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This review describes recent progress in tolerance-inducing strategies across xenogeneic immunological barriers as well as the potential benefit of a tolerance strategy for islets and kidney xenotransplantation.Using advanced gene editing technologies, xenotransplantation from multitransgenic alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of renal xenograft survival, ranging from days to greater than several months for life-supporting kidneys, and more than 2 years in a heterotopic nonlife-supporting cardiac xenograft model. Continuous administration of multiple immunosuppressive drugs has been required and attempts to taper immunosuppression have been unsuccessful. It appears likely that low levels of T cell dependent antibodies and activation of innate responses are responsible for xenograft loss. Mixed chimerism and thymic transplantation approaches have achieved xenogeneic tolerance in pig-to-mouse models and both have recently been extended to pig-to-baboon models. Encouraging results have been reported, including persistence of macrochimerism, prolonged pig skin graft survival, donor-specific unresponsiveness in vitro and detection of recent T cell emigrants in vivo.Although tolerance induction in vivo has not yet been achieved in pig-to-baboon models, recent results are encouraging that this goal will be attainable through genetic engineering of porcine donors.