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12. The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients

Author

Massart, Annick, Pallier, Annaïck, Pascual, Julio, Viklicky, Ondrej, Budde, Klemens, Spasovski, Goce, Klinger, Marian, Sever, Mehmet Sukru, Sørensen, Søren Schwartz, Hadaya, Karine, Oberbauer, Rainer, Dudley, Christopher, De Fijter, Johan W., Yussim, Alexander, Hazzan, Marc, Wekerle, Thomas, Berglund, David, De Biase, Consuelo, Pérez-Sáez, María José, Mühlfeld, Anja, Orlando, Giuseppe, Clemente, Katia, Lai, Quirino, Pisani, Francesco, Kandus, Aljosa, Baas, Marije, Bemelman, Frederike, Ponikvar, Jadranka Buturovic, Mazouz, Hakim, Stratta, Piero, Subra, Jean-François, Villemain, Florence, Hoitsma, Andries, Braun, Laura, Cantarell, Maria Carmen, Colak, Hulya, Courtney, Aisling, Frasca, Giovanni Maria, Howse, Matthew, Naesens, Maarten, Reischig, Tomas, Serón, Daniel, Seyahi, Nurhan, Tugmen, Cem, Alonso Hernandez, Angel, Beňa, Luboslav, Biancone, Luigi, Cuna, Vania, Díaz-Corte, Carmen, Dufay, Alexandre, Gaasbeek, André, Garnier, Arnaud, Gatault, Philippe, Gentil Govantes, Miguel Angel, Glowacki, François, Gross, Oliver, Hurault de Ligny, Bruno, Huynh-Do, Uyen, Janbon, Bénédicte, Jiménez del Cerro, Luis Antonio, Keller, Frieder, La Manna, Gaetano, Lauzurica, Ricardo, Le Monies De Sagazan, Hervé, Thaiss, Friedrich, Legendre, Christophe, Martin, Séverine, Moal, Marie-Christine, Noël, Christian, Pillebout, Evangeline, Piredda, Gian Benedetto, Puga, Ana Ramírez, Sulowicz, Wladyslaw, Tuglular, Serhan, Prokopova, Michaela, Chesneau, Mélanie, Le Moine, Alain, Guérif, Pierrick, Soulillou, Jean-Paul, Abramowicz, Marc, Giral, Magali, Racapé, Judith, Maggiore, Umberto, Brouard, Sophie, and Abramowicz, Daniel

Published
2016
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18. Efficient Expansion of Human Granzyme B–Expressing B Cells with Potent Regulatory Properties

Author

Chesneau, Mélanie, primary, Mai, Hoa Le, additional, Danger, Richard, additional, Le Bot, Sabine, additional, Nguyen, Thi-Van-Ha, additional, Bernard, Josselin, additional, Poullaouec, Cyrielle, additional, Guerrif, Pierrick, additional, Conchon, Sophie, additional, Giral, Magali, additional, Charreau, Béatrice, additional, Degauque, Nicolas, additional, and Brouard, Sophie, additional

Published
2020
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20. Unique and specific Agrobacterium diversity in urinary microbiota of tolerant kidney transplanted recipients

Author

Colas, Luc, Mongodin, Emmanuel, Montassier, Emmanuel, Chesneau, Mélanie, Guérif, Pierrick, Hittle, Lauren, Giral, Magali, Bromberg, Jonathan, Brouard, Sophie, Blancho, Gilles, Branchereau, Julien, Cantarovich, Diego, Cesbron, Anne, Chapelet, Agnès, Dantal, Jacques, Delbos, Florent, Deltombe, Clement, Devis, Anne, Figueres, Lucile, Garandeau, Claire, Gourraud‐Vercel, Caroline, Hourmant, Maryvonne, Kandell, Christine, Karam, Georges, Kerleau, Clarisse, Meurette, Aurelie, Moreau, Anne, Renaudin, Karine, Ville, Simon, Walencik, Alexandre, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes (UN)-Université de Nantes (UN), Institute of Transplantation Urology and Nephrology [CHU Nantes], 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), Immunointervention dans les allo et xénotransplantations, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)-ITUN, Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang [Nantes], Service de Néphrologie et Immunologie Clinique, Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôtel Dieu, Développement du Systeme Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'urologie, Hôtel-Dieu, Institut de Mathématiques de Jussieu (IMJ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), This work was carried out with the support of CENTAURE foundation grants, a Roche Organ Transplantation Research Foundation and European Society for Organ Transplantation grant, and under the auspices of the IHU‐Cesti project, which received French government financial support managed by the National Research Agency via the 'Investment Into The Future' program (ANR‐10‐IBHU‐005). The IHU‐Cesti project is also supported by Nantes Metropole and the Pays de la Loire Region. This work was also supported by the Labex IGO project (ANR‐11‐LABX‐0016‐01) funded by the Investissements d'Avenir French Government program, managed by the French National Research Agency., Le Bihan, Sylvie, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Hôtel Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Adult, Graft Rejection, Male, medicine.medical_specialty, translational research/science, Urinary system, kidney transplantation/nephrology, immunosuppression/immune modulation, 030230 surgery, clinical research/practice, Organ transplantation, 03 medical and health sciences, 0302 clinical medicine, Immune system, Risk Factors, RNA, Ribosomal, 16S, Proteobacteria, Immune Tolerance, medicine, Humans, Immunology and Allergy, Pharmacology (medical), Microbiome, Kidney transplantation, Transplantation, Kidney, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, tolerance, biology, business.industry, Graft Survival, Biodiversity, Middle Aged, Prognosis, medicine.disease, biology.organism_classification, Kidney Transplantation, 3. Good health, Calcineurin, medicine.anatomical_structure, Case-Control Studies, Immunology, Female, business, microbiomics, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

International audience; Host‐microbiota interactions can modulate the immune system both at local and systemic levels, with potential consequences for organ transplantation outcomes. In this study, we hypothesized that differences in the urinary microbiome following kidney transplantation would be associated with posttransplantation status: stable, minimally immunosuppressed, or tolerant. One hundred thirteen urine samples from stable (n = 51), minimally immunosuppressed (n = 19), and spontaneously tolerant (n = 16) patients, paired with age‐matched controls (n = 27) were profiled and compared to each other at a taxonomic level with special interest in the immunosuppressive regimen. All comparisons and correlations were adjusted on sex and time posttransplantation. Our results highlighted a unique and specific urinary microbiota associated with spontaneous tolerance characterized by a high diversity and a clear Proteobacteria profile. Finally, we report that this profile is (1) impacted by gender, (2) inversely correlated with immunosuppressive drugs (calcineurin inhibitors and mammalian target of rapamycin inhibitors), and (3) stable in time.

Published
2019
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21. Regulatory B cell generation from human Induced Pluripotent Stem Cells with a repressible granzyme B expression

Author

Dubois, Florian, Gaignerie, Anne, Flippe, Léa, Heslan, Jean-Marie, Tesson, Laurent, Chesneau, Mélanie, Haspot, Fabienne, Conchon, Sophie, David, Laurent, Brouard, Sophie, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), plate-forme GenoCellEdit (Inserm/ITUN/CHU Nantes-IFR Santé François Bonamy), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Transplantation Urologie-Néphrologie ( ITUN), plate-forme Rat Transgenesis Immunophenomic (Inserm/CHU Nantes-IFR Santé François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), and Le Bihan, Sylvie

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Kidney transplanted patients with long term graft survival harbor a higher frequency of B lymphocytes with regulatory properties. These “regulatory” B lymphocytes prevent effector T cell proliferation through the Granzyme B (GzmB) molecule. Our aim was to generate regulatory B lymphocytes from human Induced Pluripotent Stem (hIPS) cells with a repressible GzmB expression as a tool to better understand their function and ultimately to translate them toward clinical use.

Published
2019

22. CXCR5+PD1+ICOS+ circulating T follicular helpers are associated with de novo donor-specific antibodies after renal transplantation

Author

Danger, Richard, Chesneau, Mélanie, Delbos, Florent, Le Bot, Sabine, Kerleau, Clarisse, Chenouard, Alexis, Ville, Simon, Degauque, Nicolas, Conchon, Sophie, Cesbron, Anne, Giral, Magali, Brouard, Sophie, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Histocompatibilité et d'Immunogénétique [EFS Nantes], Etablissement Français du Sang [Nantes], CIC biothérapies CBT 0503 [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM), DIVAT consortium, Réseau CENTAURE [CHU Nantes] (Fondation, Centre d’Investigation Clinique en Biothérapie), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut de Transplantation et de Recherche en Transplantation (ITUN - Institut Transplantation Urologie Néphroplogie*), This work was supported by the CENTAURE foundation (www.fondation-centaure.org), which supports a French transplantation research network, the IHU-Cesti project, the DHU Oncogreffe, and the LabEX IGO thanks to French government financial support managed by the National Research Agency via the Investment into the Future program (ANR-10-IBHU-005 and ANR-11- LABX-0016-01). The IHU-Cesti project was also supported by Nantes Métropole and Région Pays de la Loire. This work was performed in the context of the ANR project BIKET (ANR-17-CE17-0008). RD was supported by a Marie Skłodowska-Curie fellowship (IF-EF) from the European Union’s Horizon 2020 research and innovation programme under the Grant Agreement No. 706296., ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-17-CE17-0008,Biket,Cellules B GZMB+, un facteur clé de l'immunité chez l'homme?(2017), European Project: 706296,H2020,H2020-MSCA-IF-2015,DISTRICT(2017), ANR-10-IBHU-0005,CESTI (TSI-IHU),CESTI (TSI-IHU)(2010), Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Le Bihan, Sylvie, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Cellules B GZMB+, un facteur clé de l'immunité chez l'homme? - - Biket2017 - ANR-17-CE17-0008 - AAPG2017 - VALID, and DECIPHERING THE ROLE OF TRIB1 IN REGULATORY T CELLS - DISTRICT - - H20202017-07-01 - 2019-06-30 - 706296 - VALID

Subjects
[SDV] Life Sciences [q-bio], donor-specific antibodi es, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, circulating T follicular helper lymphocytes, [SDV]Life Sciences [q-bio], Tfh, renal transplantation, DSA, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4+CD45RA-CXCR5+, and the three following subsets of activated cTfh were analyzed: CXCR5+PD1+, CXCR5+PD1+ICOS+, an CXCR5+PD1+CXCR3-. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5+PD1+, CXCR5+PD1+ICOS+, and CXCR5+PD1+CXCR3- cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5+PD1+ICOS+ at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing de novo DSA after the first year (p = 0.018, HR = 0.39), independently of HLA mismatches (p = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.

Published
2019
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23. Identification of a common transcriptional signature for regulatory B cells in Humans and Mice

Author

Dubois, Florian, Limou, Sophie, Chesneau, Mélanie, Brouard, Sophie, Danger, Richard, Le Bihan, Sylvie, 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), École Centrale de Nantes (ECN), CIC biothérapies CBT 0503 [Nantes], and Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Regulatory B cells (Bregs) have been described in mice and humans for their ability to regulate inflammation through a variety of mechanisms in different pathological situations. Up to date, no consensual and common Breg phenotype has been described, and whether there is a Breg lineage commitment or if they acquire their function under certain environmental conditions remains unknown. To address these points, we performed a sample size weighted meta-analysis of publicly available transcriptomic data from 4 different Bregs studies in humans and 6 Bregs studies in mice.

Published
2019

24. GZMB+ B cells, a key factor of cell immunity in human?

Author

Chesneau, Mélanie, Le Bot, Sabine, Poulaouec, Cyrielle, Danger, Richard, Dubois, Florian, Durand, Maxim, Jacquemont, Lola, Guerrif, Pierrick, Degauque, Nicolas, Giral, Magali, Brouard, Sophie, Le Bihan, Sylvie, 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), CIC biothérapies CBT 0503 [Nantes], and Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2018

25. Corrigendum: Broad Impairment of Natural Killer Cells From Operationally Tolerant Kidney Transplanted Patients

Author

Dugast, Emilie, David, Gaëlle, Oger, Romain, Danger, Richard, Judor, Jean-Paul, Gagne, Katia, Chesneau, Mélanie, Degauque, Nicolas, Soulillou, Jean-Paul, Paul, Pascale, Picard, Christophe, Guerif, Pierrick, Conchon, Sophie, Giral, Magali, Gervois, Nadine, Retière, Christelle, Brouard, Sophie, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en 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), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), European Project: 602470,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,VISICORT(2014), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Dubois Frid, Caroline, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Adverse Immune Signatures and their Prevention in Corneal Transplantation - VISICORT - - EC:FP7:HEALTH2014-04-01 - 2019-03-31 - 602470 - VALID, Centre de Recherche en Transplantation et Immunologie ( CRTI ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de transplantation urologie-néphrologie ( ITUN ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Anti-tumor immunosurveillances and immunotherapy ( CRCINA - Département INCIT - Equipe 3 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Etablissement Français du Sang [Nantes], LabEx Transplantex [Strasbourg], Université de Strasbourg ( UNISTRA ), Vascular research center of Marseille ( VRCM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), CIC biothérapies CBT 0503 [Nantes], Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), This work was realized in the context of the 'Fondation CENTAURE' (RTRS), which supports a French research network in transplantation, and in the context of the Lab-EX IGO program supported by the National Research Agency via the investment of the future program ANR-11-LABX-0016-01. This work was also supported by the FP7 VISICORT project, which has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement 602470. This research was also supported by INSERM, DHU, and IHU-CESTI institutes receiving financial support from the French Government managed by the National Research Agency (investment into the future program ANR-10-IBHU-005), Nantes Metropole, and the Pays de la Loire Region. This work was also financially supported by the EtablissementFrançais du Sang (EFS)/Pays de la Loire and by grants from the International Research Group on unrelated HEmatopoietic stem cell Transplantation (IRGHET), Agence de Biomédecine and LeucémieEspoirAtlantiqueFamille (LEAF)., ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest ( 2011 ), ANR-10-IBHU-0005/10-IBHU-0005,CESTI (TSI-IHU),CESTI (TSI-IHU) ( 2010 ), and European Project : 602470,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,VISICORT ( 2014 )

Subjects
kidney, tolerance, Immunology, Correction, Immunology and Allergy, cytotoxicity, natural killer, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Original Research, transplantation
Abstract

International audience; The role of natural killer (NK) cells in organ transplantation is controversial. This study aims to decipher their role in kidney transplant tolerance in humans. Previous studies highlighted several modulated genes involved in NK cell biology in blood from spontaneously operationally tolerant patients (TOLs; drug-free kidney-transplanted recipients with stable graft function). We performed a phenotypic, functional, and genetic characterization of NK cells from these patients compared to kidney-transplanted patients with stable graft function under immunosuppression and healthy volunteers (HVs). Both operationally TOLs and stable patients harbored defective expression of the NKp46 activator receptor and lytic molecules perforin and granzyme compared to HVs. Surprisingly, NK cells from operationally TOLs also displayed decreased expression of the CD16 activating marker (in the CD56 Dim NK cell subset). This decrease was associated with impairment of their functional capacities upon stimulation, as shown by lower interferon gamma (IFNγ) production and CD107a membranous expression in a reverse antibody-dependent cellular cytotoxicity (ADCC) assay, spontaneous lysis assays, and lower target cell lysis in the 51 Cr release assay compared to HVs. Conversely, despite impaired K562 cell lysis in the 51 Cr release assay, patients with stable graft function harbored a normal reverse ADCC and even increased amounts of IFNγ + NK cells in the spontaneous lysis assay. Altogether, the strong impairment of the phenotype and functional cytotoxic capacities of NK cells in operationally TOLs may accord with the establishment of a pro-tolerogenic environment, despite remaining highly activated after transplantation in patients with stable graft function.

Published
2017
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26. Corrigendum: Broad Impairment of Natural Killer Cells From Operationally Tolerant Kidney Transplanted Patients

Author

Dugast, Emilie, primary, David, Gaëlle, additional, Oger, Romain, additional, Danger, Richard, additional, Judor, Jean-Paul, additional, Gagne, Katia, additional, Chesneau, Mélanie, additional, Degauque, Nicolas, additional, Soulillou, Jean-Paul, additional, Paul, Pascale, additional, Picard, Christophe, additional, Guerif, Pierrick, additional, Conchon, Sophie, additional, Giral, Magali, additional, Gervois, Nadine, additional, Retière, Christelle, additional, and Brouard, Sophie, additional

Published
2018
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27. Broad Impairment of Natural Killer Cells From Operationally Tolerant Kidney Transplanted Patients

Author

Dugast, Emilie, primary, David, Gaëlle, additional, Oger, Romain, additional, Danger, Richard, additional, Judor, Jean-Paul, additional, Gagne, Katia, additional, Chesneau, Mélanie, additional, Degauque, Nicolas, additional, Soulillou, Jean-Paul, additional, Paul, Pascale, additional, Picard, Christophe, additional, Guerif, Pierrick, additional, Conchon, Sophie, additional, Giral, Magali, additional, Gervois, Nadine, additional, Retière, Christelle, additional, and Brouard, Sophie, additional

Published
2017
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28. CXCR5+PD1+ICOS+ Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation.

Author

Danger, Richard, Chesneau, Mélanie, Delbos, Florent, Le Bot, Sabine, Kerleau, Clarisse, Chenouard, Alexis, Ville, Simon, Degauque, Nicolas, Conchon, Sophie, Cesbron, Anne, Giral, Magali, and Brouard, Sophie

Subjects
T helper cells, TRANSPLANTATION of organs, tissues, etc., IMMUNOGLOBULINS, ANTIBODY formation, B cells
Abstract

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4+CD45RA−CXCR5+, and the three following subsets of activated cTfh were analyzed: CXCR5+PD1+, CXCR5+PD1+ICOS+, an CXCR5+PD1+CXCR3−. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5+PD1+, CXCR5+PD1+ICOS+, and CXCR5+PD1+CXCR3− cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5+PD1+ICOS+ at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing de novo DSA after the first year (p = 0.018, HR = 0.39), independently of HLA mismatches (p = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation. [ABSTRACT FROM AUTHOR]

Published
2019
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29. Unique and specific Proteobacteriadiversity in urinary microbiota of tolerant kidney transplanted recipients

Author

Colas, Luc, Mongodin, Emmanuel F., Montassier, Emmanuel, Chesneau, Mélanie, Guerif, Pierrick, Hittle, Lauren, Giral, Magali, Bromberg, Jonathan S., Brouard, Sophie, Blancho, Gilles, Branchereau, Julien, Cantarovich, Diego, Cesbron, Anne, Chapelet, Agnès, Dantal, Jacques, Delbos, Florent, Deltombe, Clément, Devis, Anne, Figueres, Lucile, Garandeau, Claire, Gourraud‐Vercel, Caroline, Hourmant, Maryvonne, Kandell, Christine, Karam, Georges, Kerleau, Clarisse, Meurette, Aurélie, Moreau, Anne, Renaudin, Karine, Ville, Simon, and Walencik, Alexandre

Abstract

Host‐microbiota interactions can modulate the immune system both at local and systemic levels, with potential consequences for organ transplantation outcomes. In this study, we hypothesized that differences in the urinary microbiome following kidney transplantation would be associated with posttransplantation status: stable, minimally immunosuppressed, or tolerant. One hundred thirteen urine samples from stable (n = 51), minimally immunosuppressed (n = 19), and spontaneously tolerant (n = 16) patients, paired with age‐matched controls (n = 27) were profiled and compared to each other at a taxonomic level with special interest in the immunosuppressive regimen. All comparisons and correlations were adjusted on sex and time posttransplantation. Our results highlighted a unique and specific urinary microbiota associated with spontaneous tolerance characterized by a high diversity and a clear Proteobacteriaprofile. Finally, we report that this profile is (1) impacted by gender, (2) inversely correlated with immunosuppressive drugs (calcineurin inhibitors and mammalian target of rapamycin inhibitors), and (3) stable in time. Comparing taxonomic relative abundance and diversity of urinary microbiota between healthy volunteers and tolerant, stable, and minimally immunosuppressed kidney transplanted recipients, this study identifies and associates a specific Proteobacteriaprofile in the urine of kidney transplanted recipients with spontaneous tolerance.

Published
2020
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30. Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

Author

Chesneau, Mélanie, primary, Michel, Laure, additional, Dugast, Emilie, additional, Chenouard, Alexis, additional, Baron, Daniel, additional, Pallier, Annaïck, additional, Durand, Justine, additional, Braza, Faouzi, additional, Guerif, Pierrick, additional, Laplaud, David-Axel, additional, Soulillou, Jean-Paul, additional, Giral, Magali, additional, Degauque, Nicolas, additional, Chiffoleau, Elise, additional, and Brouard, Sophie, additional

Published
2015
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31. Central Role of CD45RA− Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance

Author

Braza, Faouzi, primary, Dugast, Emilie, additional, Panov, Ivo, additional, Paul, Chloé, additional, Vogt, Katrin, additional, Pallier, Annaick, additional, Chesneau, Mélanie, additional, Baron, Daniel, additional, Guerif, Pierrick, additional, Lei, Hong, additional, Laplaud, David-Axel, additional, Volk, Hans-Dieter, additional, Degauque, Nicolas, additional, Giral, Magali, additional, Soulillou, Jean-Paul, additional, Sawitzki, Birgit, additional, and Brouard, Sophie, additional

Published
2015
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32. Decreased Frequency of Circulating Myelin Oligodendrocyte Glycoprotein B Lymphocytes in Patients with Relapsing-Remitting Multiple Sclerosis

Author

Elong Ngono, Annie, primary, Lepetit, Maud, additional, Reindl, Markus, additional, Garcia, Alexandra, additional, Guillot, Flora, additional, Genty, Athénaïs, additional, Chesneau, Mélanie, additional, Salou, Marion, additional, Michel, Laure, additional, Lefrere, Fabienne, additional, Schanda, Kathrin, additional, Imbert-Marcille, Berthe-Marie, additional, Degauque, Nicolas, additional, Nicot, Arnaud, additional, Brouard, Sophie, additional, Laplaud, David-Axel, additional, and Soulillou, Jean-Paul, additional

Published
2015
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34. The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients

Author

Maggiore, Umberto, Yussim, Alexander, Garnier, Arnaud, Gross, Oliver, Prokopova, Michaela, Le Monies De Sagazan, Hervé, Pascual, Julio, Gentil Govantes, Miguel Angel, Biancone, Luigi, Lai, Quirino, Abramowicz, Daniel, La Manna, Gaetano, Tuglular, Serhan, Bemelman, Frederike, Naesens, Maarten, Gaasbeek, André, Gatault, Philippe, Martin, Séverine, Frasca, Giovanni Maria, Colak, Hulya, Stratta, Piero, Seyahi, Nurhan, Keller, Frieder, Sulowicz, Wladyslaw, De Biase, Consuelo, Viklicky, Ondrej, Dudley, Christopher, Subra, Jean-François, Thaiss, Friedrich, Huynh-Do, Uyen, Sever, Mehmet Sukru, Hadaya, Karine, Noël, Christian, Racapé, Judith, Villemain, Florence, Guérif, Pierrick, Cantarell, Maria Carmen, Hurault De Ligny, Bruno, Berglund, David, Pérez-Sáez, María José, Kandus, Aljosa, Ponikvar, Jadranka Buturovic, Massart, Annick, Janbon, Bénédicte, De Fijter, Johan W, Howse, Matthew, Abramowicz, Marc, Glowacki, François, Klinger, Marian, Wekerle, Thomas, Mühlfeld, Anja, Braun, Laura, Pisani, Francesco, Díaz-Corte, Carmen, Legendre, Christophe, Chesneau, Mélanie, Jiménez Del Cerro, Luis Antonio, Clemente, Katia, Budde, Klemens, Tugmen, Cem, Le Moine, Alain, Spasovski, Goce, Lauzurica, Ricardo, Serón, Daniel, Reischig, Tomas, Hazzan, Marc, Hoitsma, Andries, Courtney, Aisling, Pillebout, Evangeline, Giral, Magali, Pallier, Annaïck, Cuna, Vania, Mazouz, Hakim, Brouard, Sophie, Baas, Marije, Sørensen, Søren Schwartz, Puga, Ana Ramírez, Dufay, Alexandre, Alonso Hernandez, Angel, Soulillo, Jean-Paul, Beňa, Luboslav, Moal, Marie-Christine, Piredda, Gian Benedetto, Oberbauer, Rainer, and Orlando, Giuseppe

Subjects
610 Medicine & health, 3. Good health
Abstract

BACKGROUND Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine

35. New Method for the Expansion of Highly Purified Human Regulatory Granzyme B-Expressing B Cells.

Author

Chesneau M, Le Mai H, and Brouard S

Subjects
Apoptosis immunology, B-Lymphocytes immunology, B-Lymphocytes metabolism, B-Lymphocytes, Regulatory metabolism, Cell Proliferation, Granzymes immunology, Granzymes metabolism, Humans, Lymphocyte Activation, T-Lymphocytes, Cytotoxic immunology, B-Lymphocytes, Regulatory immunology, Cell Culture Techniques methods, Granzymes isolation & purification
Abstract

Granzyme B (GZMB)-expressing B cells inhibit CD4 + T-lymphocyte proliferation in a contact- and GZMB-dependent manner, through degradation of TCR zeta or induction of T-cell apoptosis. This regulatory B-cell population is present in human healthy individuals and represents about 1% of circulating B cells. Their small proportion requires the development of expansion methods to enable their study and envision clinical applications. We describe here how to expand GZMB-expressing B cells to obtain more than 90% of highly purified GZMB + B cells, and the protocol of B/T cells coculture for the evaluation of the suppressive function of the GZMB + B-cell population.

Published
2021
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36. CXCR5 + PD1 + ICOS + Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation.

Author

Danger R, Chesneau M, Delbos F, Le Bot S, Kerleau C, Chenouard A, Ville S, Degauque N, Conchon S, Cesbron A, Giral M, and Brouard S

Subjects
Adult, Female, HLA Antigens immunology, Humans, Kidney Transplantation methods, Male, Middle Aged, Phenotype, Tissue Donors, Inducible T-Cell Co-Stimulator Protein metabolism, Isoantibodies immunology, Kidney Transplantation adverse effects, Programmed Cell Death 1 Receptor metabolism, Receptors, CXCR5 metabolism, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism
Abstract

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4 + CD45RA - CXCR5 + , and the three following subsets of activated cTfh were analyzed: CXCR5 + PD1 + , CXCR5 + PD1 + ICOS + , an CXCR5 + PD1 + CXCR3 - . Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5 + PD1 + , CXCR5 + PD1 + ICOS + , and CXCR5 + PD1 + CXCR3 - cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5 + PD1 + ICOS + at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing de novo DSA after the first year ( p = 0.018, HR = 0.39), independently of HLA mismatches ( p = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.

Published
2019
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