Recent advances and the potential for clinical use of xenotransplantation

The success of allotransplantation has paradoxically led to a shortage in the supply of organs required to meet the increasing demand. Xenografts represent a potentially infinite supply of good quality organs. Recent advances in the understanding of the immunobiology of xenograft rejection has spurred experimental approaches aimed at abrogating or suppressing human xenospecific immune responses. The limited supply of colony-bred nonhuman primates (baboons) makes it highly unlikely that this species will be of widespread use as a donor source. Therefore, the pig has been proposed as a realistic alternative donor. Delineation of the major pig xenoantigens recognized by natural human xenoreactive antibodies has led to the development of strategies aimed at depletion of antibodies or the prevention of their binding to xenogeneic endothelium. Recognition that antibody binding leads to endothelial cell activation and complement-mediated injury has led to the development of genetically modified pigs whose organs are potentially resistant to damage by human complement by virtue of the fact that their endothelial cells express membranebound human complement regulatory proteins. Finally, dissection of the relative contributions of humoral and cellular immune responses directed against xenografts from closely or distantly related species has permitted rational recommendations for the administration of immunosuppressive regimens.