The respective relevance of sensitization to alloantigens and xenoantigens in pig organ xenotransplantation

Background: Antibody-mediated rejection is a major cause of graft injury and contributes to failure of pig xeno-grafts in nonhuman primates (NHPs). Most 'natural' or elicited antibodies found in humans and NHPs are direc-ted against pig glycan antigens, but antibodies binding to swine leukocyte antigens (SLA) have also been detected. Of clinical importance is (i) whether the presence of high levels of antibodies directed towards human leukocyte antigens (HLA) (i.e., high panel-reactive antibodies) would be detrimental to the outcome of a pig organ xenograft; and (ii) whether, in the event of sensitization to pig antigens, a subsequent allotransplant would be at increased risk of graft failure due to elicited anti-pig antibodies that cross-react with human HLA or other antigens.Summary: A literature review of pig-to-primate studies indicates that relatively few highly-HLA-sensitized humans have antibodies that cross-react with pigs, predicting that most would not be at increased risk of reject-ing an organ xenograft. Furthermore, the existing evidence indicates that sensitization to pig antigens will prob-ably not elicit increased alloantibody titers; if so, 'bridging' with a pig organ could be carried out without increased risk of subsequent antibody-mediated allograft failure.Key Message: These issues have important implications for the design and conduct of clinical xenotransplanta-tion trials.