Transgenic expression of human CD47 on pig cells provides only partial protection against human macrophage-mediated destruction in human immune system mice

Tolerance induction would prevent xenograft rejection while avoiding high levels of immunosuppression. Mixed chimerism is an attractive approach to xenotolerance induction, as it tolerizes T, B and natural killer (NK) cells. However, the species-specific interaction between CD47 and signal regulatory protein alpha (SIRPα) is ineffective in the pig to human combination, and may limit pig cell and organ engraftment. Prior studies showed that human CD47 (hCD47) expression on porcine cells can inhibit phagocytosis by primate macrophages. We have now tested the effect of hCD47 expression on destruction of pig splenocytes in a human immune system (HIS) mouse model. Although the hCD47 transgene enhanced the survival of opsonized and non-opsonized porcine splenocytes in both HIS mice and non-reconstituted immunodeficient (NSG) mice, macrophage-mediated destruction of hCD47-transgenic (hCD47-tg) pig cells still occurred in HIS mice. In longer-term studies, higher levels of pig chimerism were achieved in HIS mice receiving hCD47-tg compared to control pig bone marrow (BM) cells. Taken together, these results indicate that transgenic expression of hCD47 may reduce macrophage-mediated xenograft rejection in clinical xenotransplantation, but that additional strategies are needed to fully overcome human macrophage-mediated destruction of pig cells.