The Long and Winding Road to Clinical Xenotransplantation: A Personal Journey.

backgroundThe recent clinical pig-heart transplant carried out at the University of Maryland in Baltimore is hopefully the first of many xenotransplants that will resolve the problem of the lack of availability of organs from deceased human donors. I offer my personal recollections of how xenotransplantation research has progressed since the mid-1980s, when the pig-to-nonhuman primate (NHP) organ transplant model was established. SUMMARY: Initially, hyperacute rejection or early antibody-mediated rejection was almost uniform. Among the milestones that were subsequently achieved are (i) the introduction of the first genetically engineered pigs that expressed a human complement regulatory protein, CD55, which was associated with prolonged graft function, extending to several weeks; (ii) the observation that conventional immunosuppressive therapy did not prevent an adaptive immune response, whereas the administration of an agent that blocked the CD40/<underline>CD154</underline> T-cell costimulation pathway was successful in this respect; (iii) the identification of the major pig carbohydrate xenoantigen as galactose-α1,3-galactose (Gal), followed by gene editing to delete its expression, and the demonstration of prolonged survival of organs from these pigs in NHPs; (iv) the resolution of coagulation dysfunction between a pig and primate by the introduction of genes for human coagulation regulatory proteins; (v) the recognition of a prolonged systemic inflammatory response to a xenograft and its suppression either by drug therapy or by further gene editing, and (vi) identification of two pig "non-Gal" xenoantigens and the production of triple-knockout (TKO) pigs. However, although many humans do not have antibodies against TKO pig cells, all Old World NHPs do have antibodies against these cells. This has provided an unexpected new barrier to testing TKO pig organ transplants in NHPs. KEY MESSAGES: The optimal gene-edited pig for clinical xenotransplantation may be one with 10 genetic manipulations. A pig with this genetic background provided the heart for the recent first clinical xenotransplant. In view of the current barrier to progress in the TKO pig-to-NHP model, the time has surely come when we need to consider moving from the laboratory to the clinic. Selection of patients for the first clinical trials is briefly discussed.