mean change from baseline to month 6 in VA measured in logarithm of the minimum angle of resolution (logMAR) at 100% contrast of the selected eye. Visually evoked potentials, visual field, retinal nerve fiber layer (RNFL) thickness, and health outcomes were also assessed. Results Ninety-three patients received MD1003 (n = 65) or placebo (n = 28). The study did not meet its primary endpoint, as the mean change in the primary endpoint was nonsignificantly larger (p = 0.66) with MD1003 (− 0.061 logMAR, + 3.1 letters) than with placebo (− 0.036 logMAR, + 1.8 letters). Pre-planned subgroup analyses showed that 100% contrast VA improved by a mean of + 2.8 letters (− 0.058 logMAR) with MD1003 and worsened by − 1.5 letters (+ 0.029 logMAR) with placebo (p = 0.45) in the subgroup of patients with PON. MD1003-treated patients also had nonsignificant improvement in logMAR at 5% contrast and in RNFL thickness and health outcome scores when compared with placebo-treated patients. There was no superiority of MD1003 vs placebo in patients with AON. The safety profile of MD1003 was similar to that of placebo. Conclusions MD1003 did not significantly improve VA compared with placebo in patients with MS experiencing chronic visual loss. An interesting trend favoring MD1003 was observed in the subgroup of patients with PON. Treatment was overall well tolerated. Trial registration EudraCT identifier 2013-002112-27. ClinicalTrials.gov Identifier: NCT02220244 Funding MedDay Pharmaceuticals. Electronic supplementary material The online version of this article (10.1007/s40263-018-0528-2) contains supplementary material, which is available to authorized users.

Published
2018

10. Notch signaling triggered via the ligand DLL4 impedes M2 macrophage differentiation and promotes their apoptosis

Author

Nathalie Gérard, Béatrice Charreau, Sylvain Pagie, Degauque, Nicolas, 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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Centre européen des sciences de la transplantation et de l'immunologie [CHU Nantes] (IHU CESTI), and Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut de transplantation urologie-néphrologie (ITUN)

Subjects
0301 basic medicine, Lipopolysaccharides, Macrophage, Cellular differentiation, Notch pathway, Il-4, lcsh:Medicine, Apoptosis, Ligands, Biochemistry, Monocytes, Team4, Polarization, CRTI, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, bcl-2-Associated X Protein, Receptors, Notch, Chemistry, lcsh:Cytology, JAK-STAT signaling pathway, Cell Differentiation, M2 Macrophage, Recombinant Proteins, Cell biology, STAT Transcription Factors, cardiovascular system, [SDV.IMM]Life Sciences [q-bio]/Immunology, Intercellular Signaling Peptides and Proteins, Signal transduction, BH3 Interacting Domain Death Agonist Protein, Signal Transduction, Cell signaling, JAG1, [SDV.IMM] Life Sciences [q-bio]/Immunology, Macrophage polarization, Notch signaling pathway, DLL4, M2 macrophage, 03 medical and health sciences, Interferon-gamma, Humans, lcsh:QH573-671, JAK/stat, Molecular Biology, Adaptor Proteins, Signal Transducing, Janus Kinases, Notch1, Research, Macrophages, lcsh:R, Calcium-Binding Proteins, Cell Biology, 030104 developmental biology, Interleukin-4
Abstract

Background Notch signaling controls many cellular processes, including cell fate determination, cell differentiation, proliferation and apoptosis. In mammals, four Notch receptors (Notch 1–4) can interact with five distinct ligands [Jagged1, Jagged2, Delta-like 1 (DLL1), DLL3, and DLL4]. We previously reported that Notch activation is modulated in endothelial cells and monocytes during inflammation and showed that inflammation upregulates DLL4 on endothelial cells. DLL4 promotes differentiation of blood monocytes into proinflammatory M1 macrophages. Here, we further investigated the ability of DLL4 to interfere with the polarization of blood monocytes into immunosuppressive M2 macrophages. Methods Human blood monocytes were differentiated in vitro into M0 macrophages and then polarized into M1 or M2 macrophages with LPS/IFNγ and IL-4, respectively. Polarization steps were performed in the presence of immobilized recombinant DLL4. Immune phenotype and apoptosis of macrophage subsets were analyzed and quantified by flow cytometry. Regulatory effects of DLL4 on gene expression, cell signaling and apoptotic pathways were investigated by QPCR and western blots. Results The phenotype of M2 macrophages was subject to specific alterations in the presence of recombinant DLL4. DLL4 inhibits the upregulation of IL-4 induced M2 markers such as CD11b, CD206, and CD200R. Survival of macrophages upon M2 polarization was also strongly reduced in the presence of DLL4. DLL4 induces a caspase3/7-dependent apoptosis during M2 but not M1 macrophage polarization. The Notch ligand DLL1 has no apoptotic effect. Both DLL4 signaling via Notch1 as well as DLL4-mediated apoptosis are Notch-dependent. Fully differentiated M2 macrophages became resistant to DLL4 action. Mechanistically, DLL4 selectively upregulates gene expression in macrophages upon M2 polarization, thereby affecting the Notch pattern (Notch1, 3, Jag1), activity (HES1), and transcription (IRF5, STAT1). The pro-apoptotic effectors Bax and Bak and the BH3-only proteins Bid and Bim seem to convey DLL4 apoptotic signal. Conclusion Interplay between the DLL4/Notch and IL-4/IL-4R signaling pathways impairs M2 differentiation. Thus, DLL4 may drive a Notch-dependent selection process not only by promoting M1 macrophage differentiation but also by preventing M2 macrophage differentiation through inhibition of M2-specific gene expression and apoptotic cell death.

Published
2018

11. Are the decrease in circulating anti-α1,3-Gal IgG and the lower content of galactosyl transferase A1 in the microbiota of patients with multiple sclerosis a novel environmental risk factor for the disease?

Author

Jean-Paul Soulillou, Emmanuel Montassier, Laureline Berthelot, Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), 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), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Degauque, Nicolas

Subjects
0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Disease, Gut flora, digestive system, Ribotyping, Epitope, 03 medical and health sciences, Epitopes, Multiple Sclerosis, Relapsing-Remitting, Bacterial Proteins, Team4, Risk Factors, medicine, Environmental Microbiology, Humans, CRTI, Molecular Biology, Gene, ComputingMilieux_MISCELLANEOUS, Autoantibodies, biology, Multiple sclerosis, Models, Immunological, Environmental Exposure, medicine.disease, biology.organism_classification, Galactosyltransferases, Pathophysiology, Gastrointestinal Microbiome, 030104 developmental biology, Genes, Bacterial, Immunoglobulin G, biology.protein, Etiology, Metagenome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody
Abstract

The etiology of multiple sclerosis (MS), particularly the environmental component of the disease, remains speculative. Recent reports have suggested that alterations in the gut microbiota of MS patients could contribute to the etiology or pathophysiology of the disease. In this Viewpoint, using PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) to infer the functional content of the gut microbiota, we show that the gut microbiota of MS patients is characterized by a significant decrease in the relative abundance of the enzyme EC 2.4.1.87, which corresponds to the GGTA1 gene (which codes for the α1,3-Gal epitope and is lacking in humans), against which MS patients also have low levels of IgG antibodies. The decrease in circulating anti-α1,3-Gal IgG and lower content of galactosyl transferase A1 in the microbiota of patients with multiple sclerosis could be a novel environmental risk factor for the disease.

Published
2018

12. B cells in operational tolerance

Author

Richard Danger, Jean-Paul Soulillou, Sophie Brouard, Mélanie Chesneau, Degauque, Nicolas, 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), and Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
0301 basic medicine, Graft Rejection, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Immunology, B-Lymphocyte Subsets, Receptors, Antigen, B-Cell, 030230 surgery, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Team4, medicine, Immunology and Allergy, Humans, CRTI, ComputingMilieux_MISCELLANEOUS, Immunosuppressive treatment, B-Lymphocytes, business.industry, Graft Survival, Models, Immunological, Immunosuppression, Cell Differentiation, General Medicine, Transplantation, 030104 developmental biology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Graft survival, Transplantation Tolerance, business, Biomarkers
Abstract

Transplantation is currently the therapy of choice for endstage organ failure even though it requires long-term immunosuppresive therapy, with its numerous side effects, for acceptance of the transplanted organ. In rare cases however, patients develop operational tolerance, that is, graft survival without immunosuppression. Studies conducted on these patients reveal genetic, phenotypic, and functional signatures. They provide a better understanding of the immunological mechanisms involved in operational tolerance and define biomarkers that could be used to adapt immunosuppressive treatment to the individual, safely reduce immunosuppression doses, and ideally and safely guide immunosuppression withdrawal. This review summarizes studies that suggest a role for B cells as biomarkers of operational tolerance and discusses the use of B cells as a predictive tool for immunologic risk.

Published
2017

13. Microglial control of astrocytes in response to microbial metabolites

Author

Davis M. Borucki, Ori Staszewski, David Laplaud, Matilde Borio, Luke M. Healy, Emily C. Tjon, Tradite Neziraj, Maisa C. Takenaka, Cristina Gutiérrez-Vázquez, Jorge I. Alvarez, Patrick Hewson, Kalil Alves de Lima, Jack P. Antel, Veit Rothhammer, Loic Lionel Dragin, Francisco J. Quintana, Manon Blain, Michael A. Wheeler, Alberto Ardura-Fabregat, Chun-Cheih Chao, Marco Prinz, Institute of Membrane and Systems Biology, University of Leeds, 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), University of Freiburg [Freiburg], and Degauque, Nicolas

Subjects
0301 basic medicine, Central Nervous System, Vascular Endothelial Growth Factor B, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Encephalomyelitis, Central nervous system, Lipopolysaccharide Receptors, Inflammation, Biology, Article, 03 medical and health sciences, Mice, Team4, medicine, Animals, Humans, CRTI, Symbiosis, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Multidisciplinary, Vascular Endothelial Growth Factor Receptor-1, Microglia, Multiple sclerosis, Experimental autoimmune encephalomyelitis, Neurodegeneration, Tryptophan, Transforming Growth Factor alpha, medicine.disease, Cell biology, ErbB Receptors, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Neuroimmunology, medicine.anatomical_structure, Receptors, Aryl Hydrocarbon, Astrocytes, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom
Abstract

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1–3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.

Published
2017

14. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease

Author

Peter Lamprecht, Thierry Schaeverbeke, Hendrik Schulze-Koops, Eugen Feist, Jürgen Rech, Bernhard Hellmich, Eduardo Schiffrin, Delphine S. Courvoisier, Jacques Morel, Thierry Martin, Eric Hachulla, Bruno Fautrel, Andrew Sleight, Cem Gabay, Ina Kötter, Mohamed Hamidou, François Spertini, Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Division of Rheumatology [Geneva, Switzerland], Geneva University Hospital, Geneva-Department of Internal Medicine [Genève], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Division of Immunology and Allergy [Lausanne, Suisse], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Internal Medicine II, University of Tübingen, Service de médecine interne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Rhumatologie Bordeaux (SERVICE DE RHUMATOLOGIE), CHU Bordeaux [Bordeaux], 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), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Génie des Procédés et Matériaux - EA 4038 (LGPM), CentraleSupélec, Degauque, Nicolas, Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Service de Rhumatologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen

Subjects
Adult, 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Injections, Subcutaneous, Immunology, Disease, Severity of Illness Index, Drug Administration Schedule, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Team4, Rheumatology, Prednisone, Internal medicine, medicine, Clinical endpoint, Humans, Immunology and Allergy, CRTI, Adverse effect, ComputingMilieux_MISCELLANEOUS, ddc:616, 030203 arthritis & rheumatology, Dose-Response Relationship, Drug, biology, business.industry, C-reactive protein, Interleukin-18, Interleukin, Middle Aged, Antirheumatic Agents/administration & dosage, Antirheumatic Agents/adverse effects, Antirheumatic Agents/therapeutic use, Biomarkers/blood, Female, Intercellular Signaling Peptides and Proteins/administration & dosage, Intercellular Signaling Peptides and Proteins/adverse effects, Intercellular Signaling Peptides and Proteins/therapeutic use, Interleukin-18/blood, Still's Disease, Adult-Onset/drug therapy, Still's Disease, Adult-Onset/immunology, Treatment Outcome, adult onset still’s disease, inflammation, juvenile idiopathic arthritis, 3. Good health, Clinical trial, Institutional repository, 030104 developmental biology, Antirheumatic Agents, biology.protein, Intercellular Signaling Peptides and Proteins, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Still's Disease, Adult-Onset, Biomarkers, medicine.drug
Abstract

Objectives Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. Methods In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. Results Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. Conclusions Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. Trial registration number NCT02398435.

Published
2018

15. Omstreden museum als geschenk aan de stad: De totstandkoming van een nieuw Groninger Museum

Author

Bochanen, F.A. (author) and Bochanen, F.A. (author)

Abstract

Vrijwel iedereen die langs het Groninger Museum komt heeft er een mening over, positief of negatief. Al voordat het gebouw er stond, heeft het nieuwe Groninger Museum veel stof doen opwaaien, zelfs voordat bekend was wie het gebouw zou gaan ontwerpen. Het begon allemaal met een gulle gift, een geschenk van de Gasunie. Hoe vervolgens het ontwerp- en bouwproces van het museum verliep, is het onderwerp van deze scriptie architectuurgeschiedenis., History, Architecture, Architecture

Published
2011

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