Progress in xenotransplantation

Background: XT using the pig as a donor species may provide a potential sol ution to the lack of human organs available for transplantation. However, t wo major immunological obstacles have impeded the survival of porcine organ s transplanted into primates. The first is hyperacute rejection (HR), which is a consequence of the recipient's preformed antibodies binding specifica lly to the carbohydrate structure Gal-alpha 1-3-Gal on porcine endothelial cells (EC), leading to complement activation and graft failure. Conventiona l strategies to overcome HR have focused on the inactivation or removal of essential components of the complement system, or removal of anti-xenograft antibodies from the blood of the recipient. Alternatively, genetically mod ified donor pigs, whose organs express human complement inhibitors such as human decay-accelerating factor (hDAF), have been produced. Aim: Several gr oups have shown that organs from these transgenic pigs do not undergo HR wh en transplanted into primates. Acute vascular rejection (AVR) is the second major immunological obstacle to successful XT. Several strategies are pres ently being investigated to overcome this form of rejection. The first appr oach is aimed at controlling the induced anti-xenograft humoral response wi th immunosuppressive agents primarily directed against lymphocytes. A secon d approach is aimed at preventing EC activation in the graft by inhibition of NF-kappa B, a transcription facfor which is known to play a central role in EC activation. A third approach is aimed at preserving the antithrombot ic properties of EC which usually disappear when these cells are activated. Finally, other groups are attempting to tackle AVR by exploring the role o f platelet inhibitors or by using antibodies directed against adhesion mole cules. To date, the speed and strength of the humoral xenograft rejection p rocess have impeded in vivo studies of the cell-mediated immune response in the pig-to-primate model. However, there is now evidence that human T cell s respond vigorously to pig MHC antigens and some authors have proposed tha t the induction of tolerance is essential if XT is to succeed clinically. I t is clear that additional in vivo data still need to be generated in order to fully comprehend the involvement of the cellular immune response in thi s model. Conclusions: It has now been demonstrated that organs from hDAF tr ansgenic pigs sustain the life of primates for up to 12 weeks before failin g due to the onset of AVR. It is anticipated that once AVR has been overcom e, long-term survival of porcine organs transplanted into primates should b e reproducibly achievable.