Heart Xenograft Survival With Chimeric Pig Donors and Modest Immune Suppression

The transplantation of organ xenografts from pigs could readily address the severe and growing shortage of human organ donors. Xenotransplantation of vascular organs is not feasible with current technology, however, due to severe acute rejection. In particular, acute vascular rejection (AVR), caused by induced antibodies to porcine endothelial cells, has consistently resisted efforts to prevent rejection. 1 Although the use of transgenic pigs expressing human complement inhibitors has proved effective in preventing hyperacute rejection, these grafts are usually rejected by AVR. 2 Drugs that are effective in preventing allograft rejection are not effective in preventing AVR. 3 Immune tolerance to pig cells could reduce the need for immune suppression. However, the induction of tolerance through bone marrow transplantation subjects the recipient to a period of severe immune deficiency. Furthermore, tolerance to donor hematopoietic cells following bone marrow transplantation of the recipient does not prevent AVR of vascular grafts. 4 If graft rejection by antibodies can be prevented, the graft eventually may become accommodated or resistant to injury. Accommodation has been studied extensively and proposed as a pathway to prolonged xenograft acceptance and prevention of AVR. 5–8 Engraftment of recipient lymphocytes within donor pigs could reduce the severity of xenograft rejection and the need for severe immune suppression. The lymphocytes would become tolerant to the donor tissue antigens as well as the hematopoietic cells. The specific suppressor cells could then be transferred back to the recipient. The porcine tissues could also become accommodated within the chimeric donor, before the transplantation. They would then resist injury by formed and developing antibodies following transplantation. Billingham et al. demonstrated that the environment during early immune ontogeny is conducive to immune tolerance. 9 The fetus or newborn develops specific tolerance to exposed antigens, including injected cells. In our previous studies with fetal pigs, tolerance of the injected lymphocytes to the pig was also demonstrated. 10 Tissue accommodation develops within chimeric pigs, before transplantation. 11,12 In two recipients with preformed antibodies, pig heart xenografts developed neither hyperacute rejection nor AVR. Heart explants from chimeric pigs functioned for a prolonged period when perfused with plasma from sensitized sheep. The feasibility of clinical xenotransplantation will depend on the prevention of rejection with acceptable levels of immune suppression. For the pig heart xenotransplants described here, immune suppression was limited to levels administered to allograft recipients. In this large animal study using chimeric donor pigs, AVR of pig xenografts was prevented without severe immune deficiency or toxicity.