MHC Class II Sharing Appears to Promote Intestinal Allograft Tolerance Through Linked Suppression in a Large Animal Model

Background.The relative importance of major histocompatibility complex (MHC) class I and class II matching for the induction of transplantation tolerance remains unclear. We studied selective mismatches in a clinically relevant model of intestinal transplantation (ITx) in swine with defined MHC genotypes. Methods.We performed orthotopic ITx between MHC haplotype-matched (n = 6), partially matched (having class II alleles with marked overlap, n = 2), and fully mismatched (n = 4) pairs. Immunosuppression mirrored our clinical protocol and was weaned off between days 90 and 140. Results.The fully mismatched animals did not develop evidence of tolerance. In contrast, the partially matched animals developed a previously undefined form of "split tolerance" characterized by local graft tolerance mediated by donor regulatory T cells (Treg). In haplotype-matched animals, which share 1 full class II allele, Treg were also detectable in the periphery, where they appeared to promote donor-specific hyporesponsiveness and durable mixed chimerism. In vitro analyses, including a novel mucosal mixed lymphocyte reaction assay, suggested that the mechanism by which class II sharing promotes Treg-mediated tolerance is via linked suppression to allele combinations coexpressed on the same antigen-presenting cell in vivo. Conclusions.Because humans often share some class II antigenic specificities that can be determined by tissue typing pretransplant, these findings may have important implications for the induction of clinical tolerance to ITx.