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1. High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors

Author

Antoine Marçais, Marie Marotel, Sophie Degouve, Alice Koenig, Sébastien Fauteux-Daniel, Annabelle Drouillard, Heinrich Schlums, Sébastien Viel, Laurie Besson, Omran Allatif, Mathieu Bléry, Eric Vivier, Yenan Bryceson, Olivier Thaunat, and Thierry Walzer

Subjects
natural killer, cell signaling, mTOR, education, activation threshold, Medicine, Science, Biology (General), QH301-705.5
Abstract

NK cell education is the process through which chronic engagement of inhibitory NK cell receptors by self MHC-I molecules preserves cellular responsiveness. The molecular mechanisms responsible for NK cell education remain unclear. Here, we show that mouse NK cell education is associated with a higher basal activity of the mTOR/Akt pathway, commensurate to the number of educating receptors. This higher activity was dependent on the SHP-1 phosphatase and essential for the improved responsiveness of reactive NK cells. Upon stimulation, the mTOR/Akt pathway amplified signaling through activating NK cell receptors by enhancing calcium flux and LFA-1 integrin activation. Pharmacological inhibition of mTOR resulted in a proportional decrease in NK cell reactivity. Reciprocally, acute cytokine stimulation restored reactivity of hyporesponsive NK cells through mTOR activation. These results demonstrate that mTOR acts as a molecular rheostat of NK cell reactivity controlled by educating receptors and uncover how cytokine stimulation overcomes NK cell education.

Published
2017
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2. Un nouveau type de rejet de greffe induit par les lymphocytes natural killer : le rejet chronique vasculaire « inné »

Author

Alice Koenig, Olivier Thaunat, Sarah Hamada, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), 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), Sciences, EDP, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and 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)

Subjects
0303 health sciences, business.industry, [SDV]Life Sciences [q-bio], NK cell activation, General Medicine, 030230 surgery, General Biochemistry, Genetics and Molecular Biology, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Text mining, Transplanted Organs, Immunology, Medicine, Missing self, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2020
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3. IMPact of the COVID-19 epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT)

Author

Olivier Thaunat, Camille Legeai, Dany Anglicheau, Lionel Couzi, Gilles Blancho, Marc Hazzan, Myriam Pastural, Emilie Savoye, Florian Bayer, Emmanuel Morelon, Yann Le Meur, Olivier Bastien, Sophie Caillard, Charlene Levi, Fanny Buron, Alice Koenig, Thomas Barba, Bruno Moulin, Samira Fafi-Kremer, Anglicheau Dany, Alexandre Hertig, Jérôme Tourret, Benoit Barrou, Pierre Merville, Anna Kaminski, Valérie Moal, Tristan Legris, Pierre-François Westeel, Maïté Jaureguy, Luc Frimat, Didier Ducloux, Jamal Bamoulid, Dominique Bertrand, Michel Tsimaratos, Florentine Garaix-Gilardo, Jérôme Dumortier, Sacha Mussot, Antoine Roux, Laurent Sebbag, Yannick Le Meur, Christophe Masset, Nassim Kamar, Hélène Francois, Eric Rondeau, Nicolas Bouvier, Christiane Mousson, Matthias Buchler, Philippe Gatault, Jean-François Augusto, Agnès Duveau, Cécile Vigneau, Marie-Christine Morin, Jonathan Chemouny, Leonard Golbin, Philippe Grimbert, Marie Matignon, Antoine Durrbach, Clarisse Greze, Renaud Snanoudj, Charlotte Colosio, Betoul Schvartz, Paolo Malvezzi, Christophe Mariat, Antoine Thierry, Moglie Le Quintrec, Antoine Sicard, Jean Philippe Rerolle, Anne-Élisabeth Heng, Cyril Garrouste, Henri Vacher Coponat, Éric Epailly, Olivier Brugiere, Sébastien Dharancy, Éphrem Salame, Faouzi Saliba, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Cellules B normales et pathogéniques - Normal and pathogenic B cell responses (NOPAB), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Agence de la biomédecine [Saint-Denis la Plaine], 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), Service de Néphrologie-transplantation-dialyse [Bordeaux], 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), 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), CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), CHU Lille, French nationwide Registry of Solid Organ Transplant Recipients with COVID-19: Olivier Thaunat, Emmanuel Morelon, Charlene Levi, Fanny Buron, Alice Koenig, Thomas Barba, Sophie Caillard, Bruno Moulin, Samira Fafi-Kremer, Marc Hazzan, Anglicheau Dany, Alexandre Hertig, Jérôme Tourret, Benoit Barrou, Lionel Couzi, Pierre Merville, Anna Kaminski, Valérie Moal, Tristan Legris, Pierre-François Westeel, Maïté Jaureguy, Luc Frimat, Didier Ducloux, Jamal Bamoulid, Dominique Bertrand, Michel Tsimaratos, Florentine Garaix-Gilardo, Jérôme Dumortier, Sacha Mussot, Antoine Roux, Laurent Sebbag, Yannick Le Meur, Gilles Blancho, Christophe Masset, Nassim Kamar, Hélène Francois, Eric Rondeau, Nicolas Bouvier, Christiane Mousson, Matthias Buchler, Philippe Gatault, Jean-François Augusto, Agnès Duveau, Cécile Vigneau, Marie-Christine Morin, Jonathan Chemouny, Leonard Golbin, Philippe Grimbert, Marie Matignon, Antoine Durrbach, Clarisse Greze, Renaud Snanoudj, Charlotte Colosio, Betoul Schvartz, Paolo Malvezzi, Christophe Mariat, Antoine Thierry, Moglie Le Quintrec, Antoine Sicard, Jean Philippe Rerolle, Anne-Élisabeth Heng, Cyril Garrouste, Henri Vacher Coponat, Éric Epailly, Olivier Brugiere, Sébastien Dharancy, Éphrem Salame, Faouzi Saliba, CCSD, Accord Elsevier, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Pediatrics, MESH: Registries, Registry study, 030232 urology & nephrology, Kidney transplant, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Kidney Transplantation, Postoperative Complications, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Postoperative Complications, Pandemic, MESH: COVID-19, Registries, Wasting, Kidney transplantation, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, Middle Aged, renal transplantation, 3. Good health, MESH: Waiting Lists, Nephrology, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Waiting Lists, Coronavirus disease 2019 (COVID-19), 03 medical and health sciences, Intensive care, medicine, Humans, ESRD, Epidemics, MESH: Epidemics, Aged, Retrospective Studies, MESH: Humans, business.industry, SARS-CoV-2, COVID-19, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, medicine.disease, Kidney Transplantation, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, mortality, MESH: Male, MESH: France, 030104 developmental biology, business, MESH: Female
Abstract

International audience; End stage kidney disease increase the risk of COVID-19 related death but how the kidney replacement strategy should be adapted during the pandemic is unknown. Chronic hemodialysis makes social distancing difficult to achieve. Alternatively, kidney transplantation could increase the severity of COVID-19 due to therapeutic immunosuppression and contribute to saturation of intensive care units. For these reasons, kidney transplantation was suspended in France during the first epidemic wave. Here, we retrospectively evaluated this strategy by comparing the overall and COVID-19 related mortality in kidney transplant recipients and candidates over the last three years. Cross-interrogation of two national registries for the period 1 March and 1 June 2020, identified 275 deaths among the 42812 kidney transplant recipients and 144 deaths among the 16210 candidates. This represents an excess of deaths for both populations, as compared with the same period the two previous years (mean of two previous years: 253 in recipients and 112 in candidates). This difference was integrally explained by COVID-19, which accounted for 44% (122) and 42% (60) of the deaths in recipients and candidates, respectively. Taking into account the size of the two populations and the geographical heterogeneity of virus circulation, we found that the excess of risk of death due to COVID-19 was similar for recipients and candidates in high viral risk area but four-fold higher for candidates in the low viral risk area. Thus, in case of a second epidemic wave, kidney transplantation should be suspended in high viral risk areas but maintained outside those areas, both to reduce the excess of deaths of candidates and avoid wasting precious resources.

Published
2020
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4. Missing Self–Induced Microvascular Rejection of Kidney Allografts: A Population-Based Study

Author

Aleksandar Senev, Olivier Thaunat, Evelyne Lerut, Marie-Paule Emonds, Ben Sprangers, Maarten Naesens, Jasper Callemeyn, Dirk Kuypers, Maarten Coemans, and Alice Koenig

Subjects
Oncology, Graft Rejection, Male, 030232 urology & nephrology, 030230 surgery, HLA-A3 Antigen, missing self, HLA-A11 Antigen, 0302 clinical medicine, Receptors, KIR, HLA Antigens, Kidney transplantation, education.field_of_study, Kidney, natural killer cells, biology, Histocompatibility Testing, Hazard ratio, Graft Survival, General Medicine, Middle Aged, Tissue Donors, Killer Cells, Natural, medicine.anatomical_structure, Nephrology, Receptors, KIR2DL3, Receptors, KIR2DL2, antibody-mediated rejection, Female, Antibody, Adult, Vasculitis, medicine.medical_specialty, Genotype, Population, kidney transplantation, Human leukocyte antigen, HLA-C Antigens, Antibodies, 03 medical and health sciences, Clinical Research, Internal medicine, medicine, Humans, education, Aged, business.industry, Transplant glomerulopathy, microvascular inflammation, medicine.disease, Kidney Transplantation, Confidence interval, Transplant Recipients, HLA-B Antigens, Microvessels, biology.protein, business
Abstract

BACKGROUND: Circulating anti-HLA donor-specific antibodies (HLA-DSA) are often absent in kidney transplant recipients with microvascular inflammation (MVI). Missing self, the inability of donor endothelial cells to provide HLA I-mediated signals to inhibitory killer cell Ig-like receptors (KIRs) on recipient natural killer cells, can cause endothelial damage in vitro, and has been associated with HLA-DSA-negative MVI. However, missing self's clinical importance as a nonhumoral trigger of allograft rejection remains unclear. METHODS: In a population-based study of 924 consecutive kidney transplantations between March 2004 and February 2013, we performed high-resolution donor and recipient HLA typing and recipient KIR genotyping. Missing self was defined as the absence of A3/A11, Bw4, C1, or C2 donor genotype, with the presence of the corresponding educated recipient inhibitory KIR gene. RESULTS: We identified missing self in 399 of 924 transplantations. Co-occurrence of missing self types had an additive effect in increasing MVI risk, with a threshold at two concurrent types (hazard ratio [HR], 1.78; 95% confidence interval [95% CI], 1.26 to 2.53), independent of HLA-DSA (HR, 5.65; 95% CI, 4.01 to 7.96). Missing self and lesions of cellular rejection were not associated. No HLA-DSAs were detectable in 146 of 222 recipients with MVI; 28 of the 146 had at least two missing self types. Missing self associated with transplant glomerulopathy after MVI (HR, 2.51; 95% CI, 1.12 to 5.62), although allograft survival was better than with HLA-DSA-associated MVI. CONCLUSION: Missing self specifically and cumulatively increases MVI risk after kidney transplantation, independent of HLA-DSA. Systematic evaluation of missing self improves understanding of HLA-DSA-negative MVI and might be relevant for improved diagnostic classification and patient risk stratification. ispartof: pages:8-8 ispartof: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY vol:32 issue:8 pages:2070-2082 ispartof: location:United States status: published

Published
2021

5. Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection

Author

Valérie Dubois, Sarah Hamada, Olivier Thaunat, and Alice Koenig

Subjects
Antibody-dependent cell-mediated cytotoxicity, Graft Rejection, medicine.medical_specialty, Innate immune system, biology, business.industry, Immunology, Endothelial Cells, Human leukocyte antigen, medicine.disease, Acquired immune system, Allografts, Organ transplantation, Transplant rejection, Killer Cells, Natural, Genetics, medicine, biology.protein, Immunology and Allergy, Humans, Antibody, Allorecognition, business, Alleles
Abstract

The current transplant immunology dogma defends that allograft rejection is initiated by recipient's adaptive immune system. In this prevalent model, innate immune cells in general, and NK cells in particular, are merely considered as downstream effectors which participate in the destruction of the graft only upon recruitment by adaptive effectors: alloreactive T cells or donor-specific antibodies (DSA). Challenging this vision, recent data demonstrated that recipients' NK cells are capable of a form of allorecognition because they can sense the absence of self HLA class I molecules on the surface of graft endothelial cells. Missing-self triggers mTORC1-dependent activation of NK cells, which in turn promote the development of graft microvascular inflammation and detrimentally impact graft survival. The fact that some patients develop chronic vascular rejection in absence of DSA or genetically-predicted missing self suggest that other molecular mechanisms could underly NK cell allorecognition. This review provides an overview of these proven and putative molecular mechanisms and discusses future research directions in this emerging field in organ transplant immunology. This article is protected by copyright. All rights reserved.

Published
2021

6. Improved cell signaling analysis by biofunctionalized nanospheres and imaging flow cytometry

Author

Sébastien Dussurgey, Thomas Barba, Xavier Charmetant, Antoine Sicard, Maxime Espi, Olivier Thaunat, and Alice Koenig

Subjects
0301 basic medicine, Imaging flow cytometry, Cell signaling, Histology, medicine.diagnostic_test, Chemistry, Cell Biology, Bcr signaling, Flow Cytometry, Pathology and Forensic Medicine, Flow cytometry, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immune system, Western blot, Antigen, 030220 oncology & carcinogenesis, medicine, Signal transduction, Phosphorylation, Nanospheres, Signal Transduction
Abstract

The analysis of immune cell signaling is critical for the understanding of the biology and pathology of the immune system, and thus a mandatory step for the development of efficient biomarkers and targeted therapies. Phosflow, which has progressively replaced the traditional western blot approach, relies on flow cytometry to analyze various signaling pathways at a single-cell level. This technique however suffers a lack of sensitivity largely due to the low signal/noise ratio that characterizes cell signaling analysis. In this study, we describe a new technique, which combines the use of biofunctionalized nanospheres (i.e., synthetic particulate antigens, SPAg) to stimulate the immune cells in suspension and imaging flow cytometry to identify homogenously-stimulated cells and quantify the activity of the chosen signaling pathway in selected subcellular regions of interest. Using BCR signaling as model, we demonstrate that SIBERIAN (SPAg-assIsted suB-cEllulaR sIgnaling ANalysis) allows assessing immune cell signaling with unprecedented sensitivity and specificity.

Published
2021

7. Missing Self-Induced Activation of NK Cells Combines with Non-Complement-Fixing Donor-Specific Antibodies to Accelerate Kidney Transplant Loss in Chronic Antibody-Mediated Rejection

Author

Emmanuel Morelon, Jean-Christophe Olivo-Marin, Béatrice Charreau, Jasper Callemeyn, Virginie Mathias, Sarah Mezaache, Thomas Barba, Antoine Sicard, Olivier Thaunat, Vannary Meas-Yedid, Valérie Dubois, Maud Rabeyrin, Alice Koenig, Cécile Picard, Maarten Naesens, Frédérique Dijoud, 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), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Laboratoire HLA, EFS, 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), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Agence Nationale de la Recherche (ANR-16-CE17-0007-01) and the Fondation pour la Recherche Médicale (PME20180639518)., ANR-16-CE17-0007,PETTAR,Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe(2016), 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), Meas-Yedid, Vannary, and Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe - - PETTAR2016 - ANR-16-CE17-0007 - AAPG2016 - VALID

Subjects
Graft Rejection, Male, Cell Culture Techniques, NK cells, missing self, Kidney transplant, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Medicine, Complement Activation, Kidney, Proteinuria, biology, Graft Survival, General Medicine, Middle Aged, renal transplantation, Allografts, Killer Cells, Natural, medicine.anatomical_structure, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], Complement C3d, Nephrology, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Female, donor specific antibodies, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Missing self, Antibody, medicine.symptom, Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], chronic rejection, Up Front Matters, Humans, Innate immune system, business.industry, Histocompatibility Antigens Class I, Endothelial Cells, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], [INFO.INFO-LG] Computer Science [cs]/Machine Learning [cs.LG], [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Kidney Transplantation, Complement system, Immunology, biology.protein, business
Abstract

BACKGROUND: Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules ("missing self") on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR. METHODS AND RESULTS: Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (n=73, 54%) had a higher risk of transplant failure (P=0.002). Among the remaining patients with complement-independent chronic AMR (n=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (P=0.02). In multivariable analysis, only proteinuria (HR: 7.24; P=0.01) and the presence of missing self (HR: 3.57; P=0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage. CONCLUSIONS: The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure. ispartof: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY vol:32 issue:2 pages:479-494 ispartof: location:United States status: published

Published
2021
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8. Transcriptional changes in kidney allografts with histology of antibody-mediated rejection without anti-HLA donor-specific antibodies

Author

Vannary Meas-Yedid, Leentje Van Lommel, Olivier Thaunat, Wilfried Gwinner, Marie Essig, Henriette de Loor, Evelyne Lerut, Frans Schuit, Jasper Callemeyn, Alice Koenig, Dirk Kuypers, Maarten Naesens, Ben Sprangers, Pierre Marquet, J. Chang, Jean-Christophe Olivo-Marin, Lieven Thorrez, Philip F. Halloran, Dany Anglicheau, I. Arijs, Department of Nephrology and Renal Transplantation, University Hospitals Leuven [Leuven]-Catholic University Leuven, University Hospitals Leuven [Leuven], Université Catholique de Louvain = Catholic University of Louvain (UCL), 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), Analyse d'Images Quantitative, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Analyse d'images biologiques - Biological Image Analysis (BIA), Gene Expression Unit, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hannover Medical School [Hannover] (MHH), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre 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), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Graft Rejection, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Transcription, Genetic, [SDV]Life Sciences [q-bio], Human leukocyte antigen, 030230 surgery, Kidney, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Isoantibodies, Clinical Research, Biopsy, medicine, Humans, Transplantation, Homologous, Kidney transplantation, ComputingMilieux_MISCELLANEOUS, Aged, biology, medicine.diagnostic_test, business.industry, Graft Survival, Hazard ratio, Histology, General Medicine, Middle Aged, medicine.disease, Kidney Transplantation, Tissue Donors, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Nephrology, Concomitant, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, business
Abstract

Background Circulating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype. Methods In this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status. Results Of 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFNγ-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA-positive and HLA-DSA-negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell-mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences. Conclusions ABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.

Published
2020
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9. Highly Variable Sialylation Status of Donor-Specific Antibodies Does Not Impact Humoral Rejection Outcomes

Author

Thomas Barba, Jean Harb, Stéphanie Ducreux, Alice Koenig, Virginie Mathias, Maud Rabeyrin, Eric Pouliquen, Antoine Sicard, Dimitri Chartoire, Emilie Dugast, Thierry Defrance, Emmanuel Morelon, Sophie Brouard, Valérie Dubois, Olivier Thaunat, 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), Laboratoire de Biochimie, Université de Nantes (UN), Immunoregulation And Immunointervention in Transplantation and Autoimmunity (Team 4 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Service de transplantation, néphrologie et immunologie clinique, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de pathologie, Hospices Civils de Lyon (HCL), HCL, INSERM, Subvention Transplantation et Thérapie cellulaire 2018 FRM, the Fondation CENTAURE, Etablissement Français du Sang and the Société Francophone d’Histocompatibilité et d’Immunogénétique., ANR-16-CE17-0007,PETTAR,Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe(2016), Le Bihan, Sylvie, Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe - - PETTAR2016 - ANR-16-CE17-0007 - AAPG2016 - VALID, 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), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Graft Rejection, Male, lcsh:Immunologic diseases. Allergy, 0301 basic medicine, glycosylation, medicine.drug_class, Immunology, Monoclonal antibody, DSA, sialylation, 03 medical and health sciences, 0302 clinical medicine, Agglutinin, Isoantibodies, Biopsy, medicine, Humans, Immunology and Allergy, Receptor, Complement Activation, solid organ transplantation, Original Research, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, business.industry, Donor specific antibodies, Middle Aged, N-Acetylneuraminic Acid, Tissue Donors, In vitro, Immunoglobulin Fc Fragments, Complement system, Killer Cells, Natural, carbohydrates (lipids), body regions, Log-rank test, 030104 developmental biology, Immunoglobulin G, antibody-mediated rejection, Female, lcsh:RC581-607, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

International audience; Clinical outcome in antibody-mediated rejection (AMR) shows high inter-individual heterogeneity. Sialylation status of the Fc fragment of IgGs is variable, which could modulate their ability to bind to C1q and/or Fc receptors. In this translational study, we evaluated whether DSA sialylation influence AMR outcomes. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of DSA by Luminex. The sialylation status of total IgG and DSA was quantified using Sambucus nigra agglutinin-based chromatography. All patients had similar levels of sialylation of serum IgGs (∼2%). In contrast, the proportion of sialylated DSA were highly variable (median = 9%; range = 0-100%), allowing to distribute the patients in two groups: high DSA sialylation (n = 44; 64%) and low DSA sialylation (n = 25; 36%). The two groups differed neither on the intensity of rejection lesions (C4d, ptc, and g; p > 0.05) nor on graft survival rates (Log rank test, p = 0.99). in vitro models confirmed the lack of impact of Fc sialylation on the ability of a monoclonal antibody to trigger classical complement cascade and activate NK cells. We conclude that DSA sialylation status is highly variable but has not impact on DSA pathogenicity and AMR outcome.

Published
2019
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10. Residual Activatability of Circulating Tfh17 Predicts Humoral Response to Thymodependent Antigens in Patients on Therapeutic Immunosuppression

Author

Suzan Dahdal, Carole Saison, Martine Valette, Emmanuel Bachy, Nicolas Pallet, Bruno Lina, Alice Koenig, Guillaume Monneret, Thierry Defrance, Emmanuel Morelon, and Olivier Thaunat

Subjects
Adult, Male, lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Influenza vaccine, T cell, medicine.medical_treatment, Immunology, Hemagglutinin Glycoproteins, Influenza Virus, Tfh, Lymphocyte Activation, donor-specific antibodies, 03 medical and health sciences, 0302 clinical medicine, Antigen, medicine, Humans, Immunology and Allergy, IL-2 receptor, Antigens, Aged, Original Research, Immunosuppression Therapy, immunosuppression, CD40, biology, business.industry, biomarkers, Immunosuppression, Middle Aged, Kidney Transplantation, Immunity, Humoral, Transplantation, 030104 developmental biology, medicine.anatomical_structure, ROC Curve, Antibody Formation, biology.protein, Th17 Cells, Female, Antibody, lcsh:RC581-607, business, transplantation, 030215 immunology
Abstract

The generation of antibodies against protein antigens (such as donor-specific HLA molecules) requires that T follicular helper cells (Tfh) provide help to B cells. Immunosuppressive (IS) armamentarium prevents T cell activation, yet a significant proportion of renal transplant patients develop donor-specific antibodies (DSA), which suggests that IS drugs do not efficiently block T follicular helper cells. To test this hypothesis, the number of circulating Tfh, their polarization profile, and ability to up-regulate (i) the co-stimulatory molecules CD40L and ICOS, and (ii) the activation marker CD25, following in vitro stimulation in presence of IS drugs, were compared between 36 renal transplant patients (6–72 months post transplantation) and nine healthy controls. IS drugs reduced the number of Tfh1 and 2 but had little impact on Tfh17, which was the dominant subset in transplant patients. Although, IS drugs decreased activation-induced expression of co-stimulatory molecules by Tfh, the impact was highly variable between individuals. Furthermore, 20% of transplant patients displayed normal expression of CD25 on Tfh following in vitro stimulation (i.e., “residual activatability”). To test whether residual activatability of Tfh correlates with antibody response against thymo-dependent antigens we took advantage of the 2015 influenza vaccination campaign, which provided a normalized setting for antigenic stimulation. In line with our hypothesis, responders to influenza vaccine exhibited significantly higher percentage of CD25-expressing Tfh17 after in vitro stimulation. A results that was confirmed retrospectively in nine transplanted patients at the time of first DSA detection. We concluded that “residual activatability” of Tfh17 might be used as a non-invasive biomarker to identify transplant patients at higher risk to develop DSA under immunosuppression. If validated in larger studies, this assay might help optimizing the prevention of DSA through personalized adaptation of immunosuppressive regimen.

Published
2019
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11. Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants

Author

Vannary Meas-Yedid, Sébastien Dussurgey, Thomas Barba, Emmanuel Morelon, Maud Rabeyrin, Romain Guillemain, Maud Racapé, Jean-Paul Duong-Van-Huyen, Valérie Dubois, Chien-Chia Chen, Antoine Marçais, Stéphanie Ducreux, Jean-Christophe Olivo-Marin, Maarten Naesens, Jean-Luc Taupin, Antoine Sicard, Antonino Nicoletti, Olivier Thaunat, Patrick Bruneval, Béatrice Charreau, Helena Paidassi, Alice Koenig, Virginie Mathias, Alexandre Loupy, Thierry Walzer, Thierry Defrance, Jasper Callemeyn, Paidassi, Helena, Instituts Hospitalo-Universitaires B - Organ ProtEction and ReplAcement - - OPeRa2010 - ANR-10-IBHU-0004 - IBHU - VALID, Phenotypage pour le cancer - - PHENOCAN2011 - ANR-11-EQPX-0035 - EQPX - VALID, Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe - - PETTAR2016 - ANR-16-CE17-0007 - AAPG2016 - VALID, Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, 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), 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), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Laboratoire HLA [EFS - Auvergne-Rhônes-Alpes], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Departement de Pathologie [Hospices civils de Lyon], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), SFR Biosciences, Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'immunologie, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), O.T. is supported by the Agence nationale pour la Recherche (ANR-16-CE17-0007-01), the Fondation pour la Recherche médicale (PME20180639518), and the Etablissement français du Sang. C.-C.C., E.M. and O.T. are supported by the Institut Hospitalo-Universitaire–Organ Protection and Replacement (IHU-OPeRa, ANR-10-IBHU-004). A.K. is supported by INSERM (poste accueil 2015/1239/BT), the Hospices Civils de Lyon and the Fondation du Rein. SFR Biosciences is supported by the Agence nationale pour la Recherche (ANR -11-EQPX-0035 PHENOCAN). E.M. and O.T. are members of the CENTAURE Transplantation Research Network., We thank Christelle Forcet and Violaine Tribollet for help with Xcelligence experiments, and Marie-Claude Gagnieu and Laurent Genestier for fruitful scientific discussions. The authors thank Mathilde Koenig for her contribution to the design of the figure., ANR-10-IBHU-0004,OPeRa,Organ ProtEction and ReplAcement(2010), ANR-11-EQPX-0035,PHENOCAN,Phenotypage pour le cancer(2011), ANR-16-CE17-0007,PETTAR,Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe(2016), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), 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), and 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)

Subjects
Graft Rejection, 0301 basic medicine, Cell, Translational immunology, General Physics and Astronomy, Inflammatory diseases, 030230 surgery, 0302 clinical medicine, Receptors, KIR, lcsh:Science, Receptor, Cells, Cultured, Mice, Knockout, Multidisciplinary, medicine.diagnostic_test, biology, Tissue Donors, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, Human leukocyte antigen, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Biopsy, Homologous chromosome, medicine, Animals, Humans, Transplantation, Homologous, Inflammation, business.industry, Endothelial Cells, General Chemistry, Innate immune cells, Mice, Inbred C57BL, Transplantation, 030104 developmental biology, Microvessels, Immunology, biology.protein, Heart Transplantation, lcsh:Q, K562 Cells, beta 2-Microglobulin, business, K562 cells
Abstract

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection., ‘Missing self’ is a mode of natural killer (NK) cell activation aimed to detect the lack of HLA-I molecules on infected or neoplastic cells. Here, the authors show that mismatch between donor HLA-I and cognate receptors on recipient NK cells mediates microvascular inflammation-associated graft rejection, a pathology that is preventable by mTOR inhibition.

Published
2019
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12. CD4+ T Cell Help Is Mandatory for Naive and Memory Donor-Specific Antibody Responses: Impact of Therapeutic Immunosuppression

Author

Chien-Chia Chen, Alice Koenig, Carole Saison, Suzan Dahdal, Guillaume Rigault, Thomas Barba, Morgan Taillardet, Dimitri Chartoire, Michel Ovize, Emmanuel Morelon, Thierry Defrance, Olivier Thaunat, 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), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), CarMeN, laboratoire, 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), and 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)

Subjects
CD4-Positive T-Lymphocytes, Graft Rejection, 0301 basic medicine, Isoantigens, kidney-transplant recipients, [SDV]Life Sciences [q-bio], medicine.medical_treatment, T-Lymphocyte Subsets, Immunology and Allergy, IL-2 receptor, b-cells, Cells, Cultured, t-cells, Original Research, Mice, Knockout, Mice, Inbred BALB C, mediated rejection, immunosuppression, biology, Graft Survival, Immunosuppression, Skin Transplantation, donor-specific antibody, failure, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, antibody-mediated rejection, Cytokines, Antibody, lcsh:Immunologic diseases. Allergy, mice, allograft-rejection, proliferation, T cell, Immunology, Mice, Transgenic, 03 medical and health sciences, antigen, Immune system, HLA-A2 Antigen, transplant immunology, alloantibody, medicine, Animals, Humans, Antilymphocyte Serum, Immunosuppression Therapy, CD40, business.industry, Histocompatibility Antigens Class II, alloimmune response, Kidney Transplantation, Mice, Inbred C57BL, Transplantation, 030104 developmental biology, Antibody Formation, biology.protein, lcsh:RC581-607, business, Immunologic Memory, CD8, transplantation
Abstract

Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients' spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+ CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal.

Published
2018
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13. Computer-assisted topological analysis of renal allograft inflammation adds to risk evaluation at diagnosis of humoral rejection

Author

Vannary Meas-Yedid, Antoine Sicard, Maud Rabeyrin, Lionel Badet, Frédérique Dijoud, Valérie Dubois, Valérie Hervieu, Emmanuel Morelon, Alice Koenig, Stéphanie Ducreux, Jean-Christophe Olivo-Marin, Olivier Thaunat, 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 - 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), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Département d'anatomopathologie [Hôpital Femme Mère Enfant - HCL], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Etablissement français du sang- Rhône-Alpes [Lyon], Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Service d'Urologie et Chirurgie de la Transplantation, Hôpital Edouard Herriot [CHU - HCL], 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), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Graft Rejection, Male, Pathology, Time Factors, Biopsy, 030232 urology & nephrology, Kaplan-Meier Estimate, 030230 surgery, Kidney, donor-specific antibodies, 0302 clinical medicine, Computer-Assisted, Glomerulonephritis, Isoantibodies, Diagnosis, Macrophage, Diagnosis, Computer-Assisted, Kidney transplantation, medicine.diagnostic_test, biology, Graft Survival, Humoral, Middle Aged, Allografts, Prognosis, Immunohistochemistry, 3. Good health, macrophages, medicine.anatomical_structure, Treatment Outcome, Nephrology, Complement C3d, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, antibody-mediated rejection, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Antibody, Algorithms, Adult, medicine.medical_specialty, complement-binding DSA, Inflammation, allograft pathology, 03 medical and health sciences, Young Adult, Immune system, Predictive Value of Tests, Image Interpretation, Computer-Assisted, medicine, Humans, Image Interpretation, business.industry, Immunity, inflammation quantification, medicine.disease, Kidney Transplantation, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immunity, Humoral, Immunology, biology.protein, business, Biomarkers
Abstract

International audience; Antibody-mediated rejection is associated with heterogeneous kidney allograft outcomes. Accurate evaluation of risk for graft loss at time of diagnosis is necessary to offer personalized treatment. In contrast with serological and molecular assessment, morpho-histological evaluation of antibody-mediated rejection lesions has not significantly evolved. This relies on Banff classifications designed to be of diagnostic discriminatory power rather than prognostic and face quantitative and qualitative limitations. Here we developed a method of Computer-assisted Analysis of Graft Inflammation (CAGI) to improve the classification of allograft inflammation. Digitization of immunostained biopsy sections, image processing and algorithm-driven analysis allowed quantification of macrophages, T cells, B cells, and granulocytes per unit surface of interstitium, capillaries or glomeruli. CAGI was performed on biopsy specimens of 52 patients with extensively phenotyped antibody-mediated rejection. Macrophage numbers in capillaries and interstitium, but not Banff scores or the amount of other immune cell subsets, correlated with donor-specific antibody (DSA) mean fluorescence intensity and DSA-C3d status. The quantity of macrophages in the interstitium and DSA-C3d status were the only independent predictors for significant allograft loss at the time of antibody-mediated rejection diagnosis (hazard ratio 3.71 and 2.34, respectively). A significant strategy integrating the DSA-C3d assay and the quantification of interstitial macrophages allowed identification of three groups with distinct renal prognosis: DSA-C3d-, DSA-C3d+/macrophages-low and DSAC3d+/macrophages-high. Thus, CAGI brings a missing piece to the antibody-mediated rejection puzzle by identifying morpho-histological processes that bridge in~vitro parameters of DSA pathogenicity and graft loss. Hence, this approach could be useful in future integrated strategies of risk evaluation.

Published
2017
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14. Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Author

Philippe Grimbert, Alice Koenig, Claire Leibler, and Olivier Thaunat

Subjects
0301 basic medicine, Isoantigens, Allosensitization, medicine.medical_treatment, Calcineurin Inhibitors, 030230 surgery, Kidney transplant, Abatacept, 03 medical and health sciences, 0302 clinical medicine, Adrenal Cortex Hormones, Risk Factors, Transplantation Immunology, Up Front Matters, medicine, Humans, Kidney transplantation, B-Lymphocytes, biology, business.industry, TOR Serine-Threonine Kinases, Immunosuppression, General Medicine, medicine.disease, Kidney Transplantation, Tissue Donors, Immunity, Humoral, Therapeutic immunosuppression, Calcineurin, 030104 developmental biology, Nephrology, Immunology, biology.protein, Antibody, business, Immunosuppressive Agents, medicine.drug
Abstract

The negative effect of donor-specific antibodies on the success of solid transplant is now clearly established. However, the lack of effective treatment to prevent the development of antibody-mediated lesions deepens the need for clinicians to focus on primary prevention of de novo humoral allosensitization. Among the factors associated with the risk of developing de novo donor-specific antibodies, therapeutic immunosuppression is the most obvious parameter in which improvement is possible. Beyond compliance and the overall depth of immunosuppression, it is likely that the nature of the drugs is also crucial. Here, we provide an overview of the molecular effect of the various immunosuppressive drugs on B cell biology. Clinical data related to the effect of these drugs on de novo humoral allosensitization are also examined, providing a platform from which clinicians can optimize immunosuppression for prevention of de novo donor-specific antibody generation at the individual level.

Published
2016

15. B Cells and Antibodies in Transplantation

Author

Gérard Rifle, Christophe Mariat, Olivier Thaunat, Christiane Mousson, Alice Koenig, and Kathryn J. Wood

Subjects
0301 basic medicine, Graft Rejection, Graft loss, Antibodies, 03 medical and health sciences, 0302 clinical medicine, Immune Tolerance, Medicine, Humans, Transplantation, Homologous, Immunosuppression Therapy, B-Lymphocytes, Transplantation, biology, business.industry, Graft Survival, Congresses as Topic, Immunity, Humoral, surgical procedures, operative, 030104 developmental biology, Immunoglobulin G, Immunology, biology.protein, France, Antibody, business, Immunosuppressive Agents, 030215 immunology
Abstract

Overlooked for decades, the humoral alloimmune response is increasingly recognized as a leading cause of graft loss after transplantation. However, improvement in the diagnosis of antibody-mediated rejection has not yet translated into better outcomes for transplanted patients. After an update on B cell physiology and antibody generation, the 2015 Beaune Seminar in Transplant Research challenged the conventional view of antibody-mediated rejection pathophysiology and discussed the latest promising therapeutic approaches.

Published
2016

16. B Cells Loaded with Synthetic Particulate Antigens: A Versatile Platform To Generate Antigen-Specific Helper T Cells for Cell Therapy

Author

Elisabeth Errazuriz-Cerda, Emmanuel Morelon, Angeline Rouers, Valérie Dubois, Olivier Thaunat, Thierry Defrance, Dimitri Chartoire, Stéphanie Graff-Dubois, Pascal Blanc, Morgan Taillardet, Sébastien Dussurgey, Antoine Sicard, Helena Paidassi, Arnaud Moris, Alice Koenig, 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), 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), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), SFR Biosciences, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Etablissement français du sang- Rhône-Alpes [Lyon], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Endosome, Helper-Inducer, T-Lymphocytes, Adoptive, bioengineered nanoparticle, Cell- and Tissue-Based Therapy, Bioengineering, Nanotechnology, Lymphocyte Activation, Immunotherapy, Adoptive, antigen-presenting cell, Cell therapy, 03 medical and health sciences, CD4+ T cell, Antigen, medicine, Humans, General Materials Science, Antigen-presenting cell, Gene, B cell, Vaccines, Synthetic, B-Lymphocytes, Vaccines, Effector, Chemistry, Mechanical Engineering, Synthetic, General Chemistry, T-Lymphocytes, Helper-Inducer, biomimetic, Condensed Matter Physics, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Polyclonal B cell response, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Nanoparticles, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, cell therapy
Abstract

International audience; Adoptive cell therapy represents a promising approach for several chronic diseases. This study describes an innovative strategy for biofunctionalization of nanoparticles, allowing the generation of synthetic particulate antigens (SPAg). SPAg activate polyclonal B cells and vectorize noncognate proteins into their endosomes, generating highly efficient stimulators for ex vivo expansion of antigen-specific CD4+ T cells. This method also allows harnessing the ability of B cells to polarize CD4+ T cells into effectors or regulators.

Published
2016
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17. Missing-Self Triggers NK-Mediated Microvascular Injuries and Chronic Rejection of Allogenic Kidney Transplants

Author

Antoine Sicard, Thierry Walzer, Jean Paul Duong, Chien-Chia Chen, Béatrice Charreau, Maud Rabeyrin, Valérie Dubois, Thierry Defrance, Maud Racapé, Antoine Marçais, Stéphanie Ducreux, Sébastien Dussurgey, Virginie Mathias, Olivier Thaunat, Alice Koenig, Patrick Bruneval, and Emmanuel Morelon

Subjects
Transplantation, Kidney, medicine.anatomical_structure, business.industry, Immunology, Medicine, Missing self, business
Published
2018
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18. Recent advances in renal transplantation: antibody-mediated rejection takes center stage

Author

Valérie Dubois, Maud Rabeyrin, Olivier Thaunat, Eric Pouliquen, Alice Koenig, Antoine Sicard, Emmanuel Morelon, and Chien-Chia Chen

Subjects
Transplantation, Allograft failure, business.industry, Antibody mediated rejection, Medicine, Review Article, General Medicine, Stage (cooking), business, Bioinformatics
Abstract

Overlooked for decades, antibodies have taken center stage in renal transplantation and are now widely recognized as the first cause of allograft failure. Diagnosis of antibody-mediated rejection has considerably improved with identification of antibody-mediated lesions in graft biopsies and advances made in the detection of circulating donor-specific antibodies. Unfortunately, this progress has not yet translated into better outcomes for patients. Indeed, in the absence of a drug able to suppress antibody generation by plasma cells, available therapies can only slow down graft destruction. This review provides an overview of the current knowledge of antibody-mediated rejection and discusses future interesting research directions.

Published
2015
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19. SaO032COMPUTER-ASSISTED INFLAMMATION ANALYSIS (CIA) OF KIDNEY-GRAFT BIOPSY:THE POLYGRAPH OF ANTIBODY-MEDIATED REJECTION

Author

Vannary Meas-Yedid, Maud Rabeyrin, Jean-Yves Scoazec, Jean-Christophe Olivo-Marin, Olivier Thaunat, Valérie Dubois, Alice Koenig, Frédérique Dijoud, Stéphanie Ducreux, Emmanuel Morelon, Antoine Sicard, and Lionel Badet

Subjects
Transplantation, Pathology, medicine.medical_specialty, Kidney, medicine.diagnostic_test, business.industry, Inflammation, Polygraph, medicine.anatomical_structure, Nephrology, Biopsy, Antibody mediated rejection, medicine, medicine.symptom, business
Published
2015
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20. Cohort study: 'Outcomes of kidney transplantation in patients with prosthetic heart valves'

Author

Ouahmi, Hajar, Moceri, Pamela, Zorzi, Kevin, Albano, Laetitia, Durand, Matthieu, Karimi, Fatimaezzahra, Morelon, Emmanuel, Buron, Fanny, Le Quintrec, Moglie, Pernin, Vincent, Ladriere, Marc, Girerd, Sophie, Dantal, Jacques, Loupy, Alexandre, Couzi, Lionel, Ferrari, Emile, Esnault, Vincent, Merville, Pierre, Legendre, Christophe, Giral, Magali, Sicard, Antoine, Badet, Lionel, Brunet, Maria, Cahen, Rémi, Codas, Ricardo, Daoud, Sameh, Dubois, Valérie, Fournie, Coralie, Grégoire, Arnaud, Koenig, Alice, Lévi, Charlène, Pouteil‐Noble, Claire, Rabeyrin, Maud, Rimmelé, Thomas, Thaunat, Olivier, Abdo, Nicolas, Delmas, Sylvie, Perrochia, Hélène, Serre, Jean‐Emmanuel, Szwarc, Ilan, Aarnink, Alice, Alla, Asma, Eschwege, Pascal, Frimat, Luc, Hubert, Jacques, Kormann, Raphaël, Lagrange, François, Laurain, Emmanuelle, Lecoanet, Pierre, Lemelle, Jean‐Louis, Mannuguerra, Anthony, Mazeaud, Charles, Peres, Michael, Blancho, Gilles, Branchereau, Julien, Cantarovich, Diego, Chapelet, Agnès, Deltombe, Clément, Figueres, Lucile, Garandeau, Claire, Gourraud‐Vercel, Caroline, Hourmant, Maryvonne, Karam, Georges, Kerleau, Clarisse, Meurette, Aurélie, Ville, Simon, Kandell, Christine, Moreau, Anne, Renaudin, Karine, Cesbron, Anne, Delbos, Florent, Walencik, Alexandre, Devis, Anne, Chevallier, Daniel, Tibi, Brannwel, Ahallal, Younes, Amrouche, Lucile, Anglicheau, Dany, Aubert, Olivier, Bererhi, Lynda, Martinez, Frank, Sberro‐Soussan, Rébecca, Scemla, Anne, Tinel, Claire, Zuber, Julien, Glotz, Denis, Lefaucheur, Carmen, Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Réseau CENTAURE, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), CHU Bordeaux [Bordeaux], Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), DIVAT Consortium: Lionel Badet, Maria Brunet, Fanny Buron, Rémi Cahen, Ricardo Codas, Sameh Daoud, Valérie Dubois, Coralie Fournie, Arnaud Grégoire, Alice Koenig, Charlène Lévi, Emmanuel Morelon, Claire Pouteil-Noble, Maud Rabeyrin, Thomas Rimmelé, Olivier Thaunat, Nicolas Abdo, Sylvie Delmas, Moglie Le Quintrec, Vincent Pernin, Hélène Perrochia, Jean-Emmanuel Serre, Ilan Szwarc, Alice Aarnink, Asma Alla, Pascal Eschwege, Luc Frimat, Sophie Girerd, Jacques Hubert, Raphaël Kormann, Marc Ladriere, François Lagrange, Emmanuelle Laurain, Pierre Lecoanet, Jean-Louis Lemelle, Anthony Mannuguerra, Charles Mazeaud, Michael Peres, Gilles Blancho, Julien Branchereau, Diego Cantarovich, Agnès Chapelet, Jacques Dantal, Clément Deltombe, Lucile Figueres, Claire Garandeau, Magali Giral, Caroline Gourraud-Vercel, Maryvonne Hourmant, Georges Karam, Clarisse Kerleau, Aurélie Meurette, Simon Ville, Christine Kandell, Anne Moreau, Karine Renaudin, Anne Cesbron, Florent Delbos, Alexandre Walencik, Anne Devis, Laetitia Albano, Fatimaezzahra Karimi, Antoine Sicard, Hajar Ouahmi, Daniel Chevallier, Brannwel Tibi, Matthieu Durand, Younes Ahallal, Lucile Amrouche, Dany Anglicheau, Olivier Aubert, Lynda Bererhi, Christophe Legendre, Alexandre Loupy, Frank Martinez, Rébecca Sberro-Soussan, Anne Scemla, Claire Tinel, Julien Zuber, Denis Glotz, Carmen Lefaucheur, and Retiveau, Nolwenn

Subjects
medicine.medical_specialty, medicine.medical_treatment, MESH: Heart Valves, Postoperative Hemorrhage, MESH: Kidney Transplantation, Cohort Studies, Diabetes mellitus, Internal medicine, Biological heart valve, Medicine, Endocarditis, Humans, Prospective Studies, MESH: Cohort Studies, Kidney transplantation, Dialysis, Retrospective Studies, Kidney, Transplantation, MESH: Humans, business.industry, Cardiac valve replacement, End-stage kidney disease, MESH: Postoperative Hemorrhage, MESH: Retrospective Studies, medicine.disease, Heart Valves, Kidney Transplantation, MESH: Prospective Studies, [SDV.TOX] Life Sciences [q-bio]/Toxicology, medicine.anatomical_structure, Prosthetic heart valve, Mechanical heart valve, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Cohort, Cardiology, business, Cohort study
Abstract

Main problem The number of kidney transplant candidates with prosthetic heart valves (PHVs) is increasing. Yet, outcomes of kidney transplantation in these patients are still unclear. This is the first report of post-transplant outcomes in patients with PHVs at time of kidney transplantation. Methods We conducted a matched cohort study among recipients from the multicentric and prospective DIVAT cohort to compare outcomes in patients with left-sided PHVs at time of transplantation and a group of recipients without PHV matched according to age, dialysis time, initial disease, pre-transplant DSA, diabetes and cardiovascular events. Results Of 23018 patients, 92 patients with PHVs were included and compared to 276 patients without PHV. Delayed graft function and post-operative bleeding occurred more frequently in patients with PHVs. Kidney graft survival was similar between groups. 5-year overall survival was 68.5 % in patients with PHV versus 87.9 % in patients without PHV (HR, 2.72[1.57-4.70], p=0.0004). Deaths from infection, endocarditis and bleeding were more frequent in patients with PHV. Mechanical valves, but not bioprosthetic valves, were independent risk factors for mortality (HR, 2.89[1.68-4.97], p=0.0001). Conclusions Patients with PHV have high mortality rates after kidney transplantation. These data suggest that mechanical valves, but not biological valves, increase risks of post-transplant mortality.

Published
2021
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