EXPRESSION OF A FUNCTIONAL HUMAN-COMPLEMENT INHIBITOR IN A TRANSGENICPIG AS A MODEL FOR THE PREVENTION OF XENOGENEIC HYPERACUTE ORGAN REJECTION

The serious shortage of human organs available for transplantation has engendered a heightened interest in the use of animal organs (xenogra fts) for transplantation. However, the major barrier to successful dis cordant xenogeneic organ transplantation is the phenomenon of hyperacu te rejection. Hyperacute rejection results from the deposition of high -titer preformed antibodies that activate serum complement on the lumi nal surface of the vascular endothelium, leading to vessel occlusion a nd graft failure within minutes to hours. Although endogenous membrane -associated complement inhibitors normally protect endothelial cells f rom autologous complement, they are species restricted and thus confer limited resistance to activated xenogeneic complement. To address the pathogenesis of hyperacute rejection in xenotransplantation, transgen ic mice and a transgenic pig were engineered to express the human term inal complement inhibitor hCD59. High-level cell surface expression of hCD59 was achieved in a variety of murine and porcine cell types, mos t importantly on both large vessel and capillary endothelium. hCD59-ex pressing porcine cells were significantly resistant to challenge with high-titer anti-porcine antibody and human complement. These experimen ts demonstrate a strategy for developing a pig-to-primate xenogeneic t ransplantation model to test whether the expression of a human complem ent inhibitor in transgenic pigs could render xenogeneic organs resist ant to hyperacute rejection.