Swine Leukocyte Antigen Class II Is a Xenoantigen

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d1738937e169">Background</h5> <p id="P1">Over 130 000 patients in the United States alone need a life-saving organ transplant. Genetically modified porcine organs could resolve the donor organ shortage, but human xenoreactive antibodies destroy pig cells and are the major barrier to clinical application of xenotransplantation. The objective of this study was to determine whether waitlisted patients possess preformed antibodies to swine leukocyte antigen (SLA) class II, homologs of the class II human leukocyte antigens (HLA). </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d1738937e174">Methods</h5> <p id="P2">Sera from people currently awaiting solid organ transplant were tested for IgG binding to class II SLA proteins when expressed on mammalian cells. Pig fibroblasts were made positive by transfection with the class II transactivator (CIITA). As a second expression system, transgenes encoding the alpha and beta chains of class II SLA were transfected into Human embryonic kidney (HEK293) cells. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d1738937e179">Results</h5> <p id="P3">Human sera containing IgG specific for class II HLA molecules exhibited greater binding to class II SLA positive cells than to SLA negative cells. Sera lacking antibodies against class II HLA showed no change in binding regardless of the presence of class II SLA. These antibodies could recognize either SLA-DR or SLA-DQ complexes. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d1738937e184">Conclusions</h5> <p id="P4">Class II SLA proteins may behave as xenoantigens for people with humoral immunity towards class II HLA molecules. </p> </div>

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Most cited references 20

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Rejection of the kidney allograft.

Stephen Alexander, Brian Nankivell (2010)

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Class II HLA epitope matching-A strategy to minimize de novo donor-specific antibody development and improve outcomes.

Julia Wiebe, D Pochinco, T D Blydt-Hansen … (2013)

De novo donor-specific antibody (dnDSA) develops in 15-25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA-DR/DQ/DP conformational epitopes for 286 donor-recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus-specific epitope mismatches were more numerous in patients who developed HLA-DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA-DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA-DR and DQ epitope matching outperforms traditional low-resolution antigen-based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long-term graft outcome.

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Humoral theory of transplantation.

Paul Terasaki (2003)

According to the humoral theory of transplantation, antibodies cause allograft rejection. Publications are cited showing that antibodies: (1). cause hyperacute kidney rejection, (2). lead to C4d deposits associated with early kidney graft failures, (3). are a good indicator of presensitization leading to early acute rejections, (4). were present in 96% of 826 patients who rejected a kidney graft, (5). are associated with chronic rejection in 33 studies of kidney, heart, lung and liver grafts, and (6). in three studies, appeared in the circulation BEFORE evidence of bronchiolitis obliterans in lung transplants, and BEFORE kidney rejection. In addition, a prospective cooperative study of 1629 patients in 24 centers demonstrated that antibodies foretold subsequent failures after a follow-up period of 6 months (p = 0.05). The specificity of antibodies detected in the serum of rejecting patients were often not donor specific, presumably because they were absorbed by the rejecting organ. If the humoral theory is accepted, even provisionally, transplanted patients who have antibodies could be treated with immunosuppression until the antibodies disappear to determine whether chronic rejection can be blocked. If successful, in patients who do not have antibodies, immunosuppression could be reduced until antibodies appear.