A human CD46 transgenic pig model system for the study of discordant xenotransplantation

Background. The chronic shortage in the supply of human organs available fo r allotransplantation has turned attention toward the use of animals as pot ential donors, with pigs as the most likely species under consideration. Hy peracute rejection, the initial and immediate barrier to a pig-to-primate x enograft, has been addressed by generation of transgenic pigs that express the human membrane bound complement regulatory proteins CD59 and/or CD55. D ifficulty has been encountered in generation of transgenic animals that exp ress a third membrane-bound complement-regulatory protein, CD46. Methods. We have generated transgenic animals by using a large genomic cons truct that encompasses the entire human CD46 gene. Results. We report the first description of transgenic mice and pigs that e xpress high levels of human CD46 in a cell and tissue type-specific manner, resembling patterns of endogenous CD46 expression observed in human tissue s. Furthermore, when human CD46 transgenic porcine hearts a ere transplante d into baboons, the grafts did not succumb to hyperacute rejection, and sur vival extended for up to 23 days. Under the same conditions, nontransgenic grafts underwent hyperacute rejection within 90 min. Conclusions. This is the first report to describe generation of transgenic pigs that express human CD46, and the first in vivo demonstration of the ab ility of human CD46 expressed on pig organs to regulate complement activati on and overcome hyperacute rejection upon transplantation of a vascularized organ into nonhuman primates.