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1. Rivaroxaban vs Vitamin K Antagonist in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease

Author

Laetitia, Albano, Catherine, Albert, Joachim, Alexandre, Ayham, Al-Zoebi, Cedric, Annweiler, Johann, Auer, Sanjeet, Balgobin, Joachim, Beige, Ahmed, Berami, Jean-Baptiste, Berneau, Patrick, Biggar, Ralf, Birkemeyer, Christina, Bondke, Renate, Bonin-Schnabel, Hendrik, Bonnemeier, Marc, Bouiller, Anne-Sophie, Boureau, Johannes, Brachmann, Jörg, Brosche, Sebastien, Caudmont, Guillaume, Cayla, Vianney, Charpy, Joel, Constans, Jean-Baptiste, Dally, Guillaume, De Geeter, Fédéric, Debelle, Eric, Decoulx, Nicolas, Delarche, Georg, Delle Karth, Pascal, Delsart, Michael, Derndorfer, Laurent, Desprets, Jean-Guillaume, Dillinger, Camille, Dubart, Katrin, Eberhard, Sabine, Eichinger-Hasenauer, Volker, Eissing, Christiane, Erley, Jean-Baptiste, Esteve, Emile, Ferrari, Virginie, Fossey-Diaz, Stéphane, Fromentin, Karim, Gallouj, Estelle, Gandjbakhch, Anne-Sophie, Garnier, Laure, Gilis, Bertrand, Gondouin, Franziska, Grundmann, Isabelle, Gueffet, Sebastian, Haaß, Didier, Haguenhauer, Thierry, Hannedouche, Georg, Häusler Karl, Gerd-Ulrich, Heinz, Philipp, Herold, Klaus, Hertting, Etienne, Hoffer, Joachim, Hoyer, Burkhard, Hügl, Sybille, Jänsch, Georges, Jean-Louis, Michael, Jeserich, Werner, Jung, Samuel, Kassis, Bernd-Thomas, Kellner, Marcus, Ketteler, Thomas, Kielstein Jan, René, Koning, Fabian, Krämer, Jean-Marie, Krzesinski, Ulrich, Lammers, Jean-Marie, Lefebvre, Eric, Legrand, Matthias, Leschke, Bernhard-Paul, Lodde, Christian, Maalouli, Christian, Mahnkopf, Sebastien, Mailliez, Jacques, Mansourati, Eloi, Marijon, Christian, Meyer, Detlev, Moll, Gilles, Montalescot, Serge, Motte, Vincent, Mouquet, Krassen, Nedeltchev, Anna, Neykova, Jörg, Nothroff, Raphael, Poyet, Roland, Prondzinsky, Ursula, Rauch-Kröhnert, Frank, Richard, Werner, Rieker, Andrea, Rocco, Thomas, Rostock, Daniel, Scherr, Axel, Schlitt, Hans, Schmidt-Gürtler, Norbert, Schön, Johannes, Schwab, Carsten, Schwencke, Peter, Schwimmbeck, G, Schwinger Robert H., Andreas, Schwittay, Igor, Sibon, Ulrike, Spengler, Alexander, Stadelmann, Clemens, Steinwender, Reinhard, Stöhring, Jean-Claude, Stolear, Guillaume, Taldir, Jean-Michel, Tartière, Serge, Treille, Pierre, Tremolieres, Zead, Tubail, Xavier, Warling, Morgane, Wetzstein, Adrian, Zaman, Claudia, Zemmrich, Kreutz, Reinhold, Deray, Gilbert, Floege, Jürgen, Gwechenberger, Marianne, Hahn, Kai, Luft, Andreas R., Persson, Pontus, Axthelm, Christoph, Beer, Juerg Hans, Bergler-Klein, Jutta, Lellouche, Nicolas, Taggeselle, Jens, Coleman, Craig I., and Beyer-Westendorf, Jan

Published
2024
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2. Rivaroxaban vs Vitamin K Antagonist in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease

Author

Kreutz, Reinhold, primary, Deray, Gilbert, additional, Floege, Jürgen, additional, Gwechenberger, Marianne, additional, Hahn, Kai, additional, Luft, Andreas R., additional, Persson, Pontus, additional, Axthelm, Christoph, additional, Beer, Juerg Hans, additional, Bergler-Klein, Jutta, additional, Lellouche, Nicolas, additional, Taggeselle, Jens, additional, Coleman, Craig I., additional, Beyer-Westendorf, Jan, additional, Laetitia, Albano, additional, Catherine, Albert, additional, Joachim, Alexandre, additional, Ayham, Al-Zoebi, additional, Cedric, Annweiler, additional, Johann, Auer, additional, Sanjeet, Balgobin, additional, Joachim, Beige, additional, Ahmed, Berami, additional, Jean-Baptiste, Berneau, additional, Patrick, Biggar, additional, Ralf, Birkemeyer, additional, Christina, Bondke, additional, Renate, Bonin-Schnabel, additional, Hendrik, Bonnemeier, additional, Marc, Bouiller, additional, Anne-Sophie, Boureau, additional, Johannes, Brachmann, additional, Jörg, Brosche, additional, Sebastien, Caudmont, additional, Guillaume, Cayla, additional, Vianney, Charpy, additional, Joel, Constans, additional, Jean-Baptiste, Dally, additional, Guillaume, De Geeter, additional, Fédéric, Debelle, additional, Eric, Decoulx, additional, Nicolas, Delarche, additional, Georg, Delle Karth, additional, Pascal, Delsart, additional, Michael, Derndorfer, additional, Laurent, Desprets, additional, Jean-Guillaume, Dillinger, additional, Camille, Dubart, additional, Katrin, Eberhard, additional, Sabine, Eichinger-Hasenauer, additional, Volker, Eissing, additional, Christiane, Erley, additional, Jean-Baptiste, Esteve, additional, Emile, Ferrari, additional, Virginie, Fossey-Diaz, additional, Stéphane, Fromentin, additional, Karim, Gallouj, additional, Estelle, Gandjbakhch, additional, Anne-Sophie, Garnier, additional, Laure, Gilis, additional, Bertrand, Gondouin, additional, Franziska, Grundmann, additional, Isabelle, Gueffet, additional, Sebastian, Haaß, additional, Didier, Haguenhauer, additional, Thierry, Hannedouche, additional, Georg, Häusler Karl, additional, Gerd-Ulrich, Heinz, additional, Philipp, Herold, additional, Klaus, Hertting, additional, Etienne, Hoffer, additional, Joachim, Hoyer, additional, Burkhard, Hügl, additional, Sybille, Jänsch, additional, Georges, Jean-Louis, additional, Michael, Jeserich, additional, Werner, Jung, additional, Samuel, Kassis, additional, Bernd-Thomas, Kellner, additional, Marcus, Ketteler, additional, Thomas, Kielstein Jan, additional, René, Koning, additional, Fabian, Krämer, additional, Jean-Marie, Krzesinski, additional, Ulrich, Lammers, additional, Jean-Marie, Lefebvre, additional, Eric, Legrand, additional, Matthias, Leschke, additional, Bernhard-Paul, Lodde, additional, Christian, Maalouli, additional, Christian, Mahnkopf, additional, Sebastien, Mailliez, additional, Jacques, Mansourati, additional, Eloi, Marijon, additional, Christian, Meyer, additional, Detlev, Moll, additional, Gilles, Montalescot, additional, Serge, Motte, additional, Vincent, Mouquet, additional, Krassen, Nedeltchev, additional, Anna, Neykova, additional, Jörg, Nothroff, additional, Raphael, Poyet, additional, Roland, Prondzinsky, additional, Ursula, Rauch-Kröhnert, additional, Frank, Richard, additional, Werner, Rieker, additional, Andrea, Rocco, additional, Thomas, Rostock, additional, Daniel, Scherr, additional, Axel, Schlitt, additional, Hans, Schmidt-Gürtler, additional, Norbert, Schön, additional, Johannes, Schwab, additional, Carsten, Schwencke, additional, Peter, Schwimmbeck, additional, G, Schwinger Robert H., additional, Andreas, Schwittay, additional, Igor, Sibon, additional, Ulrike, Spengler, additional, Alexander, Stadelmann, additional, Clemens, Steinwender, additional, Reinhard, Stöhring, additional, Jean-Claude, Stolear, additional, Guillaume, Taldir, additional, Jean-Michel, Tartière, additional, Serge, Treille, additional, Pierre, Tremolieres, additional, Zead, Tubail, additional, Xavier, Warling, additional, Morgane, Wetzstein, additional, Adrian, Zaman, additional, and Claudia, Zemmrich, additional

Published
2024
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3. Antibiotics versus no therapy in kidney transplant recipients with asymptomatic bacteriuria (BiRT): a pragmatic, multicentre, randomized, controlled trial

Author

Julien Coussement, Nassim Kamar, Marie Matignon, Laurent Weekers, Anne Scemla, Magali Giral, Judith Racapé, Éric Alamartine, Laurent Mesnard, Mireille Kianda, Lidia Ghisdal, Concetta Catalano, Emine N. Broeders, Olivier Denis, Karl M. Wissing, Marc Hazzan, Daniel Abramowicz, Audrey Beq, Tatiana Besse-Hammer, Marie-Noëlle Blondel-Halley, Arnaud Borsu, Vianney Charpy, Lionel Couzi, Frédéric Debelle, Arnaud del Bello, Marie de Solere, Sara Frade, Luc Frimat, Philippe Grimbert, Pierrick Guerif, Rachel Hellemans, Bénédicte Hodemon-Corne, Jean-Michel Hougardy, Alain Le Moine, Nicole Lietaer, Olivier Lortholary, Kirsty Loudon, Annick Massart, Els Meersman, Thavarak Ouk, Lissa Pipeleers, Sandrine Roisin, Sarah Tollot, Sabine Verhofstede, Martin Wojcik, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire de Liège (CHU-Liège), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Ecole de Santé Publique [Université Libre de Bruxelles], Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre Hospitalier Universitaire Brugmann [Bruxelles] (CHU), Université Catholique de Louvain = Catholic University of Louvain (UCL), Vrije Universiteit Brussel (VUB), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universiteit Antwerpen = University of Antwerpen [Antwerpen], Hôpital de Rangueil, CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Urgences néphrologiques et transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universiteit Antwerpen [Antwerpen], UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Pathologie infectieuse, Clinical sciences, Nephrology, Faculty of Medicine and Pharmacy, Service d'Urgences néphrologiques et transplantation rénale [CHU Tenon], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Antibiotics, urologic and male genital diseases, law.invention, Kidney transplantation, 0302 clinical medicine, Randomized controlled trial, Interquartile range, law, Essais, contrôle médicaments, 030212 general & internal medicine, Urinary tract infection, Néphrologie - urologie, Pyelonephritis, Incidence (epidemiology), Hazard ratio, General Medicine, Middle Aged, Sciences bio-médicales et agricoles, female genital diseases and pregnancy complications, Anti-Bacterial Agents, 3. Good health, surgical procedures, operative, Infectious Diseases, Nephrology, Female, Microbiology (medical), medicine.medical_specialty, Bacteriuria, medicine.drug_class, Urinary system, 030106 microbiology, 03 medical and health sciences, Internal medicine, medicine, Humans, Biology, Aged, Urinary tract, business.industry, bacterial infections and mycoses, medicine.disease, Transplantation d'organes, Transplant Recipients, Human medicine, business, Asymptomatic bacteriuria
Abstract

Many transplant physicians screen for and treat asymptomatic bacteriuria (ASB) during post-kidney-transplant surveillance. We investigated whether antibiotics are effective in reducing the occurrence of symptomatic urinary tract infection (UTI) in kidney transplant recipients with ASB., info:eu-repo/semantics/published

Published
2020
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4. The Presence of Renal IgG Deposits in Necrotizing Crescentic Glomerulonephritis Associated with ANCA Is Not Related to Worse Renal Clinical Outcomes

Author

Cécile Vigneau, Matthias Büchler, Nolwenn Rabot, Marie-Christine Machet, Vianney Charpy, Jean-François Augusto, Jean-Michel Halimi, Christelle Barbet, Fadi Fakhouri, Caroline Dudreuilh, Philippe Gatault, Marion Chapal, Department of Nephrology [Le Kremlin-Bicêtre], Institut francilien de recherche en néphrologie et transplantation [Le Kremlin-Bicêtre] (IFRNT), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), 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), CHU Pontchaillou [Rennes], Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomopathologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Service de néphrologie, Le Bihan, Sylvie, Service de néphrologie et immunologie clinique, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours, Service néphrologie et immunologie clinique [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Néphrologie, Immunologie clinique, and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau

Subjects
medicine.medical_specialty, ANCA - associated vasculitis, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Gastroenterology, Immunoglobulin G, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Necrotizing RPGN, 030212 general & internal medicine, Acute tubular necrosis, Anti-neutrophil cytoplasmic antibody, Kidney, biology, business.industry, Autoantibody, Glomerulonephritis, GPA, medicine.disease, dual antibody-positive disease, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, biology.protein, Anti-GBM disease, business, Vasculitis, Systemic vasculitis, Research Article
Abstract

International audience; Introduction:Diagnosing the etiology of a rapidly progressive glomerulonephritis is of vital importance to guide appropriate therapeutic management. This case highlights the complexity involved in establishing diagnosis when presentation is atypical. In certain cases diagnosis cannot be established based on clinical presentation or biopsy findings alone, and critical analysis of biopsy findings in context of clinical presentation is crucial to guide the clinical decision-making process.Case presentation: A 47-year-old Hispanic male with history of granulomatosis with polyangiitis (GPA) in remission on azathioprine, presented with fatigue and lethargy. Physical examination was unremarkable. Laboratory data revealed elevated creatinine and otherwise normal electrolytes. Urinalysis showed numerous dysmorphic red blood cells with few red cell casts. His serologic results were all negative except anti-proteinase-3 antibody at very low titers. Kidney biopsy showed necrotizing crescentic glomerulonephritis with linear immunoglobulin G staining along the basement membrane.Conclusion: This case presented conflicting serologic and histopathologic findings. The presence of anti-proteinase-3 antibody supported diagnosis of recurrence of GPA. However, linear staining of immunoglobulin G (IgG) on immunofluorescence (IF) staining of renal biopsy supported anti-glomerular basement membrane (GBM) disease. The treatment of anti-GBM disease and GPA both involve immunosuppression with prednisone and cyclophosphamide. However, patients with anti-GBM disease are also treated with plasmapheresis early in the disease presentation to prevent further damage. The patient with GPA, on the other hand, was shown to benefit from plasmapheresis only in the case of severe renal disease (serum creatinine level more than 5 mg/dL) or pulmonary hemorrhage. In this case, since the patient did not have detectable circulating anti-GBM antibody, the decision was made not to proceed with plasmapheresis. The patient was treated with a standard immunosuppressive regimen consisting of prednisone and cyclophosphamide with partial renal recovery at 2 months.

Published
2020
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5. Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection

Author

Jeremy Hervouet, Karine Renaudin, David Minault, Nicolas Poirier, Sabrina Pengam, Steven Nedellec, Caroline Mary, Vianney Charpy, Véronique Nerrière-Daguin, Julien Branchereau, Stéphanie Le Bas-Bernardet, Bernard Vanhove, Simon Ville, Alexis Chenouard, Gilles Blancho, Flora Coulon, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Effimune SAS [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Cellular and Tissular Imaging Core Facility of Nantes (MicroPICell), Université de Nantes (UN), IHU-Cesti, région Pays de la Loire et Nantes Métropole., ANR: ANR-10-IBHU005, Le Bihan, Sylvie, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, and ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010)

Subjects
lymphocytes, Graft Rejection, 0301 basic medicine, Regulatory T cell, medicine.medical_treatment, kidney transplantation, chemical and pharmacologic phenomena, 030230 surgery, Biology, acute rejection, Belatacept, Antibodies, immunology, Abatacept, Mice, 03 medical and health sciences, 0302 clinical medicine, CD28 Antigens, medicine, Animals, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, immunosuppression, CD28, hemic and immune systems, General Medicine, Tacrolimus, 3. Good health, Basic Research, 030104 developmental biology, Cytokine, medicine.anatomical_structure, Nephrology, Immunology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Immunosuppressive Agents, CD80, Papio, medicine.drug, Allotransplantation
Abstract

International audience; Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab9 antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preex-isting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.

Published
2016
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6. Advantages ofPapio anubisfor preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28

Author

Jeremy Hervouet, Lyssia Belarif, Vianney Charpy, Bernard Vanhove, David Minault, Simon Ville, Veronique Daguin, Caroline Mary, Melanie Chevalier, Gilles Blancho, Stéphanie Le Bas-Bernardet, and Nicolas Poirier

Subjects
T-Lymphocytes, medicine.medical_treatment, T cell, Immunology, Drug Evaluation, Preclinical, Mice, SCID, Biology, Antibodies, Monoclonal, Humanized, Lymphocyte Activation, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, CD28 Antigens, Species Specificity, Mice, Inbred NOD, Report, biology.animal, medicine, Animals, Humans, Immunology and Allergy, Antibodies, Blocking, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Severe combined immunodeficiency, Antibodies, Monoclonal, CD28, medicine.disease, TGN1412, Papio anubis, 3. Good health, Macaca fascicularis, Cytokine release syndrome, Cytokine, medicine.anatomical_structure, Models, Animal, Cytokines, Immunologic Memory, 030215 immunology, Baboon
Abstract

Antagonist anti-CD28 antibodies prevent T-cell costimulation and are functionally different from CTLA4Ig since they cannot block CTLA-4 and PDL-1 co-inhibitory signals. They demonstrated preclinical efficacy in suppressing effector T cells while enhancing immunoregulatory mechanisms. Because a severe cytokine release syndrome was observed during the Phase 1 study with the superagonist anti-CD28 TGN1412, development of other anti-CD28 antibodies requires careful preclinical evaluation to exclude any potential immunotoxicity side-effects. The failure to identify immunological toxicity of TGN1412 using macaques led us to investigate more relevant preclinical models. We report here that contrary to macaques, and like in man, all baboon CD4-positive T lymphocytes express CD28 in their effector memory cells compartment, a lymphocyte subtype that is the most prone to releasing cytokines after reactivation. Baboon lymphocytes are able to release pro-inflammatory cytokines in vitro in response to agonist or superagonist anti-CD28 antibodies. Furthermore, we compared the reactivity of human and baboon lymphocytes after transfer into non obese diabetic/severe combined immunodeficiency (NOD/SCID) interleukin-2rγ knockout mice and confirmed that both cell types could release inflammatory cytokines in situ after injection of agonistic anti-CD28 antibodies. In contrast, FR104, a monovalent antagonistic anti-CD28 antibody, did not elicit T cell activation in these assays, even in the presence of anti-drug antibodies. Infusion to baboons also resulted in an absence of cytokine release. In conclusion, the baboon represents a suitable species for preclinical immunotoxicity evaluation of anti-CD28 antibodies because their effector memory T cells do express CD28 and because cytokine release can be assessed in vitro and trans vivo.

Published
2014
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7. FR104, an Antagonist Anti-CD28 Monovalent Fab' Antibody, Prevents Alloimmunization and Allows Calcineurin Inhibitor Minimization in Nonhuman Primate Renal Allograft

Author

S. Le Bas-Bernardet, Jeremy Hervouet, David Minault, Karine Renaudin, Nicolas Poirier, Julien Branchereau, Vianney Charpy, Véronique Nerrière-Daguin, Flora Coulon, Caroline Mary, Sabrina Pengam, Bernard Vanhove, Simon Ville, Nahzli Dilek, Gilles Blancho, Xavier Tillou, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Effimune SAS [Nantes], Département d'Urologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'Urologie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Fondation de la Recherche Médicale, the Progreffe, Centaure foundations (France), the IHU-Cesti project, Nantes Metropole and the Pays de la Loire Region., ANR-09-BIOT-0013,TOLESTIM,Antagoniste de CD28 à action prolongée stimulateur de la tolérance en transplantation(2009), European Project, Le Bihan, Sylvie, Biotech : Biotechnologies - Antagoniste de CD28 à action prolongée stimulateur de la tolérance en transplantation - - TOLESTIM2009 - ANR-09-BIOT-0013 - Biotech - VALID, and TRIAD (EU-FP7-Health program EC-GA N8281493) - INCOMING

Subjects
Graft Rejection, Nephrology, medicine.medical_specialty, Regulatory T cell, medicine.medical_treatment, Blotting, Western, Calcineurin Inhibitors, Enzyme-Linked Immunosorbent Assay, chemical and pharmacologic phenomena, Real-Time Polymerase Chain Reaction, T-Lymphocytes, Regulatory, Immune tolerance, Immunoenzyme Techniques, Immunoglobulin Fab Fragments, CD28 Antigens, Internal medicine, Animals, Transplantation, Homologous, Immunology and Allergy, Medicine, Pharmacology (medical), RNA, Messenger, Cells, Cultured, Immunosuppression Therapy, Transplantation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Graft Survival, CD28, Immunosuppression, hemic and immune systems, Flow Cytometry, Kidney Transplantation, Tacrolimus, 3. Good health, Calcineurin, medicine.anatomical_structure, Immunology, biology.protein, Immunization, Kidney Diseases, Antibody, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Papio
Abstract

International audience; Selective targeting of CD28 might represent an effective immunomodulation strategy by preventing T cell costimulation, while favoring coinhibition since inhib-itory signals transmitted through CTLA-4; PD-L1 and B7 would not be affected. We previously showed in vitro and in vivo that anti-CD28 antagonists suppress effector T cells while enhancing regulatory T cell (Treg) suppression and immune tolerance. Here, we evaluate FR104, a novel antagonist pegylated anti-CD28 Fab' antibody fragment, in nonhuman primate renal allo-transplantation. FR104, in association with low doses of tacrolimus or with rapamycin in a steroid-free therapy, prevents acute rejection and alloantibody development and prolongs allograft survival. However , when FR104 was associated with mycophenolate mofetil and steroids, half of the recipients rejected their grafts prematurely. Finally, we observed an accumulation of Helios-negative Tregs in the blood and within the graft after FR104 therapy, confirmed by Treg-specific demethylated region DNA analysis. In conclusion , FR104 reinforces immunosuppression in calci-neurin inhibitor (CNI)-low or CNI-free protocols, without the need of steroids. Accumulation of intra-graft Tregs suggested the promotion of immunoregu-latory mechanisms. Selective CD28 antagonists might become an alternative CNI-sparing strategy to B7 antagonists for kidney transplant recipients.

Published
2015
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