Xenotransplantation: current status and a perspective on the future

Key Points The severe shortage of human organ donors limits the practice of clinical transplantation, the only effective therapy for end-stage organ failure. Xenotransplantation using pig organs might provide the most immediate solution to the scarcity of human organ donors. Immunological rejection of xenografts presents the most formidable obstacle to clinical xenotransplantation. Both innate and adaptive immune systems contribute to xenograft rejection. The availability of α1,3-galactosyltransferase-deficient pigs and pigs transgenic for human complement regulatory proteins have made it possible to overcome hyperacute rejection. However, with these pigs it has not been possible to completely prevent acute humoral xenograft rejection unless a tolerance-inducing protocol is used. Innate immune cells mediate much stronger responses to xenografts than to allografts. Genetic modifications of pigs to remove xenoantigens that interact with the activating receptors of human natural killer (NK) cells and macrophages, and to provide the ligands that interact with the inhibitory receptors of these cells may confer protection against cytotoxicity by NK cells and macrophages. Nonspecific immunosuppression has been insufficient to prevent porcine xenograft rejection in non-human primates without severe toxicity. Tolerance induction is probably required to overcome the delayed form of humoral rejection and T-cell xenoresponses. The observation of porcine endogenous retroviruses (PERVs) infecting human cells in vitro has raised concerns regarding the safety of xenotransplantation. However, studies so far have provided no evidence of xenotransplantation-associated PERV transmission to humans in vivo . The risk for xenotransplantation-mediated zoonosis will never be completely eliminated, and constant vigilance will be required as clinical xenotransplantation proceeds. Worldwide harmonization of regulatory guidelines for oversight is needed to address the infectious risks associated with clinical xenotransplantation. In contrast to allotransplantation, both the patients and the public must be included when considering the benefit versus risk of xenotransplantation. Could xenotransplantation using pigs as the transplant source solve the severe shortage of human organ donors? This Review describes the recent advances that are helping to bring this approach closer to the clinic and the obstacles that still need to be overcome. Xenotransplantation using pigs as the transplant