Qualitative, rather than quantitative, differences between HLA‐DQ alleles affect HLA‐DQ immunogenicity in organ transplantation
HLA, vol. 103, pp. e15455
Abstract
Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression-minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor-specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor-specific-antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR-Cas9-edited cells, to rebut the claim that the HLAMatchmaker eplets represent "functional epitopes." We further used unique sub-cohorts of patients, those receiving an allograft with two HLA-DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05-heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor-specific HLA-DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA-DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections.
Authors 14
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Affiliation as printed
Department of Surgery, Comprehensive Transplant Center Northwestern University Chicago Illinois USA
Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
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Affiliation as printed
Institute for Experimental Cellular Therapy University Hospital Essen Essen Germany
Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany
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Essen University Hospital · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf Essen Germany
Institute for Experimental Cellular Therapy University Hospital Essen Essen Germany
Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany
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Affiliation as printed
Department of Surgery, Comprehensive Transplant Center Northwestern University Chicago Illinois USA
Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
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Affiliation as printed
Department of Surgery, Comprehensive Transplant Center Northwestern University Chicago Illinois USA
Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
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Cynthia S. M. Kramer Aachen Department of Immunology Leiden University Medical Center Netherlands Department of Immunology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Immunology Leiden University Medical Center Netherlands
Department of Immunology, Leiden University Medical Center, Netherlands
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Affiliation as printed
Department of Surgery University of Cambridge Cambridge UK
Department of Surgery, University of Cambridge, Cambridge, UK
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Sebastiaan Heidt Aachen Department of Immunology Leiden University Medical Center Netherlands Department of Immunology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Immunology Leiden University Medical Center Netherlands
Department of Immunology, Leiden University Medical Center, Netherlands
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Affiliation as printed
Department of Surgery University of Cambridge Cambridge UK
Department of Surgery, University of Cambridge, Cambridge, UK
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Vall d'Hebron Institut de Recerca · Vall d'Hebron Hospital Universitari
Affiliation as printed
Vall d'Hebron Institut de Recerca Vall d'Hebron Hospital Universitari Barcelona Spain
Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Barcelona, Spain
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London School of Economics and Political Science
Affiliation as printed
Department of Economics London School of Economics London UK
Department of Economics, London School of Economics, London, UK
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University of Colorado Anschutz
Affiliation as printed
Department of Epidemiology University of Colorado Anschutz Medical Campus Aurora Colorado USA
Department of Surgery University of Colorado Anschutz Medical Campus Aurora Colorado USA
Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Affiliation as printed
Department of Mathematics Bar Ilan University Ramat Gan Israel
Department of Mathematics, Bar Ilan University, Ramat Gan, Israel
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Anat R. Tambur corresponding
Affiliation as printed
Department of Surgery, Comprehensive Transplant Center Northwestern University Chicago Illinois USA
Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
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