TRANSGENIC PIGS EXPRESSING HUMAN CD59 AND DECAY-ACCELERATING FACTOR PRODUCE AN INTRINSIC BARRIER TO COMPLEMENT-MEDIATED DAMAGE1

TLDR

The authors engineered pigs to express human CD59 and decay‑accelerating factor under heterologous promoters, achieving widespread organ and vascular expression and demonstrating that these proteins can be delivered to xenografts via pig‑to‑baboon heterotopic heart transplantation. Moderate expression of human CD59 and decay‑accelerating factor protects pig peripheral blood cells from human or baboon complement, blocks complement‑mediated damage in xenografts, reveals species‑specific regulatory function, and suggests that high‑level expression could overcome humoral rejection barriers in xenotransplantation.

Abstract

We characterize a line of transgenic pigs that express the human complement-regulatory proteins human CD59 and human decay-accelerating factor. These genes, under the control of heterologous promoters, are expressed in a variety of organs, including the vasculature of the heart, kidney, and liver. We demonstrate that moderate levels of these gene products are sufficient to protect peripheral blood cells from human or baboon complement. Using pig to baboon heterotopic heart transplants, we show that expression of these proteins is sufficient to block the complement-mediated damage that is the hallmark of such xenografts, when nontransgenic organs are used. These results indicate that there is significant species specificity of intrinsic complement regulatory protein function. This specificity is evident in transgenic organs in which low levels of human CD59 and human decay-accelerating factor expression significantly effect the humoral immune response that causes xenograft rejection. This result suggests that transgenic organs with high levels of human complement-regulatory protein expression will be sufficient to alleviate the humoral immunological barriers that currently block the use of xenogeneic organs for human transplantation.