Progress in xenotransplantation

XT using the pig as a donor species may provide a potential solution to the lack of human organs available for transplantation. However, two major immunological obstacles have impeded the survival of porcine organs transplanted into primates. The first is hyperacute rejection (HR), which is a consequence of the recipient's preformed antibodies binding specifically to the carbohydrate structure Gal-alpha1-3-Gal on porcine endothelial cells (EC), leading to complement activation and graft failure. Conventional 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 modified donor pigs, whose organs express human complement inhibitors such as human decay-accelerating factor (hDAF), have been produced.

Several groups have shown that organs from these transgenic pigs do not undergo HR when transplanted into primates. Acute vascular rejection (AVR) is the second major immunological obstacle to successful XT. Several strategies are presently being investigated to overcome this form of rejection. The first approach is aimed at controlling the induced anti-xenograft humoral response with immunosuppressive agents primarily directed against lymphocytes. A second approach is aimed at preventing EC activation in the graft by inhibition of NF-kappaB, a transcription factor which is known to play a central role in EC activation. A third approach is aimed at preserving the antithrombotic properties of EC which usually disappear when these cells are activated. Finally, other groups are attempting to tackle AVR by exploring the role of platelet inhibitors or by using antibodies directed against adhesion molecules. To date, the speed and strength of the humoral xenograft rejection process 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 cells respond vigorously to pig MHC antigens and some authors have proposed that the induction of tolerance is essential if XT is to succeed clinically. It 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 this model.

It has now been demonstrated that organs from hDAF transgenic pigs sustain the life of primates for up to 12 weeks before failing due to the onset of AVR. It is anticipated that once AVR has been overcome, long-term survival of porcine organs transplanted into primates should be reproducibly achievable.