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1. Subclinical rejection-free diagnostic after kidney transplantation using blood gene expression

Author

Richard Danger, Ludmilla Le Berre, Marion Cadoux, Clarisse Kerleau, Emmanuelle Papuchon, Hoa Le Mai, Thi-Van-Ha Nguyen, Pierrick Guérif, Emmanuel Morelon, Olivier Thaunat, Christophe Legendre, Dany Anglicheau, Carmen Lefaucheur, Lionel Couzi, Arnaud Del Bello, Nassim Kamar, Moglie Le Quintrec, Valentin Goutaudier, Karine Renaudin, Magali Giral, Sophie Brouard, Lionel Badet, Maria Brunet, Fanny Buron, Rémi Cahen, Ricardo Codas, Sameh Daoud, Valérie Dubois, Coralie Fournie, François Gaillard, Arnaud Grégoire, Alice Koenig, Charlène Lévi, Claire Pouteil-Noble, Maud Rabeyrin, Thomas Rimmelé, Gilles Blancho, Julien Branchereau, Diego Cantarovich, Agnès Chapelet, Jacques Dantal, Clément Deltombe, Lucile Figueres, Raphael Gaisne, Claire Garandeau, Caroline Gourraud-Vercel, Maryvonne Hourmant, Georges Karam, Delphine Kervella, Christophe Masset, Aurélie Meurette, Simon Ville, Christine Kandell, Anne Moreau, Florent Delbos, Alexandre Walencik, Anne Devis, Lucile Amrouche, Olivier Aubert, Lynda Bererhi, Alexandre Loupy, Frank Martinez, Arnaud Méjean, Rébecca Sberro-Soussan, Anne Scemla, Marc-Olivier Timsit, and Julien Zuber

Subjects
Nephrology
Published
2023
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3. Evolution of humoral lesions on follow-up biopsy stratifies the risk for renal graft loss after antibody-mediated rejection treatment

Author

Antonin Bouchet, Brieuc Muller, Jerome Olagne, Thomas Barba, Mélanie Joly, Augustin Obrecht, Maud Rabeyrin, Frédérique Dijoud, Cécile Picard, Sarah Mezaache, Antoine Sicard, Alice Koenig, Anne Parissiadis, Valérie Dubois, Emmanuel Morelon, Sophie Caillard, and Olivier Thaunat

Subjects
Graft Rejection, Transplantation, Isoantibodies, Nephrology, Biopsy, Graft Survival, Humans, Kidney Transplantation, Antibodies, Retrospective Studies, Follow-Up Studies
Abstract

Background The standard-of-care protocol, based on plasma exchanges, high-dose intravenous immunoglobulin and optimization of maintenance immunosuppression, can slow down the evolution of antibody-mediated rejection (AMR), but with high interindividual variability. Identification of a reliable predictive tool of the response to AMR treatment is a mandatory step for personalization of the follow-up strategy and to guide second-line therapies. Methods Interrogation of the electronic databases of 2 French university hospitals (Lyon and Strasbourg) retrospectively identified 81 renal transplant recipients diagnosed with AMR without chronic lesions (cg score ≤1) at diagnosis and for whom a follow-up biopsy had been performed 3–6 months after initiation of therapy. Results The evolution of humoral lesions on follow-up biopsy (disappearance versus persistence versus progression) correlated with the risk for allograft loss (logrank test, P = .001). Patients with disappearance of humoral lesions had ∼80% graft survival at 10 years. The hazard ratio for graft loss in multivariate analysis was 3.91 (P = .04) and 5.15 (P = .02) for patients with persistence and progression of lesions, respectively. The non-invasive parameters classically used to follow the intensity of humoral alloimmune response (evolution of immunodominant DSA mean fluorescence intensity) and the decline of renal graft function (estimated glomerular filtration rate decrease and persistent proteinuria) showed little clinical value to predict the histological response to AMR therapy. Conclusion We conclude that invasive monitoring of the evolution of humoral lesions by the mean of follow-up biopsy performed 3–6 months after the initiation of therapy is an interesting tool to predict long-term outcome after AMR treatment.

Published
2022
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4. Revisiting the changes in the Banff classification for antibody-mediated rejection after kidney transplantation

Author

Dirk Kuypers, Marie-Paule Emonds, Aleksandar Senev, Maud Rabeyrin, Maarten Coemans, Valérie Dubois, Olivier Thaunat, Heleen Ameye, Vicky Van Sandt, Elisabet Van Loon, Jasper Callemeyn, Ben Sprangers, Maarten Naesens, and Evelyne Lerut

Subjects
Graft Rejection, Oncology, medicine.medical_specialty, Allograft failure, Banff Classification, Biopsy, 030230 surgery, Kidney, Single kidney, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Isoantibodies, Internal medicine, Humans, Immunology and Allergy, Medicine, Pharmacology (medical), Microvascular inflammation, Kidney transplantation, Transplantation, business.industry, medicine.disease, Kidney Transplantation, Risk stratification, Antibody mediated rejection, business
Abstract

The Banff classification for antibody-mediated rejection (ABMR) has undergone important changes, mainly by inclusion of C4d-negative ABMR in Banff'13 and elimination of suspicious ABMR (sABMR) with the use of C4d as surrogate for HLA-DSA in Banff'17. We aimed to evaluate the numerical and prognostic repercussions of these changes in a single-center cohort study of 949 single kidney transplantations, comprising 3662 biopsies that were classified according to the different versions of the Banff classification. Overall, the number of ABMR and sABMR cases increased from Banff'01 to Banff'13. In Banff'17, 248 of 292 sABMR biopsies were reclassified to No ABMR, and 44 of 292 to ABMR. However, reclassified sABMR biopsies had worse and better outcome than No ABMR and ABMR, which was mainly driven by the presence of microvascular inflammation and absence of HLA-DSA, respectively. Consequently, the discriminative performance for allograft failure was lowest in Banff'17, and highest in Banff'13. Our data suggest that the clinical and histological heterogeneity of ABMR is inadequately represented in a binary classification system. This study provides a framework to evaluate the updates of the Banff classification and assess the impact of proposed changes on the number of cases and risk stratification. Two alternative classifications introducing an intermediate category are explored. ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:21 issue:7 pages:2413-2423 ispartof: location:United States status: published

Published
2021
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5. Inverted direct allorecognition triggers early donor-specific antibody responses after transplantation

Author

Xavier Charmetant, Chien-Chia Chen, Sarah Hamada, David Goncalves, Carole Saison, Maud Rabeyrin, Marion Rabant, Jean-Paul Duong van Huyen, Alice Koenig, Virginie Mathias, Thomas Barba, Florence Lacaille, Jérôme le Pavec, Olivier Brugière, Jean-Luc Taupin, Lara Chalabreysse, Jean-François Mornex, Lionel Couzi, Stéphanie Graff-Dubois, Raphaël Jeger-Madiot, Alexy Tran-Dinh, Pierre Mordant, Helena Paidassi, Thierry Defrance, Emmanuel Morelon, Lionel Badet, Antonino Nicoletti, Valérie Dubois, and Olivier Thaunat

Subjects
Graft Rejection, Isoantigens, Mice, Mice, Inbred BALB C, Isoantibodies, Antibody Formation, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Animals, Humans, Receptors, Antigen, B-Cell, General Medicine, Peptides
Abstract

The generation of antibodies against donor-specific major histocompatibility complex (MHC) antigens, a type of donor-specific antibodies (DSAs), after transplantation requires that recipient’s allospecific B cells receive help from T cells. The current dogma holds that this help is exclusively provided by the recipient’s CD4+T cells that recognize complexes of recipient’s MHC II molecules and peptides derived from donor-specific MHC alloantigens, a process called indirect allorecognition. Here, we demonstrated that, after allogeneic heart transplantation, CD3ε knockout recipient mice lacking T cells generate a rapid, transient wave of switched alloantibodies, predominantly directed against MHC I molecules. This is due to the presence of donor CD4+T cells within the graft that recognize intact recipient’s MHC II molecules expressed by B cell receptor–activated allospecific B cells. Indirect evidence suggests that this inverted direct pathway is also operant in patients after transplantation. Resident memory donor CD4+T cells were observed in perfusion liquids of human renal and lung grafts and acquired B cell helper functions upon in vitro stimulation. Furthermore, T follicular helper cells, specialized in helping B cells, were abundant in mucosa-associated lymphoid tissue of lung and intestinal grafts. In the latter, more graft-derived passenger T cells correlated with the detection of donor T cells in recipient’s circulation; this, in turn, was associated with an early transient anti–MHC I DSA response and worse transplantation outcomes. We conclude that this inverted direct allorecognition is a possible explanation for the early transient anti-MHC DSA responses frequently observed after lung or intestinal transplantations.

Published
2022

6. Data-driven Derivation and Validation of Novel Phenotypes for Acute Kidney Transplant Rejection using Semi-supervised Clustering

Author

Aleksandar Senev, Maud Rabeyrin, Valérie Dubois, Dirk Kuypers, Olivier Thaunat, Jasper Callemeyn, Evelyne Lerut, Amaryllis H. Van Craenenbroeck, Elisabet Van Loon, Gillian Divard, T. Vaulet, Katrien De Vusser, Maarten Naesens, Ben Sprangers, Olivier Aubert, Maarten De Vos, Bart De Moor, Alexandre Loupy, and Marie-Paule Emonds

Subjects
business.industry, Rand index, General Medicine, Computational biology, 030230 surgery, medicine.disease, Phenotype, Data-driven, Euclidean distance, 03 medical and health sciences, 0302 clinical medicine, Categorization, Nephrology, Medicine, Observational study, 030212 general & internal medicine, business, Cluster analysis, Kidney transplantation
Abstract

Background Over the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure. Methods The data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance. Results Based on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters. Conclusions A semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous.

Published
2021
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7. HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients

Author

Ann M. Moyer, Petra Mrázová, Guillaume Canaud, Jack F.M. Wetzels, Nadhir Yousfi, Maryvonne Hourmant, Christophe Legendre, Manish J. Gandhi, Vladimir Tesar, Mariam P. Alexander, Ondrej Viklický, Christiane Mousson, Hanna Debiec, Pierre Ronco, Philippe Rieu, Valérie Dubois, Anne-Els van de Logt, Paul Brenchley, Sylvain Guibert, Vincent Vuiblet, Charlène Levi, Patrick Hamilton, Armando Torres, Bruno Moulin, Eric Letouzé, Josep M. Cruzado, José Aurelio Ballarín Castan, Lena Berchtold, Gabriel Choukroun, Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Geneva University Hospital (HUG), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Mayo Clinic [Rochester], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service Néphrologie et transplantation rénale Adultes [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], University of Manchester [Manchester], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biospectroscopie Translationnelle - EA 7506 (BIOSPECT), Université de Reims Champagne-Ardenne (URCA), Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), University of Barcelona, Universidad de La Laguna [Tenerife - SP] (ULL), Charles University [Prague] (CU), Institute for Clinical and Experimental Medicine (IKEM), Centre hospitalier universitaire de Nantes (CHU Nantes), Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Département de Néphrologie [CHU Necker], Service de néphrologie et de transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Gestionnaire, Hal Sorbonne Université, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Urgences néphrologiques et transplantation rénale [CHU Tenon], CHU Tenon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Linkage disequilibrium, recurrence, HLA-D, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Locus (genetics), Single-nucleotide polymorphism, Glomerulonephritis, Membranous, Polymorphism, Single Nucleotide, genetic risk score, 03 medical and health sciences, 0302 clinical medicine, Membranous nephropathy, Internal medicine, medicine, Humans, genetics, PLA2R1, Alleles, Retrospective Studies, Genetic testing, next generation sequencing, medicine.diagnostic_test, business.industry, Donor selection, Receptors, Phospholipase A2, membranous nephropathy, Retrospective cohort study, medicine.disease, Kidney Transplantation, 3. Good health, [SDV] Life Sciences [q-bio], Transplantation, 030104 developmental biology, Nephrology, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business, transplantation
Abstract

Contains fulltext : 234032.pdf (Publisher’s version ) (Closed access) Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.

Published
2021
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8. Diagnostic performance of kSORT, a blood-based mRNA assay for noninvasive detection of rejection after kidney transplantation: A retrospective multicenter cohort study

Author

Evelyne Lerut, Maud Rabeyrin, Magali Giral, Kris Bogaerts, Dany Anglicheau, Marion Rabant, Valérie Dubois, Maarten Naesens, Silke Roedder, Olivier Thaunat, Sophie Brouard, Elisabet Van Loon, and Michael G. Spigarelli

Subjects
Graft Rejection, medicine.medical_specialty, Biopsy, Urology, 030230 surgery, Kidney, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Immunology and Allergy, Medicine, Pharmacology (medical), RNA, Messenger, Kidney transplantation, Retrospective Studies, Transplantation, medicine.diagnostic_test, business.industry, Area under the curve, Retrospective cohort study, medicine.disease, Kidney Transplantation, ROC Curve, Concomitant, Renal biopsy, business, Biomarkers, Cohort study
Abstract

The Kidney Solid Organ Response Test (kSORT) blood gene expression assay was developed to noninvasively detect acute rejection (AR) after kidney transplantation. Its performance in a setting with natural disease prevalence has not been evaluated. A retrospective, multicenter cohort study was conducted across all single kidney transplant recipients, transplanted between 2011 and 2015, with samples within the first year after transplantation available in existing biobanks. The primary objective was to determine the diagnostic performance of the kSORT assay to detect AR (T cell-mediated and/or antibody-mediated rejection) as compared to a concomitant renal biopsy. AR was reported on the concomitant biopsy in 188 of 1763 (10.7%) blood samples and any rejection (including borderline changes) in 614 of 1763 (34.8%) blood samples. In 320 of 1763 samples (18.2%) the kSORT risk category was indeterminate. The kSORT assay had no diagnostic value for AR (area under the curve [AUC] 0.51, 95% confidence interval [CI] 0.50-0.56; P = .46) overall, or when considering indication biopsies (N = 487) and protocol-specified biopsies (N = 1276) separately (AUC of 0.53, 95% CI 0.50-0.59, P = .44 and 0.55, 95% CI 0.50-0.61, P = .09, respectively). This large retrospective study utilizing samples obtained under real-world clinical conditions, was unable to validate the kSORT assay for detection of AR in the first year after transplantation. ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:21 issue:2 pages:740-750 ispartof: location:United States status: published

Published
2021
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9. HLA graph, a free and ready-to-use bioinformatics tool to explore anti-HLA eplets reactivity pattern

Author

Cédric Usureau, Valentine Jacob, Valérie Dubois, Dominique Masson, Isabelle Jollet, Judith Desoutter, Jean‐Luc Taupin, Nicolas Guillaume, CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Etablissement français du sang [Poitiers] (EFS), Université Paris Cité (UPC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de La Réunion - UFR Santé (UR UFRS), and Université de La Réunion (UR)

Subjects
Epitopes, HLA Antigens, Isoantibodies, Histocompatibility Testing, Immunology, Genetics, Immunology and Allergy, Computational Biology, Humans, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Alleles, Antibodies
Abstract

International audience; INTRODUCTION: HLA antigens are highly polymorphic and their immunogenicity is dependent on the configurations of polymorphic amino acids. Monitoring anti-HLA immunization is essential in organ transplantation, as antibodies directed against HLA molecules are a major cause of rejection. Anti-HLA antibodies are not specific for HLA antigens, but recognize B-cell epitopes present on HLA molecules. METHODS: To better understand antibody reactivity patterns, we calculated the Spearman correlation of the mean fluorescence intensity (MFI) of anti-HLA antibodies identified by a single antigen assay performed using a Luminex\textregistered immunobeads assay on a large number of samples. Then, we built a computer tool analyzing antibody reactivity patterns with an accessibility by a web browser linked to the International Epitope Registry. We also extended our model to Onelambda\textregistered and Lifecodes\textregistered Single Antigen class I and class II assays. RESULTS AND DISCUSSION: The resulting MFI correlations reflect HLA antibody cross-reactivity and eplets similarity. We built HLA Graph, a computer tool that analyzes the eplets involved in antibody reactivity profiles. HLA Graph is usable with Onelambda\textregistered and Lifecodes\textregistered Single Antigen class I and class II assays. The interpretation of reactivity against alleles not tested by the antibody assays and against the alpha and beta chains of HLA-DQ and HLA-DP loci were also developed. CONCLUSION: HLA Graph is a free and ready-to-use bioinformatics tool that can be used by all laboratories performing anti-HLA antibody identification by immunobead assay. This article is protected by copyright. All rights reserved.

Published
2022
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10. Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features

Author

Anne-Laurie Pinto, Bastien Joubert, Alberto Vogrig, Véronique Rogemond, Valérie Dubois, Géraldine Picard, Delphine Maucort-Boulch, Jérôme Honnorat, Mad-Hélénie Elsensohn, Ryad Tamouza, Margaux Saint-Martin, and Sergio Muñiz-Castrillo

Subjects
neuromyotonia, Human leucocyte antigen, CASPR2, Neuromyotonia, Human leukocyte antigen, 03 medical and health sciences, limbic encephalitis, 0302 clinical medicine, Cerebrospinal fluid, Medicine, 030304 developmental biology, 0303 health sciences, biology, business.industry, Limbic encephalitis, Morvan syndrome, Retrospective cohort study, medicine.disease, Phenotype, HLA, Psychiatry and Mental health, Immunology, biology.protein, Surgery, Neurology (clinical), Antibody, business, 030217 neurology & neurosurgery
Abstract

ObjectiveAntibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms.MethodsA cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied.ResultsCluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/−; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/−; 11/56, 19.6%). LE/− and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10−10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (pInterpretationSymptoms’ distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.

Published
2020
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11. Humoral Alloreactivity in VCA Recipients: Should We Learn From Our Experience?

Author

Jean Kanitakis, Emmanuel Morelon, Antoine Sicard, Valérie Dubois, and Olivier Thaunat

Subjects
Transplantation, medicine.medical_specialty, business.industry, medicine.medical_treatment, Treatment outcome, 030230 surgery, Organ transplantation, Vascularized Composite Allotransplantation, Surgery, 03 medical and health sciences, 0302 clinical medicine, otorhinolaryngologic diseases, medicine, 030211 gastroenterology & hepatology, Plasmapheresis, In patient, business, Solid organ transplantation
Abstract

Initially overlooked in favor of T cell-mediated rejection, the importance of the humoral alloimmune response has progressively emerged. As a result, antibody-mediated rejection is now widely recognized as the main cause of late allograft loss in most (if not all) types of solid-organ transplantation. Over the last 2 decades, vascularized composite allotransplantation (VCA) has appeared for replacing tissue defects in patients for whom no other satisfactory reconstructive options were available. Although it is now clear that VCA recipients can develop donor-specific antibodies, conclusions made in solid organ transplantation regarding antibody-mediated rejection may not systematically apply to VCA. Here, we propose to use the experience gained in organ transplantation to shed light on the path that shall be followed to evaluate and manage humoral alloreactivity in VCA recipients.

Published
2020
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12. Data-Driven Chronic Allograft Phenotypes: A Novel and Validated Complement for Histologic Assessment of Kidney Transplant Biopsies

Author

Thibaut Vaulet, Gillian Divard, Olivier Thaunat, Priyanka Koshy, Evelyne Lerut, Aleksandar Senev, Olivier Aubert, Elisabet Van Loon, Jasper Callemeyn, Marie-Paule Emonds, Amaryllis Van Craenenbroeck, Katrien De Vusser, Ben Sprangers, Maud Rabeyrin, Valérie Dubois, Dirk Kuypers, Maarten De Vos, Alexandre Loupy, Bart De Moor, and Maarten Naesens

Subjects
Graft Rejection, phenotyping, consensus clustering, Biopsy, Graft Survival, kidney transplantation, General Medicine, Complement System Proteins, chronic allograft rejection, Kidney, Allografts, Kidney Transplantation, machine learning, Phenotype, Nephrology, Banff classification, Humans, biopsy, Kidney Diseases
Abstract

BACKGROUND: No validated system currently exists to realistically characterize the chronic pathology of kidney transplants that represents the dynamic disease process and spectrum of disease severity. We sought to develop and validate a tool to describe chronicity and severity of renal allograft disease and integrate it with the evaluation of disease activity. METHODS: The training cohort included 3549 kidney transplant biopsies from an observational cohort of 937 recipients. We reweighted the chronic histologic lesions according to their time-dependent association with graft failure, and performed consensus k-means clustering analysis. Total chronicity was calculated as the sum of the weighted chronic lesion scores, scaled to the unit interval. RESULTS: We identified four chronic clusters associated with graft outcome, based on the proportion of ambiguous clustering. The two clusters with the worst survival outcome were determined by interstitial fibrosis and tubular atrophy (IFTA) and by transplant glomerulopathy. The chronic clusters partially overlapped with the existing Banff IFTA classification (adjusted Rand index, 0.35) and were distributed independently of the acute lesions. Total chronicity strongly associated with graft failure (hazard ratio [HR], 8.33; 95% confidence interval [CI], 5.94 to 10.88; P

Published
2022

13. Class I/Class II HLA Evolutionary Divergence Ratio Is an Independent Marker Associated With Disease-Free and Overall Survival After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Author

Anne-Marie, Daull, Valérie, Dubois, Hélène, Labussière-Wallet, Fabienne, Venet, Fiorenza, Barraco, Sophie, Ducastelle-Lepretre, Marie-Virginie, Larcher, Marie, Balsat, Lila, Gilis, Gaëlle, Fossard, Hervé, Ghesquières, Maël, Heiblig, Florence, Ader, Vincent, Alcazer, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Etablissement français du sang- Rhône-Alpes [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), Hôpital Edouard Herriot [CHU - HCL], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Center for Interdisciplinary Research and Innovation (CIRI), Aristotle University of Thessaloniki, and Hôpital de la Croix-Rousse [CHU - HCL]

Subjects
[SDV]Life Sciences [q-bio], Histocompatibility Antigens Class I, Immunology, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, graft-versus-leukemia (GVL), immune reconstitution, acute myeloid leukemia, Disease-Free Survival, Leukemia, Myeloid, Acute, hematopoietic (stem) cell transplantation (HCT), HLA Antigens, Humans, Immunology and Allergy, HLA Evolutionary divergence, graft-versus-host disease (GVHD)
Abstract

Class I Human Leukocyte Antigen (HLA) evolutionary divergence (HED) is a metric which reflects immunopeptidome diversity and has been associated with immune checkpoint inhibitor responses in solid tumors. Its impact and interest in allogeneic hematopoietic stem cell transplantation (HCT) have not yet been thoroughly studied. This study analyzed the clinical and immune impact of class I and II HED in 492 acute myeloid leukemia (AML) recipients undergoing HCT. The overall cohort was divided into a training (n=338) and a testing (n=132) set. Univariate cox screening found a positive impact of a high class I HED and a negative impact of a high class II HED on both disease-free (DFS) and overall survival (OS). These results were combined in a unique marker, class I/class II HED ratio, and assessed in the testing cohort. The final multivariate cox model confirmed the positive impact of a high versus low class I/class II HED ratio on both DFS (Hazard Ratio (HR) 0.41 [95% CI 0.2-0.83]; p=0.01) and OS (HR 0.34 [0.19-0.59]; p

Published
2022
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14. Impact of calcineurin inhibitor-free immunosuppression on de novo donor-specific antibody formation in liver transplant recipients

Author

Magdalena Meszaros, Valérie Dubois, Nicolas Congy‐Jolivet, Sarah Hamada, Céline Thevenin, Stephanie Faure, Olivier Boillot, Nassim Kamar, Georges‐Philippe Pageaux, Arnaud Del Bello, and Jérôme Dumortier

Subjects
Graft Rejection, Immunosuppression Therapy, Hepatology, Antibody Formation, Calcineurin Inhibitors, Graft Survival, Humans, Immunosuppressive Agents, Transplant Recipients, Liver Transplantation
Abstract

Low calcineurin inhibitor (CNI) levels expose liver transplant recipients to rejection episodes and potentially to antibody-mediated rejection. There are little data on the impact of CNI-free immunosuppression on de novo donor-specific HLA antibody (dnDSA) development. Here we evaluated the prevalence of dnDSA in liver transplant recipients on CNI-free maintenance regimens and their associations with histopathological abnormalities of allografts.Seven hundred and twenty-seven liver transplant recipients underwent a first liver transplant between 2000 and 2018 in three French transplant centres and had protocolized follow-up with dnDSA screening and allograft biopsy 1, 5 and 10 years after transplantation.CNIs were withdrawn in 166 (22.8%) patients with or without conversion to mammalian target of rapamycin inhibitors and/or maintenance with mycophenolic acid. DSA were present after withdrawal in 30.1% (50/166) patients on CNI-free immunosuppression compared with 16% (90/561) on CNI maintenance therapy (p 0.001). The cumulative incidence of dnDSA 10 years after transplant was 20% in the CNI group versus 28% in the CNI-free group (p 0.01). dnDSAs were associated with histological graft abnormalities (significant allograft fibrosis or rejection) (HR 2.24, 95% CI 1.2-4.1; p = 0.01). In univariate Cox regression analysis, being on a CNI-free regimen did not impact graft histology.Patients on a CNI-free IS regimen have a higher prevalence of dnDSA than patients on a standard IS regimen. dnDSAs but not CNI-free immunosuppression were associated with abnormal allograft histology.

Published
2021

15. Outcome of Liver Transplant Patients With Preformed Donor‐Specific Anti–Human Leukocyte Antigen Antibodies

Author

Olivier Boillot, Nicolas Congy-Jolivet, Laurence Lavayssière, Marie Danjoux, Jérôme Dumortier, Arnaud Del Bello, Jonathan Visentin, Valérie Dubois, Brigitte Le Bail, Martine Neau-Cransac, Valérie Hervieu, Teresa Antonini, and Nassim Kamar

Subjects
Graft Rejection, METAVIR Fibrosis Score, medicine.medical_specialty, medicine.medical_treatment, 030230 surgery, Liver transplantation, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Internal medicine, medicine, Risk of mortality, Humans, Retrospective Studies, Transplantation, Hepatology, medicine.diagnostic_test, business.industry, Graft Survival, Hazard ratio, Retrospective cohort study, Tissue Donors, Liver Transplantation, Liver biopsy, 030211 gastroenterology & hepatology, Surgery, Rituximab, business, medicine.drug
Abstract

After liver transplantation (LT), the role of preformed donor-specific anti-human leukocyte antigen antibodies (pDSAs) remains incompletely understood. We conducted a retrospective, case-control analysis to determine the impact of pDSAs after LT in 3 French transplant centers (Bordeaux, Lyon, and Toulouse). Among the 1788 LTs performed during the study period, 142 (7.9%) had at least 1 pDSA. The patient survival rate was not different between patients who received an LT with pDSAs and the matched-control group. A liver biopsy was performed 1 year after transplantation in 87 recipients. The metavir fibrosis score did not differ between both groups (1 ± 0.8 versus 0 ± 0.8; P = 0.80). However, undergoing a retransplantation (hazard ratio [HR] = 2.6, 95% confidence interval [CI], 1.02-6.77; P = 0.05) and receiving induction therapy with polyclonal antibodies (HR = 2.5; 95% CI, 1.33-4.74; P = 0.01) were associated with a higher risk of mortality. Nonetheless, high mean fluorescence intensity (MFI) donor-specific antibodies (ie, >10,000 with One Lambda assay or >5000 with Immucor assay) were associated with an increased risk of acute rejection (HR = 2.0; 95% CI, 1.12-3.49; P = 0.02). Acute antibody-mediated rejection was diagnosed in 10 patients: 8 recipients were alive 34 (1-125) months after rejection. The use of polyclonal antibodies or rituximab as an induction therapy did not reduce the risk of acute rejection, but it increased the risk of infectious complications. In conclusion, high MFI pDSAs increase the risk of graft rejection after LT, but they do not reduce medium-term and longterm patient survival. The use of a T or B cell-depleting agent did not reduce the risk of acute rejection.

Published
2019
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16. Polyclonal expansion of TCR Vb 21.3 + CD4 + and CD8 + T cells is a hallmark of multisystem inflammatory syndrome in children

Author

Olivier Dauwalder, David Klatzmann, Marie Duperril, Marion Moreews, Christine Lombard, Behrouz Kassai, Fanny Bajolle, Jean-Laurent Casanova, Anne-Laure Mathieu, Guillaume Monneret, Magali Perret, Rémi Pescarmona, Aurélie Portefaix, Jacqueline Marvel, Laurent Abel, Christophe Malcus, Tiphaine Louazon, Anne Moulin-Zinsch, Mehdi Mezidi, Lisa Giovannini-Chami, Omran Allatif, Hugues Patural, Thierry Walzer, Emilie Chopin, Francois Vandenesh, Encarnita Mariotti-Ferrandiz, Fabienne Venet, Céline Dupieux, Valérie Launay, Paul Bastard, Sophie Trouillet-Assant, Jean-Christophe Richard, Olivier Thaunat, Shen-Ying Zhang, Marine Villard, Samira Khaldi-Plassart, Kahina Saker, Alexandre Belot, Sophia Djebali, Marlène Dreux, Alicia Bellomo, Isabelle Rouvet, Robin Pouyau, Etienne Javouhey, Margaux Guerder, Sonia Teyssedre, Valérie Dubois, Kenz Le Gouge, Hugues Flodrops, Jean-Marie De Guillebon, 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), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hôpital Edouard Herriot [CHU - HCL], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de Reference des Staphylocoques, Université de Lyon, Centre hospitalier de Valence, Hôpital Louis Pradel [CHU - HCL], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Rockefeller University [New York], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hôpital de la Croix-Rousse [CHU - HCL], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-16-RHUS-0001,iMAP,iMAP(2016), Référent HAL, 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), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Immunology, T-cell receptor, Toxic shock syndrome, General Medicine, Human leukocyte antigen, Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Antigen, medicine, Cytotoxic T cell, 030212 general & internal medicine, Cytokine storm, CD8
Abstract

International audience; Multisystem inflammatory syndrome in children (MIS-C) is a delayed and severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease (KD) and toxic shock syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared with 16 KD, 58 TSS, and 42 coronavirus disease 2019 (COVID-19) cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFN-γ, sCD25, MCP1, and IL-1RA) in MIS-C, TSS, and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of patients with MIS-C and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3 + T cells from patients with MIS-C expressed high levels of HLA-DR, CD38, and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS, and acute COVID-19.

Published
2021
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17. Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection

Author

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

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

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

Published
2021

18. 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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19. Définition et standardisation des bilans d’histocompatibilité en fonction du parcours du patient et du type de donneur : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC) et de la Société Francophone d’Histocompatibilité et Immunogénétique (SFHI)

Author

Mamy Ralazamahaleo, Paul-Olivier Rouzaire, Ibrahim Yakoub-Agha, M Fort, Kahina Amokrane, Valérie Dubois, Nicolas Guillaume, Sandra Michiels, Anne Kennel, Catherine Faucher, Roberto Crocchiolo, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), and Université Clermont Auvergne (UCA)

Subjects
0301 basic medicine, Cancer Research, Standardization, High resolution, 03 medical and health sciences, 0302 clinical medicine, Time frame, Medicine, Radiology, Nuclear Medicine and imaging, Hla antibodies, ComputingMilieux_MISCELLANEOUS, Hematopoietic cell, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, General Medicine, Matched Unrelated Donor, medicine.disease, 3. Good health, Histocompatibility, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Medical emergency, Quality level, business
Abstract

Standardization of histocompatibility tests for allogeneic hematopoietic cell transplants, harmonization of information transmitted to clinicians are part of quality improvement and optimization of human and economic resources. New HLA typing technologies provide high-resolution information within a reasonable time frame. Knowledge of high-resolution HLA typing for the patient and their relatives is essential for a better interpretation of compatibilities. HLA-DPB1 typing must be considered in transplant field regardless of the donor type. The benefits of using search and match programs are considerable. It saves time and reduces additional typing costs by providing rapid information about the likelihood to identify a matched unrelated donor. A backup therapy considering alternative cell sources or treatment can therefore be quickly implemented. The importance of knowledge and consideration of patient immunization for donor choice was explored in previous workshops of the SFGM-TC (2018 and 2019). The published recommendations remain applicable. The routine follow-up protocol and in case of desensitization will be detailed here. This harmonization must be accompanied by the standardization of information to be returned to the clinician regarding the donor finding possibilities for the patient. This will guarantee a similar quality level in every center.

Published
2021
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20. Polyclonal expansion of TCR Vbeta 21.3

Author

Marion, Moreews, Kenz, Le Gouge, Samira, Khaldi-Plassart, Rémi, Pescarmona, Anne-Laure, Mathieu, Christophe, Malcus, Sophia, Djebali, Alicia, Bellomo, Olivier, Dauwalder, Magali, Perret, Marine, Villard, Emilie, Chopin, Isabelle, Rouvet, Francois, Vandenesh, Céline, Dupieux, Robin, Pouyau, Sonia, Teyssedre, Margaux, Guerder, Tiphaine, Louazon, Anne, Moulin-Zinsch, Marie, Duperril, Hugues, Patural, Lisa, Giovannini-Chami, Aurélie, Portefaix, Behrouz, Kassai, Fabienne, Venet, Guillaume, Monneret, Christine, Lombard, Hugues, Flodrops, Jean-Marie, De Guillebon, Fanny, Bajolle, Valérie, Launay, Paul, Bastard, Shen-Ying, Zhang, Valérie, Dubois, Olivier, Thaunat, Jean-Christophe, Richard, Mehdi, Mezidi, Omran, Allatif, Kahina, Saker, Marlène, Dreux, Laurent, Abel, Jean-Laurent, Casanova, Jacqueline, Marvel, Sophie, Trouillet-Assant, David, Klatzmann, Thierry, Walzer, Encarnita, Mariotti-Ferrandiz, Etienne, Javouhey, and Alexandre, Belot

Subjects
Adult, CD4-Positive T-Lymphocytes, SARS-CoV-2, Child, Preschool, Receptors, Antigen, T-Cell, alpha-beta, COVID-19, Cytokines, Humans, HLA-DR Antigens, CD8-Positive T-Lymphocytes, Child, Lymphocyte Activation, Systemic Inflammatory Response Syndrome
Abstract

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro

Published
2021

21. Superantigenic TCR Vbeta 21.3 signature in Multisystem Inflammatory Syndrome in Children

Author

Encarnita Mariotti-Ferrandiz, Marlène Dreux, Kenz Le Gouge, Aurélie Portefaix, Anne-Moulin-Zinsch, Alexandre Belot, Emilie Chopin, Marie Duperril, Marion Moreews, Hugues Patural, Thierry Walzer, Jean-Christophe Richard, Anne-Laure Mathieu, Robin Pouyau, Etienne Javouhey, Olivier Thaunat, Valérie Dubois, Hugues Flodrops, Behrouz Kassai, Marine Villard, Alicia Bellomo, Laurent Abel, Fabienne Venet, Samira Khaldi-Plassart, Sophia Djebali, David Klatzmann, Jacqueline Marvel, Sonia Teyssedre, Céline Dupieux, Tiphaine Louazon, Lisa Giovannini-Chami, Sophie Trouillet-Assant, Christine Lombard, Francois Vandenesh, Mehdi Mezidi, Shen-Ying Zhang, Guillaume Monneret, Jean-Laurent Casanova, Magali Perret, Rémi Pescarmona, Margaux Guerder, Paul Bastard, Christophe Malcus, and Isabelle Rouvet

Subjects
business.industry, medicine.medical_treatment, T cell, Toxic shock syndrome, medicine.disease, Cytokine release syndrome, Cytokine, medicine.anatomical_structure, Immune system, Immunology, medicine, Cytotoxic T cell, Interferon gamma, business, CD8, medicine.drug
Abstract

ObjectivesMultiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS).MethodsChildren with suspected MIS-C were included within the first week of diagnosis and a large scale immunoassay was performed to determein the immunologic signature of these patients.ResultsWe characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the Vβ21.3 T cell receptor β chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and Vβ21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing uncovered the polyclonal nature of the Vβ 21.3+ population. SARS-CoV2 antigene-specific production of interferon gamma in T cells was not increased in MIS-C T cells compared to COVID-19 patients suggesting the antigen-specific immune response in MIS-C patients is not pivotal to the manifestation.ConclusionsOur findings argue in favor of a strong activation of the immune system related to a superantigenic immune response in MIS-C with a specific polyclonal Vβ21.3 T cell expansion.Key messagesWhat is already known about this subject ?MIS-C occurs 3-5 weeks after acute SARS-CoV2 infection and overlap features of Toxic Shock syndrome and Kawasaki disease.MIS-C appears different in term of cytokine and autoantibodies generation from KD with subtle signs of T cells activationWhat does this study add?This study demonstrates that Vβ21.3+ CD4 and CD8 T cells are highly increased in about 50% of MIS-C and distinctive of the Vβ2+ expansion observed in toxic shock syndrome in This reflects a specific T cell activation and cytokine release syndrome similar to toxic shock syndromeHow mich this impact on clinical practice or future developments?Vβ21.3+ signature can be available on a short term basis by flowcytometry and represents a signature of the MIS-C.As for TSS, immunomodulating therapies may revert the superantigenic activation and resolve this life threatening pediatric condition.

Published
2021
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22. Characteristics of T- and NK-cell Lymphomas After Renal Transplantation: A French National Multicentric Cohort Study

Author

Valérie Moal, Véronique Leblond, Gilles Salles, Valérie Chatelet, Benoit Barrou, Alizée Maarek, Sophie Caillard, Christiane Mousson, Laurent Genestier, Luc Frimat, Antoine Durrbach, Vincent Pernin, Emmanuel Bachy, Philippe Rieu, Olivier Thaunat, Didier Ducloux, Valérie Dubois, Manon Charrier, Bénédicte Janbon, Thomas Barba, Dany Anglicheau, Antoine Thierry, Jacques Dantal, Gaelle Fossard, Anne-Elisabeth Heng, Mathias Büchler, Pierre-François Westeel, François Provôt, Denis Glotz, Elisabeth Cassuto, Jean-Philippe Rerolle, Philippe Grimbert, Philippe Gaulard, Jonathan M. Chemouny, Nacera Ouali, Christophe Mariat, and Emmanuel Morelon

Subjects
Adult, Male, medicine.medical_specialty, Skin Neoplasms, medicine.medical_treatment, Lymphoproliferative disorders, Disease, Lymphoma, T-Cell, Gastroenterology, Cohort Studies, hemic and lymphatic diseases, Internal medicine, Medicine, Humans, Prospective Studies, Aged, Transplantation, Chemotherapy, business.industry, Hazard ratio, Middle Aged, medicine.disease, Kidney Transplantation, surgical procedures, operative, Cohort, Registry data, Female, business, Cohort study
Abstract

BACKGROUND Posttransplant lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients. METHODS All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007. Crosschecking the registry data with 2 other independent national databases identified 58 cases of T/NK-cell PTLD. This cohort was then compared with (i) the 395 cases of B-cell PTLD from the registry, and of (ii) a cohort of 148 T/NK-cell lymphomas diagnosed in nontransplanted patients. RESULTS T/NK-cell PTLD occurred significantly later after transplantation and had a worse overall survival than B-cell PTLD. Two subtypes of T/NK-cell PTLD were distinguished: (i) cutaneous (28%) and (ii) systemic (72%), the latter being associated with a worse prognosis. Compared with T/NK-cell lymphomas of nontransplanted patients, overall survival of systemic T/NK-cell PTLD was worse (hazard ratio: 2.64 [1.76-3.94]; P < 0.00001). CONCLUSIONS This difference, which persisted after adjustment on tumoral mass, histological subtype, and extension of the disease at diagnosis could be explained by the fact that transplanted patients were less intensively treated and responded less to chemotherapy.

Published
2021

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

Author

Emmanuel Morelon, Jean-Christophe Olivo-Marin, Béatrice Charreau, Jasper Callemeyn, Virginie Mathias, Sarah Mezaache, Thomas Barba, Antoine Sicard, Olivier Thaunat, Vannary Meas-Yedid, Valérie Dubois, Maud Rabeyrin, Alice Koenig, Cécile Picard, Maarten Naesens, Frédérique Dijoud, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Laboratoire HLA, EFS, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Agence Nationale de la Recherche (ANR-16-CE17-0007-01) and the Fondation pour la Recherche Médicale (PME20180639518)., ANR-16-CE17-0007,PETTAR,Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe(2016), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Meas-Yedid, Vannary, and Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe - - PETTAR2016 - ANR-16-CE17-0007 - AAPG2016 - VALID

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

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

Published
2021
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24. [Definition and standardization of histocompatibility requests depending on patient course and donor type: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and the Francophone Society of Histocompatibility and Immunogenetics (SFHI)]

Author

Valérie, Dubois, Kahina, Amokrane, Roberto, Crocchiolo, Marylise, Fort, Nicolas, Guillaume, Anne, Kennel, Sandra, Michiels, Mamy, Ralazamahaleo, Paul-Olivier, Rouzaire, Ibrahim, Yakoub-Agha, and Catherine, Faucher

Subjects
Desensitization, Immunologic, Histocompatibility Testing, Hematopoietic Stem Cell Transplantation, Humans, Transplantation, Homologous, Unrelated Donors, Quality Improvement, HLA-DP beta-Chains, Societies, Medical, Tissue Donors, Follow-Up Studies
Abstract

Standardization of histocompatibility tests for allogeneic hematopoietic cell transplants, harmonization of information transmitted to clinicians are part of quality improvement and optimization of human and economic resources. New HLA typing technologies provide high-resolution information within a reasonable time frame. Knowledge of high-resolution HLA typing for the patient and their relatives is essential for a better interpretation of compatibilities. HLA-DPB1 typing must be considered in transplant field regardless of the donor type. The benefits of using search and match programs are considerable. It saves time and reduces additional typing costs by providing rapid information about the likelihood to identify a matched unrelated donor. A backup therapy considering alternative cell sources or treatment can therefore be quickly implemented. The importance of knowledge and consideration of patient immunization for donor choice was explored in previous workshops of the SFGM-TC (2018 and 2019). The published recommendations remain applicable. The routine follow-up protocol and in case of desensitization will be detailed here. This harmonization must be accompanied by the standardization of information to be returned to the clinician regarding the donor finding possibilities for the patient. This will guarantee a similar quality level in every center.

Published
2021

25. Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis

Author

Emmanuel Mignot, Pierre Labauge, Virginie Desestret, Matthew Murnane, Jérôme Honnorat, Claire Nocon, Clément Vialatte De Pémille, Thomas De Broucker, Anne-Laurie Pinto, Bastien Joubert, Irina Taifas, Sergio Muñiz-Castrillo, Valentin Wucher, Marie Benaiteau, Aditya Ambati, Julien Hedou, David M. Jones, Valérie Dubois, Laura Fechtenbaum, Alberto Vogrig, Dimitri Psimaras, Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), 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), Stanford University, Albany Medical College, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier Henri Mondor d'Aurillac, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Centre Hospitalier de Dax, Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Groupe Hospitalier Paris Saint-Joseph (hpsj), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), and Retiveau, Nolwenn

Subjects
Male, medicine.medical_specialty, Gastroenterology, Epilepsy, Atrophy, MESH: Aged, 80 and over, proteomics, limbic encephalitis, Internal medicine, Biopsy, medicine, MESH: Autoantibodies, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Pleocytosis, Depression (differential diagnoses), MESH: Limbic Encephalitis, Aged, Autoantibodies, MESH: Aged, Aged, 80 and over, MESH: Humans, MESH: Middle Aged, medicine.diagnostic_test, business.industry, MESH: Proteomics, Limbic encephalitis, Adenylate Kinase, adenylate kinase 5, human leucocyte antigen, Original Articles, Middle Aged, medicine.disease, Hyperintensity, MESH: Male, 3. Good health, MESH: Adenylate Kinase, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neurology (clinical), business, MESH: Female, Encephalitis
Abstract

Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66 years (range 48–94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR) = 13.4, 95% confidence interval (CI): 3.8–47.4], C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI: 2.9–42.5), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7–55.7), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI: 3.5–52.0) and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7–55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI: 4.8–57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.

Published
2021
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26. De Novo Complement-Binding Anti-HLA Antibodies in Heart Transplanted Patients Is Associated with Severe Cardiac Allograft Vasculopathy and Poor Long-Term Survival

Author

Guillaume Baudry, Matteo Pozzi, Matthieu Aubry, Elisabeth Hugon-Vallet, Raluca Mocan, Lara Chalabreysse, Philippe Portran, Jean-François Obadia, Olivier Thaunat, Nicolas Girerd, Valérie Dubois, Laurent Sebbag, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Groupement Hospitalier Lyon-Est (GHE), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), and BOZEC, Erwan

Subjects
immunology, de novo DSA, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, heart transplant, complement-binding DSA, cardiac allograft vasculopathy, General Medicine, et al. De Novo heart transplant, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract

Introduction: De novo anti-HLA donor specific antibodies (DSA) have been inconsistently associated with cardiac allograft vasculopathy (CAV) and long-term mortality. We tested whether C3d-binding de novo DSA were associated with CAV or long-term-survival. Methods: We included 282 consecutive patients without preformed DSA on coronary angiography between 2010 and 2012. Angiographies were classified according to CAV ISHLT grading. The primary outcome was a composite criterion of severe CAV or mortality. As the impact of de novo antibodies should be assessed only after appearance, we used a Cox regression with time-dependent covariables. Results: Of the 282 patients, 51(18%) developed de novo DSA during follow-up, 29 patients had DSA with C3d-binding ability (DSA+C3d+), and 22 were without C3d-binding ability (DSA+C3d-). Compared with patients without DSA, DSA+C3d+ patients had an increased risk for the primary outcome of severe CAV or mortality (adjusted HR = 4.31 (2.40–7.74) p < 0.001) and long-term mortality (adjusted HR = 3.48 (1.97–6.15) p < 0.001) whereas DSA+C3d- did not (adjusted HR = 1.04 (0.43–2.47) p = 0.937 for primary outcome and HR = 1.08 (0.45–2.61) p = 0.866 for mortality). Conclusion: According to this large monocentric study in heart transplant patients, donor specific antibodies were associated with worse clinical outcome when binding complement. DSA and their complement-binding ability should thus be screened for to optimize heart transplant patient follow-up.

Published
2022
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27. La chimiotaxie détourne la réponse cytotoxique des lymphocytes T alloréactifs, conférant une protection à l’endothélium vasculaire au cours du rejet cellulaire

Author

Maud Rabeyrin, N. Pallet, Y.C. Xu-Dubois, Olivier Thaunat, Valérie Dubois, Thomas Barba, M. Oberbarnscheidt, Emmanuel Morelon, and Alice Koenig

Subjects
Nephrology
Abstract

Introduction Le rejet cellulaire (TCMR) est caracterise par des lesions histologiques des compartiments tubulaires et interstitiels du greffon renal. Alors qu’elles expriment les molecules du CMH du donneur et qu’elles interagissent etroitement avec les lymphocytes T CD8+ cytotoxiques (LTc) alloreactifs, les cellules endotheliales (CE) du greffon semblent relativement epargnees au cours du TCMR. Description claire et complete de l’experience Les mecanismes qui sous-tendent cette observation ne sont pas connus. Methodes Une analyse transcriptomique « single cell » et la quantification de la transition endotheliale-mesenchymateuse (associee aux dommages endotheliaux) sur des biopsie de greffons nous ont permis de confirmer que les CE sont moins impactees que les cellules tubulaires epitheliales (CTE) au cours du TCMR. Pourtant nos experiences de cocultures ont montre que les CE mouraient avec la meme cinetique que les CTE lorsqu’elles etaient mises en contact avec des LTc alloreactifs, ecartant la possibilite d’un “privilege immunitaire” intrinseque. Resultats L’utilisation de techniques de microscopie intravitale dans un modele murin de transplantation renale a revele que la duree des interactions entre les LTc alloreactifs et les CE etait plus courte qu’avec les CTE du greffon, une observation validee dans des biopsies humaines. Cette difference dans la qualite des interactions semble due au fait que les LTc exposes a un gradient de chimiokine (comme c’est le cas lors de leur migration de la circulation vers les CTE du greffon) semblent repondre en priorite a ce signal au detriment de la mise en place d’une synapse cytotoxique. Une hypothese originale, que nous avons validee dans un modele in vitro. Conclusion Les CE sont relativement epargnees au cours du TCMR du fait des gradients chimiotactiques, qui detournent l’action cytotoxique les LTc alloreactifs au detriment des cellules epitheliales tubulaires. Ce privilege immunologique « extrinseque », a des implications majeures dans la reponse immunitaire physiologique, qui doit preserver la vascularisation des tissus.

Published
2021
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28. Massive clonal expansion of polycytotoxic skin and blood CD8

Author

Axel Patrice, Villani, Aurore, Rozieres, Benoît, Bensaid, Klara Kristin, Eriksson, Amandine, Mosnier, Floriane, Albert, Virginie, Mutez, Océane, Brassard, Tugba, Baysal, Mathilde, Tardieu, Omran, Allatif, Floriane, Fusil, Thibault, Andrieu, Denis, Jullien, Valérie, Dubois, Catherine, Giannoli, Henri, Gruffat, Marc, Pallardy, François-Loïc, Cosset, Audrey, Nosbaum, Osami, Kanagawa, Janet L, Maryanski, Daniel, Yerly, Jean-François, Nicolas, and Marc, Vocanson

Subjects
integumentary system, musculoskeletal, neural, and ocular physiology, Immunology, Receptors, Antigen, T-Cell, SciAdv r-articles, macromolecular substances, CD8-Positive T-Lymphocytes, Clone Cells, Immunophenotyping, nervous system, Stevens-Johnson Syndrome, Humans, Prospective Studies, Research Articles, Research Article
Abstract

This study highlights the key role of polycytotoxic CD8+ T cells in the severity of toxic epidermal necrolysis., Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8+ T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase. Deep T cell receptor (TCR) repertoire sequencing identified massive expansion of unique CDR3 clonotypes in blister cells. The same clones were highly expanded in patient’s blood, and the degree of their expansion showed significant correlation with disease severity. By transducing α and β chains of the expanded clonotypes into a TCR-defective cell line, we confirmed that those cells were drug specific. Collectively, these results suggest that the relative clonal expansion and phenotype of skin-recruited CTLs condition the clinical presentation of cutaneous adverse drug reactions.

Published
2020

29. HLA-B leader and survivorship after HLA-mismatched unrelated donor transplantation

Author

Stephen R. Spellman, Mary M. Horowitz, Jean Villard, Ted Gooley, Machteld Oudshoorn, Dianne De Santis, Katharine C. Hsu, Mats Bengtsson, Valérie Dubois, Alejandro Madrigal, Philip A. Stevenson, Effie W. Petersdorf, Mary Carrington, Mari Malkki, Yasuo Morishima, and Caroline McKallor

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Adolescent, Immunology, Graft vs Host Disease, Human leukocyte antigen, Survivorship, Biochemistry, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, Genotype, medicine, Humans, Child, Aged, Retrospective Studies, ddc:616, Transplantation, HLA-DQB1, business.industry, Histocompatibility Testing, Hazard ratio, Hematopoietic Stem Cell Transplantation, Infant, Cell Biology, Hematology, Odds ratio, Middle Aged, medicine.disease, Allografts, HLA-B, Survival Rate, 030104 developmental biology, Graft-versus-host disease, HLA-B Antigens, Child, Preschool, Female, business, Unrelated Donors, 030215 immunology
Abstract

Hematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B-mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1-mismatched MM patients compared with HLA-DQB1-mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1-mismatched MM or MT patients compared with HLA-DRB1-mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.

Published
2020

30. Humoral Alloreactivity in VCA Recipients: Should We Learn From Our Experience?

Author

Antoine, Sicard, Jean, Kanitakis, Valérie, Dubois, Emmanuel, Morelon, and Olivier, Thaunat

Subjects
Graft Rejection, Vascularized Composite Allotransplantation, Treatment Outcome, Isoantibodies, Histocompatibility, Graft Survival, Animals, Humans, Plasmapheresis, Composite Tissue Allografts, Immunosuppressive Agents, Immunity, Humoral
Abstract

Initially overlooked in favor of T cell-mediated rejection, the importance of the humoral alloimmune response has progressively emerged. As a result, antibody-mediated rejection is now widely recognized as the main cause of late allograft loss in most (if not all) types of solid-organ transplantation. Over the last 2 decades, vascularized composite allotransplantation (VCA) has appeared for replacing tissue defects in patients for whom no other satisfactory reconstructive options were available. Although it is now clear that VCA recipients can develop donor-specific antibodies, conclusions made in solid organ transplantation regarding antibody-mediated rejection may not systematically apply to VCA. Here, we propose to use the experience gained in organ transplantation to shed light on the path that shall be followed to evaluate and manage humoral alloreactivity in VCA recipients.

Published
2020

31. [Relevance of antibodies in hematopoietic stem cell transplantation: Antibodies anti-HLA, anti-platelets, anti-granulocytes, anti-erythrocytes and anti-MICA. Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]

Author

Florent, Delbos, Laura, Blouin, Bénédicte, Bruno, Roberto, Crocchiolo, Judith, Desoutter, Marie, Detrait, Khan Tien, Nguyen-Lejarre, Catherine, Giannoli, Claude, Lemarié, Virginie, Renac, Ibrahim, Yakoub-Agha, and Valérie, Dubois

Subjects
Blood Platelets, Erythrocytes, HLA Antigens, Histocompatibility Antigens Class I, Hematopoietic Stem Cell Transplantation, Humans, Antigens, Human Platelet, Antibodies, ABO Blood-Group System, Granulocytes
Abstract

The presence of allo-antibodies in the serum of a recipient awaiting hematopoietic stem cell transplantation (HSCT) may have an impact on transfusion efficiency and/or donor choice, especially in the absence of an identical sibling donor. Prior to transplantation, donor specific anti-HLA (Human Leukocyte Antigen) antibodies (DSA) have a recognized effect on transplant outcome, correlated with the increasing MFI value and with the ability of such antibody to fix the complement fraction. Anti-platelet antibodies (anti-HLA class I and anti-HPA [Human Platelet Antigen]) are better involved in transfusion inefficiency and can be responsible for refractory status. ABO incompatibilities require a specific treatment of the graft in presence of high titer to avoid hemolytic adverse effects. Investigations of these antibodies should be carried out on a regular basis in order to establish appropriate transfusion recommendation, select an alternative donor when possible or adapt the source of cells. After transplantation, in case of delayed recovery or graft rejection, long term aplasia, persistent mixed chimerism or late release, and after elimination of the main clinical causes, a biological assessment targeted on the different type of antibodies will have to be performed in order to orient towards the cause or the appropriate therapy. Further studies should be carried out to determine the impact of anti-MICA antibodies and recipient specific anti-HLA antibodies, on the outcome of the transplantation.

Published
2020

32. [Haploidentical hematopoietic stem cell transplant: How to choose the best donor? Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]

Author

Bénédicte Bruno, C. Giannoli, Valérie Dubois, Stéphanie Nguyen, Pascale Loiseau, Raynier Devillier, Paul-Olivier Rouzaire, Patrice Chevallier, Ibrahim Yakoub-Agha, Kahina Amokrane, Mhamed Harif, Gwendaline Guidicelli, Florent Delbos, Yves Beguin, Pauline Varlet, CCSD, Accord Elsevier, Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie, Université de Liège, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), 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), Laboratoire d'Histocompatibilité et d'Immunogénétique [EFS Nantes], Etablissement Français du Sang [Nantes], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Etablissement français du sang- Rhône-Alpes [Lyon], Service d'immunologie et d'immunogénétique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Immunogénétique humaine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Universitaire de Lille (CHU de Lille), Department of Microbiology and Immunology, East Carolina University [Greenville] (ECU), and University of North Carolina System (UNC)-University of North Carolina System (UNC)

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Myeloid, Haploidentical transplantation, medicine.medical_treatment, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, Hematopoietic stem cell transplantation, DSA, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Donor choice, medicine, Radiology, Nuclear Medicine and imaging, Greffe haplo-identique, 10. No inequality, Gynecology, business.industry, Hematology, General Medicine, medicine.disease, 3. Good health, Lymphoma, [SDV] Life Sciences [q-bio], Specific antibody, 030104 developmental biology, medicine.anatomical_structure, Oncology, Bone transplantation, 030220 oncology & carcinogenesis, Choix du donneur, Bone marrow, Stem cell, business
Abstract

International audience; Haploidentical hematopoietic stem cell transplantation has been growing steadily since 2012. The SFGM-TC has twice published guidelines concerning T-cell repleted haploidentical grafts with high dose cyclophosphamide post-transplantation. The 2013 workshop recommended using the non-myeloablative Baltimore protocol with bone marrow and developed prospective protocols to evaluate these transplantations. The 2015 workshop reported improved results of reduced conditioning regimens in Hodgkin's lymphoma and intensive conditioning in myeloid hemopathies, and a similar outcome with 10/10 HLA matched donor with the same disease-risk score thus raising the question of the qualifier "alternative" for haploidentical transplants. The current work concerns the criteria for selecting the donor. The main criterion remains the absence of anti-HLA antibodies directed against the donor present in the recipient sera (DSA - Donor Specific Antibodies). In case of DSA and in the absence of an alternative donor, desensitization protocols exist. The other criteria are impossible to prioritize: age, sex, CMV, and blood type. The degree of relatedness and the number of HLA incompatibilities do not seem to be a criterion of choice. The 'ideal' donor would be a young man, CMV-matched, without major ABO incompatibility with a marrow transplant. There is insufficient data for the KIR-ligand and NIMA/NIPA mismatch. Peripheral stem cell grafts appear to yield more acute GVHD than bone marrow grafts after intensive conditioning, but with comparable survival rates. Based on the literature review, the comparison of haploidentical with unrelated donors encourages inclusion in existing national protocols randomizing these different donors.

Published
2020
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33. Role of HLA-DP Expression in Graft-Versus-Host Disease After Unrelated Donor Transplantation

Author

Ted Gooley, Machteld Oudshoorn, Dianne De Santis, Valérie Dubois, Mari Malkki, Yasuo Morishima, Phil Stevenson, Katharina Fleischhauer, Stephen R. Spellman, Mats Bengtsson, Caroline McKallor, Jean Villard, Mary Carrington, Mary M. Horowitz, Effie W. Petersdorf, and J. Alejandro Madrigal

Subjects
Male, musculoskeletal diseases, HLA-DP Antigens, Cancer Research, Transplantation Conditioning, Medizin, Graft vs Host Disease, HLA-DP, chemical and pharmacologic phenomena, Disease, Unrelated Donor, immune system diseases, RAPID COMMUNICATIONS, Humans, Medicine, skin and connective tissue diseases, ddc:616, Hematopoietic cell, business.industry, Extramural, Hematopoietic Stem Cell Transplantation, medicine.disease, Transplantation, Graft-versus-host disease, surgical procedures, operative, Oncology, Immunology, Female, Unrelated Donors, business
Abstract

PURPOSE The main aim of this study was to evaluate the significance of HLA-DPB1 expression in acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) from HLA-A, -B, -C, -DRB1, -DQB1–matched and –mismatched unrelated donors. PATIENTS AND METHODS Between January 1, 2017, and January 10, 2019, we assessed 19,136 patients who received HCT from an HLA-A, -B, -C, -DRB1, -DQB1–matched or –mismatched unrelated donor performed in Australia, the European Union, Japan, North America, and the United Kingdom between 1988 and 2016. Among transplant recipients with one HLA-DPB1 mismatch, the patient’s mismatched HLA-DPB1 allotype was defined as low or high expression. Multivariable regression models were used to assess risks of GVHD associated with high expression relative to low expression HLA-DPB1 mismatches. The effect of increasing numbers of HLA-DPB1 mismatches on clinical outcome was assessed in HLA-mismatched transplant recipients. RESULTS In HLA-A, -B, -C, -DRB1,-DQB1–matched transplant recipients, donor mismatching against one high-expression patient HLA-DPB1 increased moderate (odds ratio [OR], 1.36; P = .001) and severe acute GVHD (OR, 1.32; P = .0016) relative to low-expression patient mismatches, regardless of the expression level of the donor’s mismatched HLA-DPB1. Among transplant recipients with one HLA-A, -B, -C, -DRB1, or -DQB1 mismatch, the odds of acute GVHD increased with increasing numbers of HLA-DPB1 mismatches (OR, 1.23 for one; OR, 1.40 for two mismatches relative to zero mismatches for moderate GVHD; OR, 1.19 for one; OR, 1.40 for two mismatches relative to zero for severe GVHD), but not with the level of expression of the patient’s mismatched HLA-DPB1 allotype. CONCLUSION The level of expression of patient HLA-DPB1 mismatches informs the risk of GVHD after HLA-A, -B, -C, -DRB1, -DQB1–matched unrelated HCT, and the total number of HLA-DPB1 mismatches informs the risk of GVHD after HLA-mismatched unrelated HCT. Prospective consideration of HLA-DPB1 may help to lower GVHD risks after transplantation.

Published
2020

34. 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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35. Prevalence, Risk Factors, and Impact of Donor‐Specific Alloantibodies After Adult Liver Transplantation

Author

Jérôme Dumortier, Olivier Boillot, Domitille Poinsot, Christine Chambon-Augoyard, Stéphanie Ducreux, Patrice Andre, Philip Robinson, Jean-Yves Scoazec, Olivier Guillaud, Valérie Hervieu, Alexie Bosch, Valérie Dubois, and Katia Vandevoorde

Subjects
Adult, Graft Rejection, Male, medicine.medical_specialty, medicine.medical_treatment, 030230 surgery, Liver transplantation, Tacrolimus, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, HLA Antigens, Isoantibodies, Liver Cirrhosis, Alcoholic, Risk Factors, Internal medicine, Prevalence, medicine, Humans, Survival analysis, Retrospective Studies, Transplantation, Hepatology, business.industry, Incidence, Incidence (epidemiology), Graft Survival, Hazard ratio, Retrospective cohort study, Middle Aged, Survival Analysis, Transplant Recipients, Liver Transplantation, Cross-Sectional Studies, Treatment Outcome, Population study, Trough level, Female, 030211 gastroenterology & hepatology, Surgery, business, Immunosuppressive Agents, Follow-Up Studies
Abstract

The incidence and impact of anti-human leukocyte antigen donor-specific alloantibodies (DSAs) developing after liver transplantation (LT) remains controversial and not extensively studied. The aim of the present study was to assess the incidence of DSAs, to identify risk factors for the development of DSAs, and to understand the impact of DSAs in a large population of adult LT recipients. This single-center retrospective study included all adult patients who underwent a first LT between 2000 and 2010 in our center. The study population mainly consisted of male patients, the mean age was 52.4 years, and the main indication was alcoholic cirrhosis (54.1%). From the 297 patients included in the cross-sectional study, 14 (4.7%) had preformed DSAs, and 59 (19.9%) presented de novo DSAs (12.2% at 1 year, 13.4% at 5 years, and 19.5% at 10 years). Multivariate analysis found that female donor sex (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.12-2.01; P = 0.01) and delay between LT and DSA screening (HR, 1.10; 95% CI, 1.01-1.20; P = 0.03) were associated with occurrence of de novo DSAs. From the 190 patients included in the subgroup longitudinal analysis, exposure to tacrolimus (mean trough level during the periods 0-2 years and 0-3 years) was significantly lower for patients having DSAs at 5 years. Concerning histology, only acute rejection (P = 0.04) and portal fibrosis ≥2 (P = 0.02) were more frequent at 1 year for patients with DSAs. Patient survival and graft survival were not significantly different according to the presence or not of DSAs at 1 year. Among the 44 patients who had de novo or persistent preformed DSAs, the diagnosis of antibody-mediated rejection was made in 4 (9.1%) patients after 1, 47, 61, and 74 months following LT. In conclusion, the results of the present study suggest that DSAs are observed in a minority of LT adult patients, with limited overall impact on graft and patient outcome.

Published
2018
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36. Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome

Author

Elisabet Ars, Claire Dossier, José Ballarín, Stéphanie Debette, Pierre Ronco, Eric Letouzé, Hanna Debiec, Tabassome Simon, Siham Chafai Elalaoui, Matthias Kretzler, Georges Deschênes, Marina Vivarelli, Manuela Colucci, Valery Elie, Matthew G. Sampson, Philippe Amouyel, Evelyne Jacqz-Aigrain, Christopher E. Gillies, Valérie Dubois, Francesco Emma, Abdelaziz Sefiani, Rosemary K B Putler, Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe labellisée Ligue contre le Cancer, Labex Immuno-oncology, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine [Bobigny], Université Paris 13 (UP13)-Sorbonne Paris Cité, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Pediatric Nephrology [Ann Arbor, MI, USA] (School of Medicine), University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Nephrology and Dialysis Department [Rome, Italy], Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù [Rome, Italy], Molecular Biology Laboratory [Barcelona, Spain] (Fundació Puigvert - UAB), Universitat Autònoma de Barcelona (UAB)-Instituto de Investigaciones Biomédicas Sant Pau [Barcelona, Spain]-Fundació Puigvert [Barcelona, Spain], Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, 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, Droit et Santé, Department of Medical Genetics [Rabat, Morocco], Institut National d’Hygiène [Rabat, Morocco], Human Genomic Center [Rabat, Morocco], Université Mohamed V - Souissi, Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche Clinique de l’Est Parisien [CHU Saint-Antoine] (URC-EST), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Internal Medicine and Computational Medicine and Bioinformatics [Ann Arbor, MI, USA], Department of Nephrology [Barcelona, Spain], Fundación Puigvert [Barcelona, Spain], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This study was funded by European Research Council grant ERC-2012- ADG_20120314 (grant agreement 322947) and Agence Nationale pour la Recherche 'Genetransnephrose' grant ANR-16-CE17-004-01. M.G.S. is supported by the Charles Woodson Clinical Research Fund and National Institutes of Health grant R01-DK108805. The Nephrotic Syndrome Study Network Consortium (NEPTUNE, U54-DK-083912) is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Disease Clinical Research Network (RDCRN) supportedthrough a collaboration between the Office of Rare Diseases Research(ORDR), the NCATS, and the National Institute of Diabetes, Digestive,and Kidney Diseases. The RDCRN is an initiative of the ORDR of theNCATS. Additional funding and/or programmatic support for thisproject has also been provided by the University of Michigan, NephCureKidney International, and the Halpin Foundation. The NEPHROVIRcohort has been supported by two grants from the Programme Hospitalier de Recherche Clinique: grants PHRC 2007-AOM07018 and PHRC 2011-AOM11002. The NEPHROVIR network is coordinated by the Pediatric Nephrology Unit of Robert Debré Hospital, the 'Unité de Recherche Clinique de l’Est Parisien,' and the 'Délégation de la Recherche Clinique de la Région Ile-de-France.' M.V. and M.C. are supported by the Associazone per la Cura del bambino Nefropatico Organizzazione Non Lucrativa di Utilità Sociale., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Universitat Autònoma de Barcelona (UAB)-Fundació Puigvert [Barcelona, Spain]-Instituto de Investigaciones Biomédicas Sant Pau [Barcelona, Spain], 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), Université Mohammed V de Rabat [Agdal] (UM5), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Département de Néphrologie = Service de Néphrologie et Dialyses [CHU Tenon], CHU Tenon [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), and RONCO, Pierre

Subjects
Male, 0301 basic medicine, 030232 urology & nephrology, Genome-wide association study, Cohort Studies, 0302 clinical medicine, Africa, Northern, HLA-DQ beta-Chains, Medicine, Child, Genetics, nephrotic syndrome, genetic renal disease, General Medicine, Phenotype, Italy, Nephrology, Child, Preschool, Cohort, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Steroids, France, pediatrics, Quantitative Trait Loci, Black People, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, HLA-DQ Antigens, Up Front Matters, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, SNP, Allele, Alleles, Genetic association, focal segmental glomerulosclerosis, genome-wide association study, Butyrophilins, business.industry, HLA-DR Antigens, Genetic architecture, HLA-DRB5 Chains, 030104 developmental biology, Spain, Case-Control Studies, Expression quantitative trait loci, gene expression, business, HLA-DRB1 Chains
Abstract

Background Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort. Methods We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular cis -expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts. Results Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3′ untranslated region of HLA-DQB1 ( P =9.3×10 −23 ). Conditional analysis identified two additional independent risk alleles upstream of HLA-DRB1 (rs28366266, P =3.7×10 −11 ) and in the 3′ untranslated region of BTNL2 (rs9348883, P =9.4×10 −7 ) within introns of HCG23 and LOC101929163 . These three risk alleles were independent of the risk haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1. Conclusions Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.

Published
2018
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38. Après traitement d’un rejet humoral aigu, la réalisation d’une biopsie de contrôle permet de stratifier le risque de perte de greffon rénal

Author

Olivier Thaunat, A. Bouchet, J. Olagne, Sophie Caillard, Alice Koenig, B. Muller, A. Parissiadi, Valérie Dubois, Maud Rabeyrin, and Emmanuel Morelon

Subjects
Nephrology
Abstract

Introduction La survenue d’un rejet humoral, c’est-a-dire medie par l’apparition d’anticorps specifiques du donneur (DSA), represente desormais la premiere cause de perte de transplant renal. Les protocoles de traitement actuels, associant la plasmapherese et l’administration d’immunoglobulines polyvalentes a une majoration de l’immunosuppression de base permettent uniquement de ralentir la progression inexorable vers l’insuffisance renale terminale, avec une efficacite tres variable selon les individus. Evaluer correctement la reponse au traitement est un element pronostique indispensable de la strategie de surveillance du patient atteint de rejet humoral, et permet de guider l’utilisation des traitements de seconde ligne. Description Quatre-vingt-un patients traites pour un rejet humoral aigu entre 2004 et 2017, avec une biopsie de controle post-traitement disponible, ont ete inclus dans une etude retrospective bicentrique (centre hospitaliers universitaires de Lyon et Strasbourg). Methodes L’evolution apres traitement des parametres de suivi cliniques, histologiques et immunologiques a ete analysee. Resultats L’evolution des lesions de rejet humoral sur la biopsie (disparition, persistance ou progression) correlait avec le risque de perte du transplant renal (Logrank test, p = 0,001). Les patients dont les lesions ont disparu avaient une survie du transplant d’environ 80 % a 10 ans. Les patients qui avaient une persistance ou une progression des lesions histologiques sur la biopsie de controle apres traitement avaient un risque plus eleve de perte du transplant (HR : 3,91, p = 0,04 ; HR : 5,15, p = 0,02 respectivement). Aucun des parametres non invasifs habituellement utilises apres traitement pour surveiller l’intensite de la reponse humorale (evolution de la MFI du DSA immunodominant) ou le declin de la fonction renale (perte de DFG, persistance d’une proteinurie) n’a permis de predire l’evolution des lesions histologiques ( Fig. 1 ). Conclusion La surveillance invasive de l’evolution des lesions humorales par une biopsie de controle quelques mois apres traitement du rejet humoral aigu est un outil fiable pour predire la survie du greffon a long terme.

Published
2021
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39. Corrigendum to Berchtold L, Letouzé E, Alexander MP, et al. HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients. Kidney Int. 2021;99:671–685

Author

Valérie Dubois, Eric Letouzé, Paul Brenchley, Christophe Legendre, Pierre Ronco, Philippe Rieu, Manish J. Gandhi, Hanna Debiec, Vincent Vuiblet, Maryvonne Hourmant, Petra Mrázová, Sylvain Guibert, Ann M. Moyer, Guillaume Canaud, Jack F.M. Wetzels, Anne Els van de Logt, José Aurelio Ballarín Castan, Christiane Mousson, Patrick Hamilton, Nadhir Yousfi, Charlène Levi, Mariam P. Alexander, Ondřej Viklický, B. Moulin, Gabriel Choukroun, Lena Berchtold, Armando Torres, Josep M. Cruzado, and Vladimir Tesar

Subjects
Kidney, medicine.medical_specialty, business.industry, INT, medicine.disease, Gastroenterology, Kidney transplant, medicine.anatomical_structure, Membranous nephropathy, Nephrology, Internal medicine, Risk allele, medicine, business
Published
2021
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40. Étude du chimérisme après allogreffe de cellules hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Author

Pauline Varlet, Jacques-Olivier Bay, Pascaline Etancelin, Christophe Ferrand, Mehdi Alizadeh, Olivier Farchi, Valérie Dubois, Ibrahim Yakoub-Agha, Virginie Renac, Laure Goursaud, Jean Bourhis, Isabelle Mollet, HLA Department, EFS Rhone-Alpes, Etablissement français du sang [Rennes] (EFS Bretagne), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier Universitaire de Lille (CHU de Lille), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Pasteur de Lille, and 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)

Subjects
03 medical and health sciences, Cancer Research, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Radiology, Nuclear Medicine and imaging, Hematology, General Medicine, ComputingMilieux_MISCELLANEOUS, 3. Good health, 030215 immunology
Abstract

Resume L’analyse du chimerisme est une etape importante pour le suivi de l’allogreffe de cellules souches hematopoietiques. Elle permet de quantifier chez les patients allogreffes l’origine donneuse ou receveuse d’une population cellulaire obtenue a partir d’un prelevement sanguin ou medullaire. En complement des resultats de l’hemogramme, cette technique est indispensable pour verifier la qualite de la prise du greffon. L’objectif de cet article est ainsi de proposer des recommandations quant aux techniques utilisees, a l’analyse des resultats obtenus et aux decisions therapeutiques potentielles dans le cadre des allogreffes de CSH realisees pour des pathologies malignes et non malignes.

Published
2017
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41. Deleterious impact of C3d-binding donor-specific anti-HLA antibodies after pediatric liver transplantation

Author

Valérie Dubois, Alain Lachaux, Eduardo Couchonnal, Olivier Guillaud, Christine Rivet, Jérôme Dumortier, Stéphanie Ducreux, Patrice Andre, Rémi Dubois, Sophie Collardeau-Frachon, Alexie Bosch, Jean-Yves Scoazec, Valérie Hervieu, and Olivier Boillot

Subjects
Graft Rejection, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Immunology, Human leukocyte antigen, 030230 surgery, Liver transplantation, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Antigen, HLA Antigens, Isoantibodies, Biliary atresia, Internal medicine, medicine, Humans, Immunology and Allergy, Hla antibodies, Child, Transplantation, biology, business.industry, Histocompatibility Testing, Infant, Liver Failure, Acute, medicine.disease, Survival Analysis, Liver Transplantation, body regions, Cross-Sectional Studies, Complement C3d, Child, Preschool, Cohort, biology.protein, Female, 030211 gastroenterology & hepatology, Antibody, business, Pediatric population
Abstract

The prevalence and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation (LT) have not been extensively studied, especially in pediatric population.The present cross-sectional study included 100 patients who underwent a first LT in childhood. Anti HLA immunization study was performed at a single time point during routine follow-up using Luminex® single antigen tests with classical anti-IgG conjugate and anti-C3d conjugate.The main indication for LT was biliary atresia (52%) and median age at LT was 4.6years. The median time between LT and DSA assessment was 7.8years (range 1-21years). DSA was identified in twenty-four patients (24%) after LT, with a prevalence of 8%, 28%, 33%, 50%, respectively 0-5years, 5-10years, 10-15years and15years after LT. DSA were mainly class II (23/24) with a mean MFI of 9.731±5.489 and 18 (79.3%) were C3d-binding DSA. Multivariate analysis disclosed that time elapsed since LT (p0.01) and history of fulminant hepatitis (p=0.04) were significantly associated with a higher rate of DSA. Liver function tests (at time of DSA assessment) were not different according to the presence or not of DSA (or C3d-binding DSA). Regarding histology, the DSA group had a higher rate of chronic rejection, cirrhosis and centrilobular fibrosis or cirrhosis. In addition, patients with C3d-binding DSA and high MFI (10,000) had a significant poorer long-term graft survival (p=0.03).In our pediatric cohort of LT, prevalence of DSA was high and increased regularly with time. Presence of C3d positive-DSA with high MFI was associated with a higher rate of graft loss.

Published
2017
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42. Face Transplantation: Partial Graft Loss of the First Case 10 Years Later

Author

Jean-Michel Dubernard, Emmanuel Morelon, Sylvie Testelin, Olivier Thaunat, Gabriel Choukroun, Palmina Petruzzo, Stéphanie Dakpé, Lionel Badet, Valérie Dubois, Jean Kanitakis, and Bernard Devauchelle

Subjects
medicine.medical_specialty, Necrosis, medicine.medical_treatment, 030230 surgery, 03 medical and health sciences, 0302 clinical medicine, medicine, Carcinoma, Immunology and Allergy, Pharmacology (medical), Transplantation, Lung, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Eculizumab, medicine.disease, Thrombosis, Surgery, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Plasmapheresis, medicine.symptom, business, medicine.drug
Abstract

Ten years after the first face transplantation, we report the partial loss of this graft. After two episodes of acute rejection (AR) occurred and completely reversed in the first posttransplantation year, at 90 months posttransplantation the patient developed de novo class II donor-specific antibodies, without clinical signs of AR. Some months later, she developed several skin rejection episodes treated with steroid pulses. Despite rapid clinical improvement, some months later the sentinel skin graft underwent necrosis. Microscopic examination showed intimal thickening, thrombosis of the pedicle vessel, and C4d deposits on the endothelium of some dermal vessels of the facial graft. Flow magnetic resonance imaging of the facial graft showed a decrease of the distal right facial artery flow. Three steroid pulses of 500 mg each, followed by intravenous immunoglobulins (2 g/kg), five sessions of plasmapheresis, and three cycles of bortezomib 1.3 mg/m2 , were administered. Despite rescue therapy with eculizumab, necrosis of the lips and the perioral area occurred, which led to surgical removal of the lower lip, labial commissures, and part of the right cheek in May 2015. In January 2016, the patient underwent conventional facial reconstruction because during the retransplantation evaluation a small-cell lung carcinoma was discovered, causing the patient's death in April 2016.

Published
2017
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43. Total donor chimerism with bone marrow GVHD after multivisceral transplantation

Author

Cécile Chambrier, Mauricette Michallet, Olivier Boillot, Jérôme Dumortier, Assia Eljaafari, Adriana Plesa, Valérie Dubois, Mohamad Sobh, Laure Lebras, Arnaud Hot, and Vincent Alcazer

Subjects
medicine.medical_specialty, Fatal outcome, business.industry, Donor chimerism, Hematology, 030204 cardiovascular system & hematology, Surgery, 03 medical and health sciences, Multivisceral transplantation, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Bone marrow, business
Published
2018
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44. Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies

Author

Véronique Rogemond, Sergio Muñiz-Castrillo, Ling Lin, Emmanuel Mignot, Valérie Dubois, Nicole Fabien, Alberto Vogrig, Aditya Ambati, Jérôme Honnorat, Bastien Joubert, and Géraldine Picard

Subjects
Adult, Male, endocrine system diseases, Cerebellar Ataxia, Genome-wide association study, Human leukocyte antigen, Comorbidity, Stiff-Person Syndrome, HLA-DQ alpha-Chains, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Stiff person syndrome, HLA-DQ Antigens, Limbic Encephalitis, medicine, Genetic predisposition, HLA-DQ beta-Chains, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Allele, Aged, Autoantibodies, Glutamic acid decarboxylase, Aged, 80 and over, Type 1 diabetes, biology, business.industry, Glutamate Decarboxylase, Haplotype, nutritional and metabolic diseases, Middle Aged, medicine.disease, HLA, Diabetes Mellitus, Type 1, Neurology, Haplotypes, Immunology, biology.protein, Female, Neurology (clinical), Antibody, Cerebellar ataxia, Limbic encephalitis, business, 030217 neurology & neurosurgery, HLA-DRB1 Chains
Abstract

The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01–DQB1*02:01–DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p = 0.03, OR 3.96, 95% CI [1.54–10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p = 0.05, OR 3.54, 95% CI [1.40–8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p = 0.05, OR 0.15, 95% CI [0.02–0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers (p > 0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.

Published
2019

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

Author

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

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

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

Published
2019
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46. Class II Human Leukocyte Antigen Epitope Mismatch Predicts De Novo Donor‐Specific Antibody Formation After Liver Transplantation

Author

Céline Thevenin, Georges-Philippe Pageaux, Olivier Boillot, Olivier Guillaud, Matthias Niemann, Valérie Dubois, Magdalena Meszaros, Stéphanie Faure, Jérôme Dumortier, José Ursic-Bedoya, Service Médico-Chirurgical des Maladies de l'Appareil Digestif et de Transplantation Hépatique, CHU Saint-Eloi, Etablissement français du sang- Rhône-Alpes [Lyon], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hospices Civils de Lyon (HCL), Hôpital Edouard Herriot [CHU - HCL], Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Michel-Avella, Amandine

Subjects
Transplantation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hepatology, business.industry, Donor specific antibodies, medicine.medical_treatment, Human leukocyte antigen, 030230 surgery, Liver transplantation, Epitope, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immunology, Medicine, Surgery, business, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

International audience

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

Author

Vannary Meas-Yedid, Sébastien Dussurgey, Thomas Barba, Emmanuel Morelon, Maud Rabeyrin, Romain Guillemain, Maud Racapé, Jean-Paul Duong-Van-Huyen, Valérie Dubois, Chien-Chia Chen, Antoine Marçais, Stéphanie Ducreux, Jean-Christophe Olivo-Marin, Maarten Naesens, Jean-Luc Taupin, Antoine Sicard, Antonino Nicoletti, Olivier Thaunat, Patrick Bruneval, Béatrice Charreau, Helena Paidassi, Alice Koenig, Virginie Mathias, Alexandre Loupy, Thierry Walzer, Thierry Defrance, Jasper Callemeyn, Paidassi, Helena, Instituts Hospitalo-Universitaires B - Organ ProtEction and ReplAcement - - OPeRa2010 - ANR-10-IBHU-0004 - IBHU - VALID, Phenotypage pour le cancer - - PHENOCAN2011 - ANR-11-EQPX-0035 - EQPX - VALID, Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe - - PETTAR2016 - ANR-16-CE17-0007 - AAPG2016 - VALID, Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Transplantation, Néphrologie et Immunologie Clinique [Hôpital Edouard Herriot, HCL], Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Laboratoire HLA [EFS - Auvergne-Rhônes-Alpes], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Departement de Pathologie [Hospices civils de Lyon], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), SFR Biosciences, Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'immunologie, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), O.T. is supported by the Agence nationale pour la Recherche (ANR-16-CE17-0007-01), the Fondation pour la Recherche médicale (PME20180639518), and the Etablissement français du Sang. C.-C.C., E.M. and O.T. are supported by the Institut Hospitalo-Universitaire–Organ Protection and Replacement (IHU-OPeRa, ANR-10-IBHU-004). A.K. is supported by INSERM (poste accueil 2015/1239/BT), the Hospices Civils de Lyon and the Fondation du Rein. SFR Biosciences is supported by the Agence nationale pour la Recherche (ANR -11-EQPX-0035 PHENOCAN). E.M. and O.T. are members of the CENTAURE Transplantation Research Network., We thank Christelle Forcet and Violaine Tribollet for help with Xcelligence experiments, and Marie-Claude Gagnieu and Laurent Genestier for fruitful scientific discussions. The authors thank Mathilde Koenig for her contribution to the design of the figure., ANR-10-IBHU-0004,OPeRa,Organ ProtEction and ReplAcement(2010), ANR-11-EQPX-0035,PHENOCAN,Phenotypage pour le cancer(2011), ANR-16-CE17-0007,PETTAR,Ciblage de PECAM-1 pour la prévention et le traitement du rejet humoral en transplantation d'organe(2016), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

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

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

Published
2019
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48. Pregnancy and donor-specific HLA-antibody-mediated rejection after liver transplantation: 'Liaisons dangereuses'?

Author

Valérie Dubois, Jérôme Dumortier, Alain Lachaux, Eduardo Couchonnal, Alexie Bosch, Olivier Boillot, Christine Rivet, Domitille Erard-Poinsot, Olivier Thaunat, Tomas Dedic, Olivier Guillaud, Christine Chambon-Augoyard, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Département d'hépatologie, University of Barcelona, Département de pédiatrie [Hôpital Edouard Herriot - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université de Lyon, Laboratoire de Planétologie et Géodynamique UMR6112 (LPG), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA), Université Claude Bernard Lyon 1 (UCBL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Etablissement français du sang- Rhône-Alpes [Lyon], and CCSD, Accord Elsevier

Subjects
Adult, Graft Rejection, Risk, medicine.medical_specialty, Blood transfusion, Adolescent, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Anti-HLA antibodies, 030230 surgery, Liver transplantation, Single Center, Gastroenterology, Organ transplantation, Young Adult, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Isoantibodies, Pregnancy, Internal medicine, medicine, Humans, Immunology and Allergy, Monitoring, Physiologic, Retrospective Studies, Transplantation, business.industry, Age Factors, Retrospective cohort study, Rejection, medicine.disease, Survival Analysis, Immunity, Humoral, Liver Transplantation, 3. Good health, Pregnancy Complications, [SDV] Life Sciences [q-bio], body regions, Population study, Female, business, Follow-Up Studies, 030215 immunology
Abstract

Background Risk factors for the development of anti-HLA antibodies include blood transfusion, organ transplantation, and pregnancy. Humoral rejection, mediated by donor-specific anti-HLA antibodies (DSA), has been studied in all kind of solid organ transplantations, and several studies have suggested that post-liver transplantation (LT) DSA may play a role in acute and chronic rejection. Objective The aim of the present study was to assess the impact of pregnancy on the occurrence of DSA and the impact of DSA in a large population of young female LT recipients. Methods This single center retrospective study included all female patients who underwent a first LT between January 1990 and December 2010 and who were of childbearing age during post-LT follow-up (i.e. 18 to 40 years old). Results The study population consisted in 73 patients, and the mean age at LT was 20.9 years (0.6–39.9); 32 patients were transplanted during childhood. The global incidence of de novo DSA was 42.5% (31/73), after a median delay of 15.5 years (1–25) of follow-up after LT. Most de novo DSA were anti-class II alone (90.3%), and included anti-DQ for 80.6%. From the 73 patients, 33 presented at least one pregnancy after LT (45.2%) and before DSA screening. Multivariate analysis disclosed that history of pregnancy (OR = 6.37; 95%CI, 2.17–18.63, p = 0.001) and younger age at LT (OR = 0.96; 95%CI:0.92–0.99, p = 0.033) were significantly associated with de novo DSA. Among the 31 patients who had de novo DSA, the diagnosis of antibody-mediated rejection was made in 8 patients (25.8%), after a median delay of 74 months after LT; 6/8 (75.0%) had history of pregnancy. During follow-up, 3 of these 8 patients lost their liver graft and died. Conclusion The results of the present study suggest that close monitoring of DSA in young women with history of pregnancy should be recommended regarding the risk of DSA-mediated rejection.

Published
2019
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49. Polymorphisme des gènes HLA et KIR et l’impact sur le devenir de la greffe et le choix du donneur non apparenté de cellules souche hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Author

Pauline Varlet, Florent Delbos, Anne Brignier, Ibrahim Yakoub-Agha, Valérie Dubois, Vincent Elsermans, Christophe Picard, Katia Gagne, Anne Kennel, Béatrice Pédron, Anne Cesbron, Aurélie Ravinet, Pascale Loiseau, Sociétés, Acteurs, Gouvernement en Europe (SAGE), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne (PRISME-GSPE), Centre National de la Recherche Scientifique (CNRS), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Service Immunologie Biologique [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Etablissement Français du Sang [Nantes], 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), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche en Communications et en Cybernétique de Nantes (IRCCyN), Mines Nantes (Mines Nantes)-École Centrale de Nantes (ECN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS), Sociétés, Acteurs, Gouvernement en Europe ( SAGE ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne ( PRISME-GSPE ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'hématologie ( ERL 8254 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -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 ), 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 ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut de Recherche en Communications et en Cybernétique de Nantes ( IRCCyN ), Mines Nantes ( Mines Nantes ) -École Centrale de Nantes ( ECN ) -Ecole Polytechnique de l'Université de Nantes ( Polytech Nantes ), Université de Nantes ( UN ) -Université de Nantes ( UN ) -PRES Université Nantes Angers Le Mans ( UNAM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), 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)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mines Nantes (Mines Nantes)-École Centrale de Nantes (ECN)-Ecole Polytechnique de l'Université de Nantes (Polytech Nantes)

Subjects
Cancer Research, medicine.medical_specialty, Bone marrow transplantation, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Hematopoietic stem cell transplantation, 03 medical and health sciences, 0302 clinical medicine, Unrelated Donor, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Radiology, Nuclear Medicine and imaging, ComputingMilieux_MISCELLANEOUS, Gynecology, [ SDV ] Life Sciences [q-bio], business.industry, French, Hematology, General Medicine, language.human_language, 3. Good health, Clinical Practice, Transplantation, Oncology, 030220 oncology & carcinogenesis, language, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, 030215 immunology
Abstract

In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its sixth annual workshop series in September 2015 in Lille. This event brought together practitioners from across the country with the purpose of offering careful analysis of published studies on clinical practice issues that remain to be disputed. This article addresses the impact of HLA and KIR gene polymorphism on the outcome of the transplantation in order to optimize unrelated donor selection.

Published
2016
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50. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

Author

Christophe Picard, Cécile Macquin, Sergi Querol, Catherine Paillard, Katharina Fleischhauer, Gaëlle Giacometti, Bronno van der Holt, Ibrahim Yakoub-Agha, Wassila Ilias, Anne Cesbron, Myriam Labopin, Masao Ota, Jorge Sierra, Fabio Ciceri, Dominique Charron, Ryad Tamouza, Régis Peffault de Latour, Xavier Lafarge, Katia Gagne, Seiamak Bahram, Myriam Maumy-Bertrand, Meiggie Untrau, Pascale Loiseau, Raphael Carapito, Jürgen Kuball, Bruno Lioure, Frans H.J. Claas, Noel Milpied, Antoine Toubert, Jan J. Cornelissen, Irina Kotova, Philippe Moreau, Eric Spierings, Mauricette Michallet, Arnon Nagler, Annette Schmitt-Graeff, Angélique Pichot, Petya Apostolova, Mohamad Mohty, Aurore Morlon, Myriam Labalette, Nicolas Jung, Didier Blaise, Yoshihiko Katsuyama, Hidetoshi Inoko, A. Parissiadis, Frédéric Bertrand, Marius Kwemou, Sandra Michel, Machteld Oudshoorn, Gérard Socié, Robert Zeiser, Peter A. von dem Borne, Valérie Dubois, Luca Vago, Carapito, Raphael, Jung, Nicola, Kwemou, Mariu, Untrau, Meiggie, Michel, Sandra, Pichot, Angélique, Giacometti, Gaëlle, Macquin, Cécile, Ilias, Wassila, Morlon, Aurore, Kotova, Irina, Apostolova, Petya, Schmitt Graeff, Annette, Cesbron, Anne, Gagne, Katia, Oudshoorn, Machteld, Van Der Holt, Bronno, Labalette, Myriam, Spierings, Eric, Picard, Christophe, Loiseau, Pascale, Tamouza, Ryad, Toubert, Antoine, Parissiadis, Anne, Dubois, Valérie, Lafarge, Xavier, Maumy Bertrand, Myriam, Bertrand, Frédéric, Vago, Luca, Ciceri, Fabio, Paillard, Catherine, Querol, Sergi, Sierra, Jorge, Fleischhauer, Katharina, Nagler, Arnon, Labopin, Myriam, Inoko, Hidetoshi, Von Dem Borne, Peter A., Kuball, Jürgen, Ota, Masao, Katsuyama, Yoshihiko, Michallet, Mauricette, Lioure, Bruno, De Latour, Régis Peffault, Blaise, Didier, Cornelissen, Jan J., Yakoub Agha, Ibrahim, Claas, Fran, Moreau, Philippe, Milpied, Noël, Charron, Dominique, Mohty, Mohamad, Zeiser, Robert, Socié, Gérard, Bahram, Seiamak, inconnu, Inconnu, Institut de Recherche Mathématique Avancée (IRMA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'Etudes et de recherches en Statistiques et Développement (LERSTAD), Université Gaston Bergé Sénégal, Laboratoire d'Acoustique Environnementale (IFSTTAR/AME/LAE), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Lyon-PRES Université Nantes Angers Le Mans (UNAM), Physique des interactions ioniques et moléculaires (PIIM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Etablissement Français du Sang [Nantes], Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Service de pneumologie [Rennes] = Pneumology [Rennes], CHU Pontchaillou [Rennes], Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Sociétés, Acteurs, Gouvernement en Europe (SAGE), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne (PRISME-GSPE), Centre National de la Recherche Scientifique (CNRS), Centre de Transfusion Sanguine Aquitaine-Limousin (CTS AQUITAINE-LIMOUSIN), Centre de Transfusion Sanguine, Ospedale San Raffaele, Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Barcelona Cord Blood Bank, Agrosystèmes tropicaux (ASTRO), Institut National de la Recherche Agronomique (INRA), Chaim Sheba Medical Center [Ramat Gan, Israel], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Université Paris Diderot - Paris 7 (UPD7), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'Investigations Biomédicales-Hématologie, Oncologie et Greffes (CIB-HOG), Hôpital St Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Centre d'Investigations Biomédicales-Hématologie, Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-ENSIIE-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), ALWP-EBMT & Département d'hématologie et de thérapie cellulaire [AP-HP Hôpital Saint-Antoine], AP-HP - Hôpital Saint-Antoine, Hematology, Institut de Recherche Mathématique Avancée ( IRMA ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Mathématiques et Modélisation d'Evry ( LaMME ), Institut National de la Recherche Agronomique ( INRA ) -Université d'Évry-Val-d'Essonne ( UEVE ) -ENSIIE-Centre National de la Recherche Scientifique ( CNRS ), laboratoire d'Etudes et de recherches en Statistiques et Développement ( LERSTAD ), Laboratoire d'Acoustique Environnementale ( IFSTTAR/AME/LAE ), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Université de Lyon-PRES Université Nantes Angers Le Mans ( UNAM ), Laboratoire d'Histoire des Sciences et de Philosophie - Archives Henri Poincaré ( LHSP ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Physique des interactions ioniques et moléculaires ( PIIM ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Functional Genomics and Cancer, Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes], Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Sociétés, Acteurs, Gouvernement en Europe ( SAGE ), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne ( PRISME-GSPE ), Centre National de la Recherche Scientifique ( CNRS ), Centre de Transfusion Sanguine Aquitaine-Limousin ( CTS AQUITAINE-LIMOUSIN ), Géographie de l'environnement ( GEODE ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse - Jean Jaurès ( UT2J ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Agrosystèmes tropicaux ( ASTRO ), Institut National de la Recherche Agronomique ( INRA ), Hospices Civils de Lyon ( HCL ), IFR Saint-Louis, institut d'hématologie ( ISLIH ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Erasmus MC University medical Centre / Daniel den Hoed Cancer centre, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Laboratoire de Mathématiques et Modélisation d'Evry, PRES Université Nantes Angers Le Mans (UNAM)-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS)-ENSIIE-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medizin, Graft vs Host Disease, Hematopoietic stem cell transplantation, Biochemistry, Linkage Disequilibrium, immune system diseases, HLA Antigens, Cytotoxic T cell, Child, ComputingMilieux_MISCELLANEOUS, HLA-DQB1, biology, Histocompatibility Testing, Incidence, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Allografts, 3. Good health, surgical procedures, operative, NK Cell Lectin-Like Receptor Subfamily K, Child, Preschool, Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, Adolescent, Immunology, Human leukocyte antigen, 03 medical and health sciences, MHC class I, medicine, Journal Article, Humans, Aged, Retrospective Studies, Transplantation, [ SDV ] Life Sciences [q-bio], Histocompatibility Antigens Class I, Infant, Newborn, Infant, Cell Biology, medicine.disease, Histocompatibility, stomatognathic diseases, 030104 developmental biology, Graft-versus-host disease, Chronic Disease, biology.protein
Abstract

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

Published
2016
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