allograft rejection. Clinical attempts at renal xenotransplantation were soon abandoned in favour of the use of cadaver and living related human donor organs. A limited number of unsuccessful nonhuman primate-to-human heart and liver transplants were also performed during the 1960s and 1970s.

In the 1980s, the introduction of cyclosporine (CsA) helped to revolutionize clinical solid organ transplantation. With this powerful new immunosuppressive agent, many felt the species barrier between humans and apes could be overcome. In 1984, Bailey et al performed a baboon-to-human heart transplant into a newborn infant (Baby Fae) using an ABO incompatible donor. Baby Fae's clinical course was characterized by progressive cardiac failure, beginning three days posttransplant and resulting in death 20 days posttransplant. Histological evaluation of the xenograft demonstrated humoral rejection. It is important to note that Baby Fae was blood type O-rare in baboons-and that an ABO-compatible donor was not available. This donor-recipient blood group incompatibility complicates analysis of the cause of xenograft loss. Her course did suggest that CsA alone may not be sufficient to bridge interspecies barriers, and that future strategies would probably require intervention against antibody.

The 1980s saw the advent of intensive scientific investigation in xeno-transplantation using small and large animal models. Hamster organs placed into untreated rats are rejected over several days; this rodent model has been used as a small animal correlate of transplantation between closely related primate species. Using the hamster-to-rat species combination, several investigators reported extension of heart and liver xenograft survival with a variety of immunosuppressive regimens. In general, these studies indicate that protocols combining both antihumoral and anti-T-cell immunosuppression are most effective. Importantly, extended hamster xenograft survival appears to require prolonged suppression of rat xenoreactive antibody synthesis (a phenomenon likely to require agents with B-cell and T-cell immunosuppressive action) or prevention of the deleterious consequences of antidonor antibody binding to the graft (i.e., complement activation), or both.

Results from these rodent studies have been applied to nonhuman primate models with some success. Using different nonhuman primate combinations, prolonged xenograft survival of hearts and kidneys has been achieved with protocols directed at both cellular and humoral immune responses. These studies indicate that different primate species combinations vary in the aggressiveness of the immune response generated against the donor and that the intensity of the humoral response is a significant determinant of graft survival.

Successful extension of liver xenograft survival in the hamster-to-rat combination with FK506 and cyclophosphamide served as the basis for two clinical attempts at baboon-to-human liver transplantation by Starzl et al. Patients received an aggressive immunosuppressive regimen, including FK506, cyclophos-phamide, steroids, and perioperative prostaglandin E1. Although extended graft survival was achieved in both cases, the patients died of infectious and neurological complications. Both liver xenografts displayed evidence of antibody-mediated

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