OVERCOMING HYPERACUTE XENOGRAFT REJECTION WITH TRANSGENIC ANIMALS

Xenotransplantation offers an alternative source of organs to solve th e current critical shortage of donor organs required for patients with end-stage kidney, heart and liver disease. For social, ethical and lo gistical purposes, pigs appear to be the most appropriate donor animal . The immunological barriers to xenotransplantation are greater than i n allotransplantation because of the presence of preformed natural ant ibodies in the serum of the recipient. The rapid binding of antibody t o donor endothelial cells is followed by complement activation, cell d amage and vascular thrombosis. Antirejection therapies aimed at reduci ng the level of antibody, complement activity and cell-mediated immuni ty in the recipient may result in a significant increase in complicati ons such as infections and malignancies compared with allotransplantat ion. Transgenic technology may permit modification of the donor organ, enabling it to evade the rapid antibody- and complement-mediated dest ruction. The main strategies to prevent xenotransplant rejection have been to reduce expression of 'Gal', the major target epitope for natur al antibody, and to inhibit complement activation. Transgenic animals expressing membrane-bound inhibitors of the complement pathway and enz ymes that compete fur Gal synthesis have been generated. Both approach es provide limited protection, and preliminary experiments in vitro su ggest that a combination approach may reduce antibody- and complement- mediated cellular damage.