Overcoming hyperacute xenograft rejection with transgenic animals

Xenotransplantation offers an alternative source of organs to solve the current critical shortage of donor organs required for patients with end-stage kidney, heart and liver disease. For social, ethical and logistical purposes, pigs appear to be the most appropriate donor animal. The immunological barriers to xenotransplantation are greater than in allotransplantation because of the presence of preformed natural antibodies in the serum of the recipient. The rapid binding of antibody to donor endothelial cells is followed by complement activation, cell damage and vascular thrombosis. Antirejection therapies aimed at reducing the level of antibody, complement activity and cell-mediated immunity in the recipient may result in a significant increase in complications such as infections and malignancies compared with allotransplantation. Transgenic technology may permit modification of the donor organ, enabling it to evade the rapid antibody- and complement-mediated destruction. The main strategies to prevent xenotransplant rejection have been to reduce expression of 'Gal', the major target epitope for natural antibody, and to inhibit complement activation. Transgenic animals expressing membrane-bound inhibitors of the complement pathway and enzymes that compete for Gal synthesis have been generated. Both approaches provide limited protection, and preliminary experiments in vitro suggest that a combination approach may reduce antibody- and complement-mediated cellular damage.