Kidney Xenotransplantation in Nonhuman Primates

There is a critical and continuing shortage of deceased human donor kidneys for transplantation in patients with end-stage renal disease (ESRD). This could be resolved if kidneys from genetically engineered pigs offered an alternative with an acceptable clinical outcome. Genetic engineering has followed two major paths: (i) deletion of pig xenoantigens, against which all humans have ʼnatural’ antibodies and (ii) insertion of ‘protective’ human transgenes, e.g., complement-regulatory proteins, to resist the human immune response. Pigs with nine genetic manipulations are now available. In these pigs, all three of the known pig xenoantigens have been deleted. In many patients, there is no serum antibody binding to cells from these pigs (comparable to binding to human O-negative red blood cells). These data indicate that there is minimal or no risk of early antibody-mediated rejection of a kidney transplanted from one of these pigs. Conventional pharmacologic immunosuppressive therapy (as used in allotransplantation) is inadequate to prevent an adaptive immune response to a transplanted pig kidney. However, when novel agents that block the CD40/CD154 costimulation pathway, e.g., an anti-CD40 monoclonal antibody, are administered, the adaptive immune response of nonhuman primates is suppressed, leading to pig kidney graft survival of many months in the absence of rejection. In the absence of innate and adaptive immune responses, the function of the transplanted pig kidneys has generally been good. The data reported from pig-to-NHP studies on renal transplantation are reviewed. In future, the pigs will also be manipulated to control the adaptive immune response, thus enabling exogenous immunosuppressive therapy to be significantly reduced or, indeed, ultimately unnecessary.