Xenotransplantation of pig kidneys to nonhuman primates: I. Development of the model

Long-term survival of discordant xenografts will require control of both humoral and cellular aspects of the immune response. Because cellular responses to xenografts appear to be more potent than those encountered by allografts, recipients of xenogeneic tissues are likely to require more immunosuppression, with potential for unacceptably high complication rates. We have therefore directed our attention toward the induction of tolerance to some or all of the xenogeneic antigens recognized in the primate anti-pig cellular immune response, utilizing mixed lymphohematopoietic chimerism as the means for tolerance induction. We report here our initial series of 16 animals in which the conditions for application of this treatment regimen were established. In 14 cynomolgus monkey recipients, induction therapy consisted of low dose whole body irradiation, thymic irradiation, and ATG, followed by infusion of pig bone marrow and a pig kidney transplant. Other aspects of the regimen included splenectomy and removal of monkey anti-porcine natural antibodies by extracorporeal perfusion of the recipient's blood through a pig liver. Two control animals received either no treatment or extracorporeal perfusion but no additional induction therapy. Five of the experimental animals were treated posttransplant with an anti-IgM monoclonal antibody, five with Cyclosporin A, and two with a combination of both immunosuppressants. Both IgM and IgG natural antibodies were removed effectively by liver perfusion in all but one monkey, as determined by flow cytometry. Antibody liters remained low for 5–7 days, but increased progressively thereafter. The longest kidney survival in this series was 13 days, in an animal which maintained excellent kidney function for the first 11 days posttransplant. Peripheral chimerism was detected only transiently on day 10 in the peripheral blood of this recipient. We conclude that extracorporeal perfusion by this technique removes natural antibodies and prevents hyperacute rejection, permitting maintenance of excellent renal xenograft function for at least 11 days. Additional manipulations appear to be required to achieve mixed chimerism and tolerance of the cellular immune system in this model.