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1. Bispecific antibodies tethering innate receptors induce human tolerant-dendritic cells and regulatory T cells

Author

Lamendour, Lucille, primary, Gilotin, Mäelle, additional, Deluce-Kakwata Nkor, Nora, additional, Lakhrif, Zineb, additional, Meley, Daniel, additional, Poupon, Anne, additional, Laboute, Thibaut, additional, di Tommaso, Anne, additional, Pin, Jean-Jacques, additional, Mulleman, Denis, additional, Le Mélédo, Guillaume, additional, Aubrey, Nicolas, additional, Watier, Hervé, additional, and Velge-Roussel, Florence, additional

Published
2024
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2. Anticalin N- or C-Terminal on a Monoclonal Antibody Affects Both Production and In Vitro Functionality

Author

Aubrey, Nicolas, primary, Gouilleux-Gruart, Valérie, additional, Dhommée, Christine, additional, Mariot, Julie, additional, Boursin, Fanny, additional, Albrecht, Nicolas, additional, Bergua, Cécile, additional, Croix, Cécile, additional, Gilotin, Mäelle, additional, Haudebourg, Eloi, additional, Horiot, Catherine, additional, Matthias, Laetitia, additional, Mouline, Caroline, additional, Lajoie, Laurie, additional, Munos, Audrey, additional, Ferry, Gilles, additional, Viaud-Massuard, Marie-Claude, additional, Thibault, Gilles, additional, and Velge-Roussel, Florence, additional

Published
2022
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4. Neospora caninum: a new class of biopharmaceuticals in the therapeutic arsenal against cancer

Author

Lantier, Louis, Poupée-Beaugé, Agathe, di Tommaso, Anne, Ducournau, Céline, Epardaud, Mathieu, Lakhrif, Zineb, Germon, Stéphanie, Debierre-Grockiego, Françoise, Mévélec, Marie-Noëlle, Battistoni, Arthur, Coënon, Loïs, Deluce-Kakwata-Nkor, Nora, Velge-Roussel, Florence, Beauvillain, Céline, Baranek, Thomas, Lee, Gordon Scott, Kervarrec, Thibault, Touzé, Antoine, Moiré, Nathalie, Dimier-Poisson, Isabelle, Chanteloup, Nathalie Katy, Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT), 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), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kymeris Santé, Département de Pathologie [CHRU Tours], Université Francois Rabelais [Tours], ARD2020 Biomedicaments program (2017 00118200), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Tours, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Université Francois Rabelais [Tours]-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.CAN]Life Sciences [q-bio]/Cancer, immunity, [SDV] Life Sciences [q-bio], Oncolytic and Local Immunotherapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, parasitic diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, immunotherapy, cellular, RC254-282
Abstract

International audience; Background Microorganisms that can be used for their lytic activity against tumor cells as well as inducing or reactivating antitumor immune responses are a relevant part of the available immunotherapy strategies. Viruses, bacteria and even protozoa have been largely explored with success as effective human antitumor agents. To date, only one oncolytic virus-T-VEC-has been approved by the US Food and Drug Administration for use in biological cancer therapy in clinical trials. The goal of our study is to evaluate the potential of a livestock pathogen, the protozoan Neospora caninum, non-pathogenic in humans, as an effective and safe antitumorous agent.Methods/Results We demonstrated that the treatment of murine thymoma EG7 by subcutaneous injection of N. caninum tachyzoites either in or remotely from the tumor strongly inhibits tumor development, and often causes their complete eradication. Analysis of immune responses showed that N. caninum had the ability to 1) lyze infected cancer cells, 2) reactivate the immunosuppressed immune cells and 3) activate the systemic immune system by generating a protective antitumor response dependent on natural killer cells, CD8-T cells and associated with a strong interferon (IFN)-gamma secretion in the tumor microenvironment. Most importantly, we observed a total clearance of the injected agent in the treated animals: N. caninum exhibited strong anticancer effects without persisting in the organism of treated mice. We also established in vitro and an in vivo non-obese diabetic/severe combined immunodeficiency mouse model that N. caninum infected and induced a strong regression of human Merkel cell carcinoma. Finally, we engineered a N. caninum strain to secrete human interleukin (IL)-15, associated with the alpha-subunit of the IL-15 receptor thus strengthening the immuno-stimulatory properties of N. caninum. Indeed, this NC1-IL15hRec strain induced both proliferation of and IFN-gamma secretion by human peripheral blood mononuclear cells, as well as improved efficacy in vivo in the EG7 tumor model.Conclusion These results highlight N. caninum as a potential, extremely effective and non-toxic anticancer agent, capable of being engineered to either express at its surface or to secrete biodrugs. Our work has identified the broad clinical possibilities of using N. caninum as an oncolytic protozoan in human medicine.

Published
2020

6. Tethering Innate Surface Receptors on Dendritic Cells: A New Avenue for Immune Tolerance Induction?

Author

Lamendour, Lucille, Deluce-Kakwata-Nkor, Nora, Mouline, Caroline, Gouilleux-Gruart, Valérie, Velge-Roussel, Florence, Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), and Université de Tours

Subjects
Inflammation, immune tolerance, DC subsets, Fc receptors, therapeutic antibodies, Autoimmunity, Cell Differentiation, chemical and pharmacologic phenomena, Review, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, biochemical phenomena, metabolism, and nutrition, pathogen recognition receptors, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, lcsh:Chemistry, lcsh:Biology (General), lcsh:QD1-999, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Animals, Humans, bacteria, dendritic cells, antibody format, lcsh:QH301-705.5
Abstract

International audience; Dendritic cells (DCs) play a key role in immunity and are highly potent at presenting antigens and orienting the immune response. Depending on the environmental signals, DCs could turn the immune response toward immunity or immune tolerance. Several subsets of DCs have been described, with each expressing various surface receptors and all participating in DC-associated immune functions according to their specific skills. DC subsets could also contribute to the vicious circle of inflammation in immune diseases and establishment of immune tolerance in cancer. They appear to be appropriate targets in the control of inflammatory diseases or regulation of autoimmune responses. For all these reasons, in situ DC targeting with therapeutic antibodies seems to be a suitable way of modulating the entire immune system. At present, the field of antibody-based therapies has mainly been developed in oncology, but it is undergoing remarkable expansion thanks to a wide variety of antibody formats and their related functions. Moreover, current knowledge of DC biology may open new avenues for targeting and modulating the different DC subsets. Based on an update of pathogen recognition receptor expression profiles in human DC subsets, this review evaluates the possibility of inducing tolerant DCs using antibody-based therapeutic agents

Published
2020

7. Molecular Sciences Tethering Innate Surface Receptors on Dendritic Cells: A New Avenue for Immune Tolerance Induction?

Author

Lamendour, Lucille, Deluce-Kakwata-Nkor, Nora, Mouline, Caroline, Gouilleux-Gruart, Valérie, Velge-Roussel, Florence, GICC EA 7501, FRAME (Fc récepteur, anticorps et micro-environnement) (FRAME), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), and Université de Tours-Université de Tours

Subjects
immune tolerance, DC subsets, Fc receptors, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], bacteria, therapeutic antibodies, chemical and pharmacologic phenomena, dendritic cells, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, biochemical phenomena, metabolism, and nutrition, antibody format, pathogen recognition receptors, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Abstract

International audience; Dendritic cells (DCs) play a key role in immunity and are highly potent at presenting antigens and orienting the immune response. Depending on the environmental signals, DCs could turn the immune response toward immunity or immune tolerance. Several subsets of DCs have been described, with each expressing various surface receptors and all participating in DC-associated immune functions according to their specific skills. DC subsets could also contribute to the vicious circle of inflammation in immune diseases and establishment of immune tolerance in cancer. They appear to be appropriate targets in the control of inflammatory diseases or regulation of autoimmune responses. For all these reasons, in situ DC targeting with therapeutic antibodies seems to be a suitable way of modulating the entire immune system. At present, the field of antibody-based therapies has mainly been developed in oncology, but it is undergoing remarkable expansion thanks to a wide variety of antibody formats and their related functions. Moreover, current knowledge of DC biology may open new avenues for targeting and modulating the different DC subsets. Based on an update of pathogen recognition receptor expression profiles in human DC subsets, this review evaluates the possibility of inducing tolerant DCs using antibody-based therapeutic agents.

Published
2020

13. Association between polymorphism in the human programmed death-1 (PD-1) gene and cytomegalovirus infection after kidney transplantation

Author

Hoffmann, Thomas W., Halimi, Jean-Michel, Buchler, Mathias, Velge-Roussel, Florence, Goudeau, Alain, Al-Najjar, Azmi, Marliere, Jean-Frederic, Lebranchu, Yvon, and Baron, Christophe

Subjects
Genetic polymorphisms -- Research, Cytomegalovirus infections -- Genetic aspects, Cytomegalovirus infections -- Risk factors, Cytomegalovirus infections -- Research, Apoptosis -- Genetic aspects, Apoptosis -- Research, Kidneys -- Transplantation, Kidneys -- Complications and side effects, Kidneys -- Research, Health
Published
2010

16. Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation

Author

Meley, Daniel, Héraud, Audrey, Gouilleux-Gruart, Valerie, Ivanes, Fabrice, Velge-Roussel, Florence, Signalisation et physiopathologie des cellules épithéliales, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules dendritiques, immunointervention et greffes (CDG), Université de Tours (UT), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Laboratoire d'immunologie parasitaire, Université Francois Rabelais [Tours]-UFR de Sciences Pharmaceutiques [Tours], Université de Tours, Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Velge-Roussel, Florence

Subjects
musculoskeletal diseases, rheumatoid arthritis, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], dendritic cell, Immunology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], tocilizumab, inflammation, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], il-6 receptor subunits, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, skin and connective tissue diseases, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

International audience; Tocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL-6Rα (sIL-6Rα), and mIL-6Rα] in human monocyte-derived DCs. Human DCs were derived from CD14 + monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL-6Rα expression, and largely increased sIL-6Rα secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Rα in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL-6Rα. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans-signaling activation that might explain the poor clinical benefit in some RA patients.

Published
2017

17. Induction de sous-populations de cellules Dendritiques humaines Tolérogènes par des fragments d’anticorps

Author

Kakwata-Deluce, N., Lamendour, L., Lakhrif, Zineb, Nicolas, A., Di Tommaso, A., Aubrey, Nicolas, Chabot, V., Dehaut, F., Velge-Roussel, Florence, Cellules Dendritiques, Immunomodulation et Greffes [Tours] (UFR de Médecine - EA4245), Université Francois Rabelais [Tours], EFS Centre Atlantique, Partenaires INRAE, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Université François Rabelais (Tours). FRA., Biotechnocentre. FRA., and Institut National de la Recherche Agronomique (INRA)-Université de Tours

Subjects
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV]Life Sciences [q-bio], anticorps, tolérance immunitaire, [SDV.IMM]Life Sciences [q-bio]/Immunology, cellule dendritique, humain, ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2017

19. Both expansion of regulatory GRI(+) CD11b(+) myeloid cells and anergy of T lymphocytes participate in hyporesponsiveness of the lung-associated immune system during acute toxoplasmosis

Author

Voisin, MB, Buzoni-Gatel, D, Bout, Daniel, Velge-Roussel, Florence, Inconnu, Immunologie Parasitaire et Vaccinologie, Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT)-UMR 483, and Institut National de la Recherche Agronomique (INRA)-Université de Tours-UMR 483

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2004

25. Induction of human CD4+regulatory T cells by mycophenolic acid‐treated dendritic cells

Author

Lagaraine, Christine, Lemoine, Roxane, Baron, Christophe, Nivet, Hubert, Velge‐Roussel, Florence, and Lebranchu, Yvon

Abstract

Depending on their degree of maturation, costimulatory molecule expression, and cytokine secretion, dendritic cells (DC) can induce immunity or tolerance. DC treated with mycophenolic acid during their maturation (MPA‐DC) have a regulatory phenotype and may therefore provide a new approach to induce allograft tolerance. Purified CD4+T cells stimulated in a human in vitro model of mixed culture by allogeneic MPA‐DC displayed much weaker proliferation than T cells activated by mature DC and were anergic. This hyporesponsiveness was alloantigen‐specific. Interestingly, T cells stimulated by MPA‐DC during long‐term coculture in four 7‐day cycles displayed potent, suppressive activity, as revealed by marked inhibition of the proliferation of naive and preactivated control T cells. These regulatory T cells (Tregs) appeared to have antigen specificity and were contact‐dependent. Tregs induced by MPA‐DC were CD25+glucocorticoid‐induced TNFR+CTLA‐4+CD95+, secreted IL‐5 and large amounts of IL‐10 and TGF‐β, and displayed enhanced forkhead box p3 expression. These results obtained in vitro demonstrate that human MPA‐DC can induce allospecific Tregs that may be exploited in cell therapy to induce allograft tolerance.

Published
2008
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26. Both Expansion of Regulatory GR1+CD11b+Myeloid Cells and Anergy of T Lymphocytes Participate in Hyporesponsiveness of the Lung-Associated Immune System during Acute Toxoplasmosis

Author

Voisin, Mathieu-Benoît, Buzoni-Gatel, Dominique, Bout, Daniel, and Velge-Roussel, Florence

Abstract

ABSTRACTOral infection with Toxoplasma gondiileads to transient systemic hyporesponsiveness. In this report, we characterized the presence in the lungs of GR1+CD11b+myeloid cells that have potent nitric oxide-dependent immunoregulatory properties. We also demonstrated the interleukin 2-reversible anergy of both pulmonary CD8+and CD4+activated T lymphocytes with infection.

Published
2004
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27. Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

Author

Fabrice Ivanes, Christophe Baron, Florence Velge-Roussel, Roseline Guibon, Lauriane Benoist, Stéphanie Chadet, Dominique Babuty, Denis Angoulvant, Charlotte Salmon-Gandonnière, Sébastien Roger, Cellules Dendritiques, Immunomodulation et Greffes [Tours] (UFR de Médecine - EA4245), Université Francois Rabelais [Tours], Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation (FHU SUPORT), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie et immunologie clinique [CHRU Tours] (EA4245 UT), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours-Hôpital Bretonneau, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Université de Tours-Université de Tours, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Velge-Roussel, Florence, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Time Factors, [SDV.IMM] Life Sciences [q-bio]/Immunology, Purinergic Antagonists, Transcription, Genetic, medicine.medical_treatment, Receptor expression, Immunology, Primary Cell Culture, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Pharmacology, Biology, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Adenosine Triphosphate, Downregulation and upregulation, medicine, Immunology and Allergy, Humans, RNA, Small Interfering, Receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Immunosuppression Therapy, 0303 health sciences, Interleukin-6, Receptors, Purinergic P2, Purinergic receptor, Dendritic Cells, Hypoxia-Inducible Factor 1, alpha Subunit, Interleukin-12, Cell Hypoxia, Interleukin-10, Oxygen, Cytokine, Gene Expression Regulation, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Signal transduction, medicine.symptom, Signal Transduction
Abstract

High concentrations of extracellular ATP (eATP) resulting from cell damage may be found during an ischemia/reperfusion (I/R) episode at the site of injury. eATP activates purinergic receptors in dendritic cells (DCs) and may inhibit inflammation. This immunosuppressive activity could be of interest in the field of I/R, which is an inflammatory condition involved in myocardial infarction, stroke, and solid organ transplantation. However, the specific purinergic receptor responsible for this effect remains to be identified. In this study, we report that eATP induced maturation of human monocyte-derived DCs. Additionally, eATP inhibited IL-12 production whereas IL-10 levels remained unchanged in activated DCs. These effects were prevented by the P2Y11R antagonist NF340. Interestingly, a 5-h hypoxia prevented the effects of eATP on cytokine production whereas a 1-h hypoxia did not affect the eATP-mediated decrease of IL-12 and IL-6. We showed a time-dependent downregulation of P2Y11R at both mRNA and protein levels that was prevented by knocking down hypoxia-inducible factor-1α. In this study, we showed an immunosuppressive role of P2Y11R in human DCs. Additionally, we demonstrated that the time-dependent downregulation of P2Y11R by hypoxia orientates DCs toward a proinflammatory phenotype that may be involved in post-I/R injuries as observed after organ transplantation.

Published
2015

28. Expression of Concern: The Orai-1 and STIM-1 complex controls human dendritic cell maturation

Author

Yvon Lebranchu, Romain Félix, David Crottès, Florence Velge-Roussel, Jérémy Fauconnier, Anthony Delalande, Jean-Yves Le Guennec, Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Physiopathologie cardiovasculaire, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Laboratoire d'immunologie parasitaire, Université Francois Rabelais [Tours]-UFR de Sciences Pharmaceutiques [Tours], This work was supported by a doctoral fellowship from French Ministere de la recherche., Université de Tours, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Néphrologie et d’Immunologie Clinique, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Velge-Roussel, Florence, and Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Lipopolysaccharides, Anatomy and Physiology, ORAI1 Protein, [SDV]Life Sciences [q-bio], Biochemistry, Physical Chemistry, Calcium in biology, Tours, 0302 clinical medicine, Molecular Cell Biology, Electrochemistry, Signaling in Cellular Processes, RNA, Small Interfering, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Calcium signaling, 0303 health sciences, Multidisciplinary, Voltage-dependent calcium channel, ORAI1, Calcium Channel Blockers, Signaling Cascades, Calcium Imaging, Neoplasm Proteins, Cell biology, [SDV] Life Sciences [q-bio], Chemistry, Interleukin 10, Gene Knockdown Techniques, Cytokines, Medicine, France, Research Article, Signal Transduction, Expression of Concern, Boron Compounds, Science, Immunology, Biophysics, Neuroimaging, Biology, Signaling Pathways, 6 UFR des Sciences Pharmaceutiques, 03 medical and health sciences, Chemical Biology, Calcium-Mediated Signal Transduction, Humans, Stromal Interaction Molecule 1, Calcium Signaling, Antigen-presenting cell, 030304 developmental biology, Tumor Necrosis Factor-alpha, Membrane Proteins, Dendritic Cells, Dendritic cell, Antigens, Differentiation, Calcium Signaling Cascade, Calcium, Cytokine secretion, Calcium Channels, Neuroscience, 030215 immunology
Abstract

Ca(2+) signaling plays an important role in the function of dendritic cells (DC), the professional antigen presenting cells. Here, we described the role of Calcium released activated (CRAC) channels in the maturation and cytokine secretion of human DC. Recent works identified STIM1 and Orai1 in human T lymphocytes as essential for CRAC channel activation. We investigated Ca(2+) signaling in human DC maturation by imaging intracellular calcium signaling and pharmalogical inhibitors. The DC response to inflammatory mediators or PAMPs (Pathogen-associated molecular patterns) is due to a depletion of intracellular Ca(2+) stores that results in a store-operated Ca(2+) entry (SOCE). This Ca(2+) influx was inhibited by 2-APB and exhibited a Ca(2+)permeability similar to the CRAC (Calcium-Released Activated Calcium), found in T lymphocytes. Depending on the PAMPs used, SOCE profiles and amplitudes appeared different, suggesting the involvement of different CRAC channels. Using siRNAi, we identified the STIM1 and Orai1 protein complex as one of the main pathways for Ca(2+) entry for LPS- and TNF-α-induced maturation in DC. Cytokine secretions also seemed to be SOCE-dependent with profile differences depending on the maturating agents since IL-12 and IL10 secretions appeared highly sensitive to 2-APB whereas IFN-γ was less affected. Altogether, these results clearly demonstrate that human DC maturation and cytokine secretions depend on SOCE signaling involving STIM1 and Orai1 proteins.

Published
2013

29. Unexpected impairment of TNF-α-induced maturation of human dendritic cells in vitro by IL-4

Author

Yvon Lebranchu, Frédéric Dehaut, Laurence Martin, Florence Velge-Roussel, Valérie Chabot, Daniel Meley, Luc Sensebé, Christophe Baron, Velge-Roussel, Florence, Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT), Service Recherche du laboratoire d’Histocompatibilité et d’Immunogénétique [Tours], Etablissement Français du Sang Centre Atlantique [Tours] (EFS Centre Atlantique [Tours]), STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), This work was supported in part by a grant from La Ligue contre le Cancer, Université de Tours, Service de Néphrologie et d’Immunologie Clinique, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
CD4-Positive T-Lymphocytes, 0301 basic medicine, Receptors, CCR7, medicine.medical_treatment, T cell, Immune function, Biology, Lymphocyte Activation, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Maturation, medicine, Humans, RNA, Messenger, IL-2 receptor, Interleukin 4, Migration, Cell Proliferation, CD86, Medicine(all), [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tumor Necrosis Factor-alpha, Biochemistry, Genetics and Molecular Biology(all), Research, CCL19, Cell Differentiation, Dendritic Cells, General Medicine, Dendritic cell, Th1 Cells, Interleukin-12, Cell biology, 030104 developmental biology, Cytokine, medicine.anatomical_structure, Immunology, Interleukin 12, Interleukin-4, Immunotherapy, Chemokines, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

International audience; Background: An efficient strategy for programing dendritic cells (DCs) for cancer immunotherapy is the optimiza‑ tion of their maturation so that they can efficiently stimulate cancer‑specific T cell responses. Interleukin (IL)‑4 has appeared as an essential cytokine, widely used in vitro with granulocyte macrophage‑colony stimulating factor (GM‑CSF) to differentiate monocytes into immature DCs (iDC) and to prevent macrophage formation. Conflicting data have been published regarding the effect of IL‑4 on functional DC maturation. To further understand IL‑4's effects on DC maturation and function in vitro, we choose the most commonly used maturation factor tumor necrosis factor (TNF)‑α. Methods: Human monocyte‑derived iDC were treated for 48 h with GM‑CSF and TNF‑α in the presence (IL‑4 + ‑DC) or absence (IL‑4 − ‑DC) of IL‑4 and functions of both DC populations were compared. Results: On mixed lymphocyte reaction assay, IL‑4 + ‑DC were less potent than IL‑4 − ‑DC at inducing the proliferation of allogeneic CD4 + T cells and the proportion of activated T cells expressing CD69 and/or CD25 was smaller. Interleu‑ kin‑4 reduced the cell‑surface expression of TNF‑α‑induced DC maturation markers CD83, CD86, HLA‑DR and CD25 and generated a heterogeneous population of DCs. IL‑4 + ‑DC secreted less IL‑12 and more IL‑10 than IL‑4 − ‑DC follow‑ ing activation by soluble CD40L, and IL‑4 + ‑DC‑activated T cells secreted lesser amounts of T helper (Th) 1 cytokines (IL‑2 and interferon‑γ). Importantly, IL‑4 impaired the in vitro migratory capacity of DCs in response to CCL21 and CCL19 chemokines. This effect was related to reduced expression of CCR7 at both mRNA and protein levels. Conclusion: Interleukin‑4 used with GM‑CSF and TNF‑α during the maturation of DCs in vitro impaired DC functions and disturbed the maturation effect of TNF‑α. Finally, our study reinforces the view that the quality of the DC matura‑ tion stimulus, which regulates DC migration and cytokine production, may be a decisive feature of the immunogenic‑ ity of DCs.

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30. Tethering Innate Surface Receptors on Dendritic Cells: A New Avenue for Immune Tolerance Induction?

Author

Lamendour L, Deluce-Kakwata-Nkor N, Mouline C, Gouilleux-Gruart V, and Velge-Roussel F

Subjects
Animals, Dendritic Cells pathology, Humans, Inflammation immunology, Inflammation pathology, Inflammation therapy, Autoimmunity, Cell Differentiation immunology, Dendritic Cells immunology, Immune Tolerance
Abstract

Dendritic cells (DCs) play a key role in immunity and are highly potent at presenting antigens and orienting the immune response. Depending on the environmental signals, DCs could turn the immune response toward immunity or immune tolerance. Several subsets of DCs have been described, with each expressing various surface receptors and all participating in DC-associated immune functions according to their specific skills. DC subsets could also contribute to the vicious circle of inflammation in immune diseases and establishment of immune tolerance in cancer. They appear to be appropriate targets in the control of inflammatory diseases or regulation of autoimmune responses. For all these reasons, in situ DC targeting with therapeutic antibodies seems to be a suitable way of modulating the entire immune system. At present, the field of antibody-based therapies has mainly been developed in oncology, but it is undergoing remarkable expansion thanks to a wide variety of antibody formats and their related functions. Moreover, current knowledge of DC biology may open new avenues for targeting and modulating the different DC subsets. Based on an update of pathogen recognition receptor expression profiles in human DC subsets, this review evaluates the possibility of inducing tolerant DCs using antibody-based therapeutic agents.

Published
2020
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31. Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation.

Author

Meley D, Héraud A, Gouilleux-Gruart V, Ivanes F, and Velge-Roussel F

Abstract

Tocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL-6Rα (sIL-6Rα), and mIL-6Rα] in human monocyte-derived DCs. Human DCs were derived from CD14 + monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL-6Rα expression, and largely increased sIL-6Rα secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Rα in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL-6Rα. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans -signaling activation that might explain the poor clinical benefit in some RA patients.

Published
2017
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32. Both expansion of regulatory GR1+ CD11b+ myeloid cells and anergy of T lymphocytes participate in hyporesponsiveness of the lung-associated immune system during acute toxoplasmosis.

Author

Voisin MB, Buzoni-Gatel D, Bout D, and Velge-Roussel F

Subjects
Acute Disease, Administration, Oral, Animals, Humans, Lung cytology, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Toxoplasma immunology, Toxoplasmosis, Animal parasitology, CD11b Antigen metabolism, Lung immunology, Myeloid Progenitor Cells immunology, T-Lymphocytes immunology, Toxoplasma pathogenicity, Toxoplasmosis, Animal immunology
Abstract

Oral infection with Toxoplasma gondii leads to transient systemic hyporesponsiveness. In this report, we characterized the presence in the lungs of GR1(+) CD11b(+) myeloid cells that have potent nitric oxide-dependent immunoregulatory properties. We also demonstrated the interleukin 2-reversible anergy of both pulmonary CD8(+) and CD4(+) activated T lymphocytes with infection.

Published
2004
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