PROLONGED SURVIVAL OF ORTHOTOPIC CARDIAC XENOGRAFTS IN AN hDAF TRANSGENIC PIG-TO-BABOON MODEL

Abstract

444 Our laboratory has previously demonstrated inhibition of hyperacute rejection (HAR) and sustained graft survival in a pig-to-primate model of heterotopic cardiac xenotransplantation using pigs transgenic for human Decay Accelerating Factor (hDAF). Building on this work, we have developed an orthotopic model and now report up to 39-day cardiac xenograft function in a life-supporting capacity under cover of clinically acceptable immunosuppression. Using hearts from hDAF transgenic pigs, orthotopic cardiac transplants were performed in 6 baboons. The immunosuppressive regimen consisted of induction with four doses of cyclophosphamide, followed by maintenance therapy with cyclosporin A, mycophenolate mofetil and a tapering course of corticosteroids. Two of the baboons died on post-operative days 2 and 11, respectively, of causes unrelated to graft function or rejection. One of the baboons died on the day of operation, and its xenograft was found to be hyperacutely rejected, possibly due to a significantly higher pre-operative level of anti-porcine antibodies compared to other animals in the series (p<0.05). The remaining animals survived 12-39 days with each of the grafts demonstrating evidence of mild (n=1), moderate (n=1) and moderate to severe (n=1) humoral xenograft rejection on post-mortem examination. Mean survival was 14 days, with a median of 12. Endomyocardial biopsy performed on the longest survivor on post-operative day 36 revealed only patches of subendocardial fibrosis with no signs of active rejection. This animal was active throughout its post-operative course and remained free of signs or symptoms of cardiopulmonary failure. The hDAF transgene combined with a clinically acceptable immunosuppressive regimen enables sustained, life-supporting function of porcine cardiac xenografts in non-human primates to beyond one month. This small series includes the longest survival recorded to date of an orthotopic discordant cardiac xenograft. These results thus represent progress in the development of a viable strategy for clinical xenotransplantation.