A HUMAN CD46 TRANSGENIC PIG MODEL SYSTEM FOR THE STUDY OF DISCORDANT XENOTRANSPLANTATION

TLDR

The chronic shortage of human organs has spurred interest in pig xenografts, and hyperacute rejection has been mitigated by transgenic pigs expressing human complement‑regulatory proteins CD59 and CD55. We generated CD46 transgenic pigs using a large genomic construct containing the full human CD46 gene, producing high‑level, cell‑ and tissue‑specific expression that mirrors human patterns. Transplantation of CD46 transgenic porcine hearts into baboons prevented hyperacute rejection and extended survival to 23 days, whereas nontransgenic grafts rejected within 90 minutes, demonstrating that human CD46 on pig organs regulates complement activation and overcomes hyperacute rejection in primate transplantation.

Abstract

The chronic shortage in the supply of human organs available for allotransplantation has turned attention toward the use of animals as potential donors, with pigs as the most likely species under consideration. Hyperacute rejection, the initial and immediate barrier to a pig-to-primate xenograft, has been addressed by generation of transgenic pigs that express the human membrane-bound complement-regulatory proteins CD59 and/or CD55. Difficulty has been encountered in generation of transgenic animals that express a third membrane-bound complement-regulatory protein, CD46.We have generated transgenic animals by using a large genomic construct that encompasses the entire human CD46 gene.We report the first description of transgenic mice and pigs that express high levels of human CD46 in a cell and tissue type-specific manner, resembling patterns of endogenous CD46 expression observed in human tissues. Furthermore, when human CD46 transgenic porcine hearts were transplanted into baboons, the grafts did not succumb to hyperacute rejection, and survival extended for up to 23 days. Under the same conditions, nontransgenic grafts underwent hyperacute rejection within 90 min.This is the first report to describe generation of transgenic pigs that express human CD46, and the first in vivo demonstration of the ability of human CD46 expressed on pig organs to regulate complement activation and overcome hyperacute rejection upon transplantation of a vascularized organ into nonhuman primates.