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1. Prospective Measures of Adherence by Questionnaire, Low Immunosuppression and Graft Outcome in Kidney Transplantation

Author

Olivier Thaunat, Françoise Hau, Mathilde Prezelin-Reydit, Isabelle Etienne, Laetitia Albano, Virginie Renac, Valérie Dubois, Cécile Vigneau, Monique Pourtein, Sophie Caillard, A. Parissiadis, Jonathan Visentin, Jean-Luc Taupin, Gwendaline Guidicelli, Lionel Couzi, Christophe Mariat, Benoit Barrou, Lena Absi, Pierre Merville, CHU Bordeaux [Bordeaux], AURAD Aquitaine, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), EFS, Cellules B normales et pathogéniques - Normal and pathogenic B cell responses (NOPAB), 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), CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion, Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Hôpital Pasteur [Nice] (CHU), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Etablissement français du sang, Auvergne-Loire [Saint-Etienne] (EFS), Etablissement Français du Sang, École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] (EFS Bretagne), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, France REIN AQUITAINE, 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), EFS-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Chard-Hutchinson, Xavier, 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
medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, graft survival, kidney transplantation, 030230 surgery, Logistic regression, HLA Sensitization, Article, 03 medical and health sciences, 0302 clinical medicine, Morisky scale, Internal medicine, medicine, adherence, Kidney transplantation, immunosuppression, business.industry, Immunosuppression, General Medicine, medicine.disease, Predictive value, 3. Good health, [SDV] Life Sciences [q-bio], body regions, Calcineurin, Medicine, Trough level, business, dnDSA
Abstract

Background: Non-adherence with immunosuppressant medication (MNA) fosters development of de novo donor-specific antibodies (dnDSA), rejection, and graft failure (GF) in kidney transplant recipients (KTRs). However, there is no simple tool to assess MNA, prospectively. The goal was to monitor MNA and analyze its predictive value for dnDSA generation, acute rejection and GF. Methods: We enrolled 301 KTRs in a multicentric French study. MNA was assessed prospectively at 3, 6, 12, and 24 months (M) post-KT, using the Morisky scale. We investigated the association between MNA and occurrence of dnDSA at year 2 post transplantation, using logistic regression models and the association between MNA and rejection or graft failure, using Cox multivariable models. Results: The initial percentage of MNA patients was 17.7%, increasing to 34.6% at 24 months. Nineteen patients (8.4%) developed dnDSA 2 to 3 years after KT. After adjustment for recipient age, HLA sensitization, HLA mismatches, and maintenance treatment, MNA was associated neither with dnDSA occurrence, nor acute rejection. Only cyclosporine use and calcineurin inhibitor (CNI) withdrawal were strongly associated with dnDSA and rejection. With a median follow-up of 8.9 years, GF occurred in 87 patients (29.0%). After adjustment for recipient and donor age, CNI trough level, dnDSA, and rejection, MNA was not associated with GF. The only parameters associated with GF were dnDSA occurrence, and acute rejection. Conclusions: Prospective serial monitoring of MNA using the Morisky scale does not predict dnDSA occurrence, rejection or GF in KTRs. In contrast, cyclosporine and CNI withdrawal induce dnDSA and rejection, which lead to GF.

Published
2021
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2. Does a Useful Test Exist to Properly Evaluate the Pathogenicity of Donor-specific Antibodies? Lessons From a Comprehensive Analysis in a Well-studied Single-center Kidney Transplant Cohort

Author

Mélanie Joly, Nadine Froelich, Peggy Perrin, Philippe Guntz, Jérôme Olagne, Gabriela Gautier Vargas, Christian Gachet, Noëlle Cognard, Bruno Moulin, Sophie Caillard, and A. Parissiadis

Subjects
Graft Rejection, Male, Time Factors, Biopsy, 030230 surgery, Single Center, Gastroenterology, 0302 clinical medicine, HLA Antigens, Isoantibodies, Child, Kidney, medicine.diagnostic_test, biology, Complement Fixation Tests, Graft Survival, Middle Aged, medicine.anatomical_structure, Treatment Outcome, Complement C3d, Child, Preschool, Cohort, 030211 gastroenterology & hepatology, Female, Antibody, Adult, medicine.medical_specialty, Adolescent, Renal function, 03 medical and health sciences, Young Adult, Monitoring, Immunologic, Predictive Value of Tests, Internal medicine, medicine, Humans, Clinical significance, Aged, Retrospective Studies, Transplantation, business.industry, Donor specific antibodies, Complement C1q, Reproducibility of Results, Kidney Transplantation, body regions, biology.protein, business, Biomarkers
Abstract

Background Donor-specific antibodies (DSA) play a major role in antibody-mediated rejection (AMR) and graft dysfunction. However, the clinical relevance of complement-binding anti-HLA antibodies remains unclear. Methods Here, we analyzed DSA detected in the serum (sDSA) using single antigen bead, C1q, and C3d assays combined with the study of intragraft DSA (gDSA) in 86 patients who had DSA and underwent a kidney biopsy for cause (n = 58) or without evidence of kidney dysfunction (n = 28). DSA characteristics were collected and related to the presence of AMR, graft histological features, and allograft survival. Results Forty-five patients (52%) had C1q DSA, and 42 (51%) had C3d DSA. Allograft biopsies revealed AMR in 63 cases (73%), regardless of kidney function. gDSA were identified in 74% of biopsies. We observed a strong correlation among single antigen bead mean fluorescence intensity and complement assays positivity, presence of gDSA, and AMR occurrence. Conclusions Complement-binding DSA per se were not significantly associated with allograft survival in the entire study sample. Finally, gDSA predicted subsequent graft loss in patients who showed a stable renal function at the day of biopsy. Our data suggest that DSA mean fluorescence intensity and presence of gDSA might provide prognostic information during posttransplant monitoring.

Published
2020

3. Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus host disease in conjunction with the CMV status

Author

Philippe Moreau, Machteld Oudshoorn, Catherine Paillard, Valérie Dubois, Raphael Carapito, Irina Kotova, Antoine Toubert, Ismail Aouadi, Perrine Spinnhirny, Eric Spierings, A. Parissiadis, Ibrahim Yakoub-Agha, Mauricette Michallet, Myriam Labalette, Seiamak Bahram, Régis Peffault de Latour, Jürgen Kuball, Mohamad Mohty, Christophe Picard, Bronno van der Holt, Didier Blaise, Ryad Tamouza, Myriam Maumy-Bertrand, Frédéric Bertrand, Pascale Loiseau, Véronique Rolli, Jan J. Cornelissen, Aurore Morlon, Anne Cesbron, Gérard Socié, Yasuo Morishima, Peter A. von dem Borne, Frans H.J. Claas, Cécile Macquin, Angélique Pichot, Bruno Lioure, Dominique Charron, Katia Gagne, Equipe Plate-forme GENOMAX (Inserm U1109), Fédération Hospitalo-Universitaire OMICARE-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA)-Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), INSERM Franco-Japanese Nextgen HLA Laboratory [Strasbourg] (FJ-HLA), Laboratoire International Associé (LIA), INSERM Franco-Japanese Nextgen HLA Laboratory[Nagano], Pôle de Biologie - Laboratoire d’Immunologie [Nouvel Hôpital Civil, Strasbourg] (Plateau Technique de Biologie), Nouvel Hôpital Civil - NHC [Strasbourg], BIOMICA SA [Strasbourg], Etablissement Français du Sang [Nantes], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Europdonor operated by Matchis Foundation [Leiden], Leiden University Medical Center (LUMC), Erasmus MC Cancer Institute, Rotterdam, Laboratoire d'Immunologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Medical Center [Utrecht], Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Etablissement Français du Sang - Grand Est (EFS - alsace strasbourg), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de Recherche Mathématique Avancée (IRMA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), 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), Hôpital Hôtel-Dieu [Paris], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre & marie Curie, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Aichi Cancer Center Research Institute, This work was supported by grants from the Agence Nationale de la Recherche (ANR) (ANR-11-LABX-0070_TRANSPLANTEX), and the INSERM (UMR_S 1109), the Institut Universitaire de France (IUF), all to SB, from the University of Strasbourg (IDEX UNISTRA) to CP and SB, from the European regional development fund (European Union) INTERREG V program (project n°3.2 TRIDIAG) to RC and SB, and from MSD-Avenir grant AUTOGEN to SB., We would like to thank Prof. Robert Zeiser (University of Freiburg/Germany) for critical reading of this manuscript. We thank Martin Verniquet for critical review of statistical analyses. We would also like to thank Nicole Raus (SFGM-TC, Lyon, France) for retrieving the clinical data from the ProMISe database., Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Hospitalo-Universitaire OMICARE-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA), 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), Universiteit Leiden, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hematology, Erasmus MC other, and Bernardo, Elizabeth

Subjects
medicine.medical_specialty, Congenital cytomegalovirus infection, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Typing, Amino Acids, Retrospective Studies, Transplantation, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, medicine.disease, 3. Good health, Graft-versus-host disease, 030220 oncology & carcinogenesis, Cytomegalovirus Infections, business, 030215 immunology
Abstract

International audience; Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.

Published
2020
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4. Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function

Author

Pouliquen, Eric, Baltzinger, P., Lemle, A., Chen, Chien-Chia, Parissiadis, A., Borot, S., Frimat, L., Girerd, S., Berney, T., Lablanche, S., Benhamou, P. Y., Morelon, E., Badet, L., Dubois, V., Kessler, L., Thaunat, Olivier, Network, Gragil, 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), Service d'Endocrinologie - Diabète et Maladies Métaboliques, Hôpitaux Universitaires de Strasbourg, Etablissement Français du Sang - Grand Est (EFS - alsace strasbourg), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Department of Surgery, University of Geneva [Switzerland], Service d'Endocrinologie, Pôle Digidune, CHU Grenoble, Service d'Urologie et Chirurgie de la Transplantation, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Etablissement français du sang- Rhône-Alpes [Lyon], Université de Lyon, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, CHU Strasbourg, Geneva University Hospital (HUG), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée [2016-2019] (LBFA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), Service d'urologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), EFS de Lyon, 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 Université de Genève = University of Geneva (UNIGE)

Subjects
Graft Rejection, Male, antibody-mediated (ABMR) [rejection], [SDV]Life Sciences [q-bio], medicine.medical_treatment, Islets of Langerhans Transplantation, 030232 urology & nephrology, 030230 surgery, Postoperative Complications, 0302 clinical medicine, HLA Antigens, Risk Factors, Isoantibodies, Immunology and Allergy, Pharmacology (medical), Longitudinal Studies, ComputingMilieux_MISCELLANEOUS, Sensitization, geography.geographical_feature_category, ddc:617, biology, Graft Survival, Middle Aged, Prognosis, Islet, Tissue Donors, 3. Good health, medicine.anatomical_structure, Immunosuppressive drug, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, Type 1, Adult, Human leukocyte antigen, clinical research/practice, 03 medical and health sciences, Diabetes mellitus, Diabetes Mellitus, alloantibody, medicine, Humans, Retrospective Studies, Transplantation, geography, business.industry, islet transplantation, Insulin, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Transplant Recipients, body regions, rejection: antibody-mediated (ABMR), Immunology, biology.protein, business, Follow-Up Studies
Abstract

International audience; Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

Published
2017
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5. Prognostic Value of the Persistence of C1q-Binding Anti-HLA Antibodies in Acute Antibody-Mediated Rejection in Kidney Transplantation

Author

Valérie Chabot, Gilles Blancho, Raj Purgus, A. Parissiadis, Barbara Proust, Christiane Mousson, Moglie Le Quintrec, Philippe Grimbert, Matthias Büchler, Philippe Gatault, Paolo Malvezzi, Johnny Sayegh, Vincent Vuiblet, Valérie Chatelet, Yvon Lebranchu, Gwendaline Guidicelli, Isabelle Top, Frédéric Dehaut, Dany Anglicheau, Jérôme Tourret, Emmanuel Morelon, Elodie Bailly, Pierre François Westeel, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Francois Rabelais [Tours], 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), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Néphrologie-Dialyse-Transplantation rénale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), 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), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Etablissement Français du Sang - Grand Est (EFS - alsace strasbourg), Service de Néphrologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Service de néphrologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Lille, 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), CHU Marseille, CHU Amiens-Picardie, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10

Subjects
Graft Rejection, Male, Time Factors, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, 030230 surgery, Gastroenterology, 0302 clinical medicine, HLA Antigens, Isoantibodies, Risk Factors, Kidney transplantation, ComputingMilieux_MISCELLANEOUS, Plasma Exchange, biology, Graft Survival, Immunoglobulins, Intravenous, Middle Aged, 3. Good health, Treatment Outcome, Predictive value of tests, Female, Rituximab, France, Antibody, Immunosuppressive Agents, Protein Binding, medicine.drug, Adult, medicine.medical_specialty, Placebo, 03 medical and health sciences, Predictive Value of Tests, Glomerulopathy, Internal medicine, Complement C4b, medicine, Humans, Aged, Transplantation, business.industry, Complement C1q, Transplant glomerulopathy, medicine.disease, Kidney Transplantation, Peptide Fragments, biology.protein, business
Abstract

International audience; Background: The differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown.Methods: We included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment.Results: Twenty-five patients were included: 68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect.Conclusion: The presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.

Published
2018
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6. HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation

Author

Virginie Moalic, A. Parissiadis, Mauricette Michallet, Matthieu Filloux, Florent Delbos, Marie-Thérèse Rubio, Edouard Forcade, Patrice Chevallier, A. Dormoy, Xavier Lafarge, Virginie Renac, Anne Cesbron, Béatrice Pédron, Christophe Picard, Pascale Loiseau, Abdelali Boudifa, Kahina Amokrane, Federico Garnier, F Quainon, Dominique Masson, Peter van Endert, Françoise Hau, M Fort, Raphaël Porcher, Ibrahim Yakoub-Agha, Valérie Dubois, Isabelle Jollet, Julie Bonneau, Etienne Daguindau, Natacha Maillard, Gérard Socié, Anne Kennel, Jacques-Olivier Bay, Anne Devys, Erwann Quelvennec, Régis Peffault de Latour, Stéphanie Ducreux, Myriam Labalette, Claude-Eric Bulabois, Muriel De Matteis, Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon, Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Etablissement français du sang [Angers], Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Etablissement français du sang - Normandie (EFS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'histocompatibilité et d'immunogénétique [Angers], Université d'Angers (UA), 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), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie Médicale [Rennes], Etablissement français du sang [Rennes] (EFS Bretagne), Etablissement Français du Sang - Grand Est (EFS - alsace strasbourg), CHU Toulouse [Toulouse], Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Etablissement français du sang [Poitiers] (EFS), Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang [Nantes], CHU Clermont-Ferrand, Etablissement français du sang [Clermont-Ferrand] (EFS), Agence de la biomédecine [Saint-Denis la Plaine], Hopital Saint-Louis [AP-HP] (AP-HP), Immunogénétique humaine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'épidémiologie, biostatistique et recherche clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté]), CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]

Subjects
Oncology, medicine.medical_specialty, Hematopoietic cell, business.industry, [SDV]Life Sciences [q-bio], Hazard ratio, Hematology, Disease, Matched Unrelated Donor, 3. Good health, Transplantation, 03 medical and health sciences, 0302 clinical medicine, Increased risk, Unrelated Donor, 030220 oncology & carcinogenesis, Internal medicine, medicine, business, 030215 immunology, HLA-DRB3
Abstract

International audience; Matching for HLA‐A, ‐B, ‐C, and ‐DRB1 loci (8/8 match) is currently the gold standard for unrelated donor hematopoietic cell transplantation (HCT). In Europe, patients are also matched at the HLA‐DQB1 loci (10/10 match). However, there is increasing evidence that matching at HLA‐DRB3/4/5 loci may help to lower transplant‐related morbidity and mortality. We therefore investigated the impact of HLA‐DRB3/4/5 mismatches on outcomes in 1975 patients who received a first 10/10 matched unrelated donor (MUD) HCT in France from 2000 to 2012 for a hematological malignancy. High‐resolution typing was performed at HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, ‐DPB1, and ‐DRB3/4/5 loci for all donor/recipient pairs. Compared with DRB3/4/5‐matched pairs, patients who received a MUD HCT from a DRB3/4/5 mismatched donor had a significantly increased risk of grade II‐IV acute graft‐versus‐host disease (aGVHD) (Adjusted Hazard Ratio (HR) 1.43 (1.07 to 1.90)) associated with lower graft‐versus‐host disease‐free and relapse‐free survival (GRFS) (Adjusted HR 1.20 (1.02 to 1.42)). Conversely, we observed no differences in terms of chronic GVHD, nonrelapse mortality, relapse and overall survival. However, we believe that patients stand to benefit from DRB3/4/5 loci being considered for unrelated donor selection to improve GRFS and then quality of life after unrelated HCT.

Published
2018
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7. Impact of KIR/HLA genetic combinations on double umbilical cord blood transplantation outcomes. Results of a French multicentric retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and the Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI)

Author

F Quainon, Evelyne Marry, C Retière, J.-F. Eliaou, A. Parissiadis, O Avinens, A Boudifa, Dominique Masson, N Legrand, Nicole Raus, Ibrahim Yakoub-Agha, A Batho, P Rettman, Florent Delbos, David Senitzer, Anne Kennel, A. Dormoy, Xavier Lafarge, Anne Devys, L. Absi, I Theodorou, M de Matteis, Anne Cesbron, M Drouet, Pascale Loiseau, Florent Malard, M Fort, Katia Gagne, Christophe Picard, Immunovirologie et polymorphisme génétique, 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 de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ArcelorMittal Maizières Research SA, ArcelorMittal, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC), Etablissement Français du Sang Nouvelle Aquitaine [Bordeaux] (EFS Bordeaux Nouvelle Aquitaine), Etablissement français du sang [Nice] (EFS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Paul Painlevé (LPP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Groupe Immunité des Muqueuses et Agents Pathogènes (GIMAP), Université Jean Monnet - Saint-Étienne (UJM), Etablissement français du sang [Clermont-Ferrand] (EFS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Etablissement français du sang [Caen], Ambiances, Architectures, Urbanités (AAU ), École Centrale de Nantes (ECN)-École nationale supérieure d'architecture de Nantes (ENSA Nantes)-École nationale supérieure d'architecture de Grenoble (ENSAG)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang - Grand Est (EFS - alsace strasbourg), 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), CHU Limoges, City of Hope National Medical Center, Registre France Greffe de Moelle [Saint-Denis La Plaine] (RFGM), Agence de la biomédecine [Saint-Denis la Plaine], Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Etablissement Français du Sang [Nantes], Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Arcelor Research S.A, Arcelor, Laboratoire d'Immunologie, CHU Saint-Eloi, Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Etablissement français du sang [Besançon] ( EFS ), Centre de Transfusion Sanguine Aquitaine-Limousin ( CTS AQUITAINE-LIMOUSIN ), Centre de Transfusion Sanguine, Etablissement français du sang [Nice] ( EFS ), Laboratoire Paul Painlevé - UMR 8524 ( LPP ), Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Groupe Immunité des Muqueuses et Agents Pathogènes ( GIMAP ), Université Jean Monnet [Saint-Étienne] ( UJM ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ambiances architecturales et urbaines ( AAU ), Ministère de la Culture et de la Communication ( MCC ) -École nationale supérieure d'architecture de Grenoble ( ENSAG ) -École nationale supérieure d'architecture de Nantes ( ENSA Nantes ) -École Centrale de Nantes ( ECN ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'allergologie, Centre Hospitalier Universitaire d'Angers, Registre France Greffe de Moelle [Saint-Denis La Plaine] ( RFGM ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Biologie des Organismes et Ecosystèmes Aquatiques ( BOREA ), Université des Antilles ( UA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut de Recherche pour le Développement ( IRD ) -Muséum National d'Histoire Naturelle ( MNHN ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Laboratoire Paul Painlevé - UMR 8524 (LPP), Université Jean Monnet [Saint-Étienne] (UJM), Centre National de la Recherche Scientifique (CNRS)-Université de Lille, École nationale supérieure d'architecture de Nantes (ENSA Nantes)-Ministère de la Culture et de la Communication (MCC)-École nationale supérieure d'architecture de Grenoble (ENSAG)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Nantes (ECN), Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA)-Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)

Subjects
0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Human leukocyte antigen, 03 medical and health sciences, 0302 clinical medicine, Receptors, KIR, HLA Antigens, Transplantation Immunology, Humans, Medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Progenitor cell, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Gynecology, Transplantation, [ SDV ] Life Sciences [q-bio], business.industry, Umbilical Cord Blood Transplantation, French, Retrospective cohort study, Hematology, medicine.disease, humanities, language.human_language, 3. Good health, Treatment Outcome, 030104 developmental biology, Graft-versus-host disease, Immunology, language, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cord Blood Stem Cell Transplantation, France, Stem cell, business, 030215 immunology
Abstract

Impact of KIR/HLA genetic combinations on double umbilical cord blood transplantation outcomes. Results of a French multicentric retrospective study on behalf of the Societe Francophone de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) and the Societe Francophone d’Histocompatibilite et d’Immunogenetique (SFHI)

Published
2016
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8. Matching of MHC Class I Chain-Related Genes a and B Is Associated with Reduced Incidence of Severe Acute Graft-Versus-Host Disease after Unrelated Hematopoietic Stem Cell Transplantation

Author

Myriam Labopin, Nicole Raus, Régis Peffault de Latour, Mohamad Mohty, Katharina Fleischhauer, Gérard Socié, Daniel Hanau, Nicolas Jung, Ibrahim Yakoub-Agha, Xavier Lafarge, Miriam Hoffmann, Raphael Carapito, Jordi Sierra, Philippe Moreau, Anne Cesbron, Masao Ota, Seiamak Bahram, Arnon Nagler, A. Parissiadis, Mauricette Michallet, Ryad Tamouza, Franz Claas, Gaëlle Giacometti, Myriam Labalette, Ronnie van der Holt, Pascale Loiseau, Fabio Ciceri, Didier Blaise, Eric Spierings, Meiggie Untrau, Valérie Dubois, Catherine Paillard, Luca Vago, Noel Milpied, Antoine Toubert, Hidetoshi Inoko, Sergio Querol, Christophe Picard, Angélique Pichot, Dominique Charron, Sandra Michel, Katia Gagne, Bruno Lioure, Machteld Oudshoorn, Carapito, R, Jung, N, Untrau, M, Michel, S, Pichot, A, Giacometti, G, Cesbron, A, Gagne, K, Oudshoorn, M, Van der Holt, R, Labalette, M, Spierings, E, Picard, C, Loiseau, P, Tamouza, R, Toubert, A, Hanau, D, Parissiadis, A, Dubois, V, Raus, N, Lafarge, X, Vago, L, Ciceri, F, Paillard, C, Querol, S, Sierra, J, Fleischhauer, K, Nagler, A, Hoffmann, M, Milpied, N, Michallet, M, Lioure, B, de Latour, Rp, Labopin, M, Inoko, H, Claas, F, Blaise, D, Yakoub-Agha, I, Moreau, P, Charron, D, Ota, M, Mohty, M, Socie, G, Bahram, S, Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
medicine.medical_treatment, Immunology, Medizin, Hematopoietic stem cell transplantation, Human leukocyte antigen, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, medicine, Minor histocompatibility antigen, Cumulative incidence, 030304 developmental biology, 0303 health sciences, Univariate analysis, business.industry, Donor selection, Cell Biology, Hematology, 3. Good health, Transplantation, surgical procedures, operative, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, CD8, 030215 immunology
Abstract

Background: Graft-versus-host disease (GVHD) is a major cause of mortality after unrelated hematopoietic stem cell transplantations (HSCT). Despite the development of modern immunosuppressive strategies, a nearly perfectly controlled compatibility of the classical HLA genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) and availability of numerous so-called minor histocompatibility antigens (e.g. HY or HA-1), its incidence remains largely unexplained to date. MIC genes (MHC class I chain-related) - a distinct lineage of MHC class I genes – are promising candidates to explain, at least partially, the incidence of GVHD in HLA-matched transplantations. MICA and MICB are highly polymorphic (100 alleles for MICA and 40 for MICB) and encode functional cell-surface glycoproteins up-regulated by cell stress. They interact with NKG2D, an activating receptor expressed on the surface of cytotoxic αβ CD8+ and γδ T lymphocytes and natural killer cells. MIC genes are already known to have a HLA-independent effect on solid graft outcomes and may play a similar role in HSCT by triggering GVHD. Objective: The objective of the present study was to determine the impact of donor/patient matching at the MICA and MICB loci on the incidence of GVHD in patients undergoing unrelated HSCT. Methods: We retrospectively analyzed a multicenter cohort of 1072 unrelated transplantations performed between 1996 and 2013. All donor-recipient pairs were fully typed at high resolution for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 and were matched for ten of ten HLA alleles (HLA 10/10 matched). High resolution genotyping of MICA and MICB was performed by sequenced-based typing in order to define matching grades between donors and patients. The endpoints of the study were acute and chronic GVHD. Apart from HLA-DPB1 matching, statistical models were adjusted for major clinical variables which have been shown to be associated with outcome (patient’s age, patient’s and donor’s sex, patient’s and donor’s serological status for cytomegalovirus, year of transplantation, time to transplantation, transplantation center, source of stem cells, conditioning regimen, GVHD prophylaxis, treatment with anti-thymocyte globulin, disease category and severity at transplantation). Results: Of the 1072 transplantations, 134 (12.5 %) and 380 (35.4 %) were mismatched at the MICA and MICB locus, respectively. Both MICA and MICB mismatches were significantly associated with an increased incidence of severe acute GVHD (grades III-IV) in univariate and multivariate models (multivariate model: HR = 2.32, 95 % CI = 1.84-2.92; p=0.0003 for MICA and HR = 1.49, 95 % CI = 1.24-1.79; p=0.03 for MICB). At day 100 post-HSCT severe acute GVHD incidences in mismatched vs. matched transplantations were 19.62 % vs. 15.08 % and 20.00 % vs. 14.84 % for MICA and MICB, respectively (Figure 1). Chronic GVHD was associated with MICA and MICB mismatches in univariate analysis (HR = 1.55, 95 % CI = 1.27-1.89; p=0.029 for MICA and HR=1.38, 95 % CI = 1.19-1.62; p=0.03 for MICB), but showed only a trend for association in multivariate models. Figure 1 Estimated cumulative incidence curves of grades III–IV acute GVHD according to MICA (panel A) and MICB (panel B) matching status. The solid and dashed lines represent MIC matched and mismatched grafts, respectively. The Fine and Gray model was used with relapse and death considered as competing risks. Figure 1. Estimated cumulative incidence curves of grades III–IV acute GVHD according to MICA (panel A) and MICB (panel B) matching status. The solid and dashed lines represent MIC matched and mismatched grafts, respectively. The Fine and Gray model was used with relapse and death considered as competing risks. Conclusion: To date this is the largest reported MICA and MICB sequence analysis whether in HSCT or solid organ transplantation. Inclusion of MICA and MICB typing in the donor selection process may be a practical clinical strategy for lowering the risks of severe acute GVHD after unrelated HSCT. Disclosures No relevant conflicts of interest to declare.

Published
2014
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9. Pre-existing donor-specific antibodies are detrimental to kidney allograft only when persistent after transplantation

Author

Christian Gachet, Bruno Moulin, Francoise Heibel, C. Muller, Gabriela Gautier-Vargas, Veronique Renner, A. Parissiadis, Francois Lefebre, Sophie Caillard, Jérôme Olagne, Laura Braun, Camille Becmeur, Peggy Perrin, and Noëlle Cognard

Subjects
Adult, Graft Rejection, Male, medicine.medical_specialty, 030232 urology & nephrology, Urology, 030230 surgery, Kidney, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Antigen, HLA Antigens, Isoantibodies, Risk Factors, medicine, Humans, Renal Insufficiency, Kidney transplantation, Retrospective Studies, Immunosuppression Therapy, Transplantation, biology, business.industry, Donor specific antibodies, Histocompatibility Testing, Graft Survival, Middle Aged, medicine.disease, Allografts, Kidney Transplantation, Tissue Donors, Surgery, body regions, surgical procedures, operative, medicine.anatomical_structure, Allograft rejection, Area Under Curve, Multivariate Analysis, biology.protein, Graft survival, Female, Antibody, business, Immunosuppressive Agents, Glomerular Filtration Rate
Abstract

Donor-specific antibodies (DSA) increase the risk of allograft rejection and graft failure. They may be present before transplant or develop de novo after transplantation. Here, we studied the evolution of preformed DSA and their impact on graft outcome in kidney transplant recipients. Using the Luminex Single Antigen assay, we analyzed the sera on the day of transplantation of 239 patients who received a kidney transplant. Thirty-seven patients (15.5%) had pre-existing DSA detected the day of transplantation. After 5 years, the pre-existing DSA disappeared in 22 patients whereas they persisted in 12. Variables associated with DSA persistence were age50 years (P = 0.009), a history of previous transplantation (P = 0.039), the presence of class II DSA (P = 0.009), an MFI of preformed DSA3500 (P 0.001), and the presence of two or more DSA (P 0.001). DSA persistence was associated with a higher risk of graft loss and antibody-mediated rejection. Previously undetected preformed DSA are deleterious to graft survival only when they persist after transplantation.

Published
2016

10. Survenue d’une thrombopénie sévère et durable, au décours d’une greffe de moelle allogénique, imputable à l’existence chez l’hôte d’une allo-immunisation anti-HPA-1

Author

A. Parissiadis, Daniel Hanau, Ana Berceanu, J.-P. Cazenave, N. Froelich, Karin Bilger, Sylvie Tourne, B. Lioure, M. Schwebel, and A. Laplace

Subjects
business.industry, medicine.medical_treatment, Biochemistry (medical), Clinical Biochemistry, Immunosuppression, Hematology, Human leukocyte antigen, Haematopoiesis, medicine.anatomical_structure, ABO blood group system, Immunology, medicine, Plasmapheresis, Platelet, Bone marrow, business, Autotransfusion
Abstract

A 56 year-old, multiparous woman suffering from a myeloproliferative syndrome, who had received multiple red blood cell and platelet transfusions, was the recipient of an allograft of peripheral blood stem cells derived from her HLA-A, B, DR, DQ and DP and ABO identical sister, following myeloablative conditioning. The persistence of severe, isolated thrombopenia resistant to platelet transfusions led to the discovery of anti-HLA class I allo-immunisation. As HLA compatible platelet transfusions did not result in satisfactory platelet increments, we then discovered the simultaneous presence of anti-HPA-1a allo-immunisation. Genotyping of the HPA-1 systems of the patient (HPA-1B/B) and her sister (HPA-1A/B) enabled us to elucidate the mechanism underlying the persistent thrombopenia and the inefficacy of transfusion. In fact, only transfusion of HPA-1B/B platelets (HLA compatible or incompatible) proved to be efficacious. To reduce the level of anti-HPA-1a antibodies, we performed plasmapheresis sessions and used an anti-CD20 monoclonal antibody. It was only on achieving total haematopoietic chimerism, through rapid interruption of the immunosuppression, that we obtained spontaneous normalisation of the platelet count. The present case emphasises the necessity, before undertaking any allograft of haematopoietic stem cells - even if the latter come from a strictly HLA identical member of the family - of performing a search for eventual anti-HPA allo-immunisation.

Published
2010
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11. Evidence for humoral rejection of a pancreatic islet graft and rescue with rituximab and IV immunoglobulin therapy

Author

N. Froelich, P.Y. Benhamou, M. Pinget, A. Parissiadis, François Bayle, Laurence Kessler, François Moreau, J.‐P. Cazenave, Thierry Berney, and D. Hanau

Subjects
Graft Rejection, medicine.drug_class, Islets of Langerhans Transplantation, Human leukocyte antigen, Monoclonal antibody, Antibodies, Monoclonal, Murine-Derived, Antigen, medicine, Immunology and Allergy, Humans, Immunologic Factors, Pharmacology (medical), Transplantation, Type 1 diabetes, geography, geography.geographical_feature_category, biology, business.industry, Antibodies, Monoclonal, Immunoglobulins, Intravenous, Middle Aged, medicine.disease, Islet, Immunity, Humoral, Treatment Outcome, Immunology, biology.protein, Pancreatic islet transplantation, Female, Antibody, business, Rituximab
Abstract

We describe the decline in islet function, in relation to HLA sensitization, in an islet transplant recipient and the recovery of this function after treatment with anti-CD20 monoclonal antibody and IV immunoglobulins. A 51-year-old woman with type 1 diabetes received one intraportal islet infusion. Following this transplantation, she became insulin independent. A search for HLA antibodies by using an ELISA technique remained consistently negative for HLA class I and II. It was only 2 years after the islet transplantation that this search became positive against class II antigens, reaching a peak of reactivity concomitantly with the appearance of a deterioration of glucose control requiring low-dose insulin therapy. Luminex® screening and single-antigen assays then revealed the presence of both nondonor-specific and donor-specific antibodies against HLA class II molecules. This immunization, already present in the pretransplant serum, had increased during the 6 months preceding the clinical deterioration. Since these data nevertheless pointed to antibody-mediated rejection of the islet allograft, treatment with anti-CD20 monoclonal antibody and IV immunoglobulins was initiated. One month later, the search by ELISA for antibodies against HLA class II antigens became negative, the Luminex® tests normalizing more gradually. As the result of an improvement in glucose control, the patient was again insulin-free.

Published
2009

12. Incidence of Specific Class II Antibodies after Kidney Graft Loss

Author

C. Meyer, A. Parissiadis, M. M. Tongio, P. Wolf, and M.L. Woehl-Jaegle

Subjects
Kidney, biology, business.industry, Incidence (epidemiology), Human leukocyte antigen, Graft loss, Peripheral blood mononuclear cell, medicine.anatomical_structure, Immunization, Immunology, medicine, biology.protein, Platelet, Antibody, business
Abstract

A group of 80 kidney graft recipients was studied for HLA immunization after loss of graft function. Sera were screened (1) by the classical lymphocytotoxicity technique using PBMC, CLL cells and normal B cells isolated with magnetic beads, with and without DTT and before and after platelet adsorption to remove class I antibodies and (2) by ELISA techniques.

Published
2007
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13. 529 Significance of Anti-HLA Immunization in Lung Transplantation

Author

D. Hanau, N. Santelmo, A. Parissiadis, S. Renaud, Ronald C. Kessler, Jérémie Reeb, Pierre Emmanuel Falcoz, A.C. Lejay, Z. Mansour, and Gilbert Massard

Subjects
Pulmonary and Respiratory Medicine, Transplantation, Immunization, business.industry, medicine.medical_treatment, Immunology, Medicine, Lung transplantation, Surgery, Human leukocyte antigen, Cardiology and Cardiovascular Medicine, business
Published
2012
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14. Identification and Long-Term Consequences of Antibodies Which Bound C1q in 118 Kidney Transplant Recipients With Donor Specific Antibodies

Author

Peggy Perrin, A. Parissiadis, Jérôme Olagne, Laura Braun, B. Moulin, Sophie Caillard, Christian Gachet, C. Froelich, G Gautier Vargas, and Francoise Heibel

Subjects
Transplantation, biology, business.industry, Donor specific antibodies, Immunology, biology.protein, Medicine, Identification (biology), Antibody, business, Kidney transplant
Published
2014
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15. Evolution and Impact of Pre-Existing Donor Specific Antibodies in a Monocentric Cohort of Adult Kidney Transplant Recipients

Author

Christian Gachet, Jérôme Olagne, C. Flick, Francoise Heibel, G Gautier Vargas, A. Parissiadis, Sophie Caillard, Peggy Perrin, C. Muller, Laura Braun, and B. Moulin

Subjects
Transplantation, medicine.medical_specialty, business.industry, Internal medicine, Donor specific antibodies, Cohort, medicine, business, Kidney transplant
Published
2014
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16. Unilateral necrotising toxoplasmic retinochoroiditis as the main clinical manifestation of a peptide transporter (TAP) deficiency

Author

Parissiadis, A, Dormoy, A, Fricker, D, Hanau, D, de la Salle, H, Cazenave, J-P, Lenoble, P, and Donato, L

Subjects
Corneal endothelium, Pathology, medicine.medical_specialty, Letter, business.industry, Chorioretinitis, Transporter associated with antigen processing, Human leukocyte antigen, medicine.disease, Corneal inflammation, Sensory Systems, Toxoplasmosis, Cellular and Molecular Neuroscience, Ophthalmology, medicine, Medical history, business, Rare disease
Abstract

Congenital HLA class I deficiency is a rare disease frequently resulting in chronic inflammation of the respiratory tract, and/or skin granulomas.1,2 The deficiency may be unnoticed for decades, so pathological outcome is relatively unpredictable.3 We here describe a 14 year old patient with a severe ocular toxoplasmosis who is HLA class I deficient, as a result of a homozygous mutation in the gene encoding one of the two subunits of the peptide transporter associated with antigen processing (TAP). We propose that such a defect should be investigated in patients with severe ocular toxoplasmosis without acquired immunodeficiency. At the time of referral, the patient did not have any particular medical history except an exaggerated reaction to an intradermal tuberculin test 1 year earlier. His right eye displayed a strong reduction of acuity with anterior and posterior inflammatory lesions and pain. There was corneal inflammation with flare in the anterior chamber, anterior uveitis with cellular deposits on the corneal endothelium (keratic precipitates) but without posterior synechiae and grade B3 vitritis. …

Published
2005
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17. Positive cross matches and liver transplant outcome

Author

Wohel-Jaegle Marie-Lorraine, Wolf Philippe, Simeoni Umberto, Parissiadis Anne, Boudjema Karim, Tongio Marie-M, Meyer Carole, and Fischbach Michel

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Immunology, Immunology and Allergy, Medicine, General Medicine, business, Outcome (game theory)
Published
1996
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