Experimental Models

3. Xenotransplantation of organs has been studied primarily in small animal models and in pig-to-nonhuman-primate combinations.

Small animal models. The principal model used involves transplantation of hamster or mouse hearts to rats. For the most part, the rejection of a hamster heart by a rat is similar to the rejection of a mouse heart. However, the rat does not have sufficient preformed xenoreactive natural antibodies to reject a mouse or hamster heart hyperacutely; thus rejection is dependent on the synthesis of anti-graft antibodies that, together with recipient complement, lead to rejection of the organ.(²⁷) Transplantation of mouse or hamster hearts to rats is therefore thought to be a good model of acute vascular rejection. The preliminary findings that have emerged from small animal transplants are the following: administration of immunosuppression to the rat can lead to long-term survival of hamster hearts.(²⁸) In this sense, rejection of a hamster organ transplanted to a rat appear to differ from acute vascular rejection of a pig organ in a non-human primate in which hyperacute rejection has been overcome. In the pig-to-nonhuman-primate model, immunosuppression alone is currently unable to lead to long-term survival. The second finding in the hamster or mouse heart transplants to rats has been the achievement of "accommodation".(²⁹) Accommodation refers to the survival of an organ in the presence of anti-graft antibodies and complement. Short-term inhibition of complement coupled with continuing inhibition of T cells leads to long-term survival in these two situations. An interesting finding regarding accommodation is that the surviving organ expresses genes in its endothelium and smooth muscle cells that protect the organ from rejection.(³⁰) To what extent these protective genes can be used therapeutically to aid pig organ survival in primates is not clear. Isolated cases of accommodation have been described in human allogeneic transplants as well.(³¹)

Large animal models. The principal model today remains transgenic pigs expressing hDAF (³²) and, in some cases, other human genes inhibiting complement cascade, coupled with immunosuppression in order to achieve survival. In most cases, normal pig organs are rejected hyperacutely by non-human primates, and thus, more rapidly than transgenic pig organs expressing hDAF.(³³) Even when hyperacute rejection is avoided, the hDAF transgenic organs are rejected in non-human primates by a process that mimics acute vascular rejection, although rejection can be very much delayed.(³⁴) Transgenic pig hearts have been shown to survive for up to 99 days when they are not asked to do life-supporting work (heterotopic transplant).(³⁵) When placed in the position of having to support life (orthotopic transplant), the longest survival periods have been a month for a cardiac xenograft(³⁶) and 78 days for a renal xenograft;(³⁷) most organs are rejected in a shorter period of time. Scientists propose two different approaches, which can be combined for achieving longer survival periods of pig organs in primates. The first is to try different immunosuppressive protocols, and the second is to produce pigs that express additional transgenes that might inhibit rejection factors associated with acute vascular rejection.