Xenotransplantation from pigs could provide a potential solution to the severe shortage of allogeneic donor organs. Because xenogeneic tissues are subject to vigorous immune rejection, tolerance induction is likely to be essential to the success of clinical xenotransplantation. Here we explore the possibility of inducing human T-cell tolerance to porcine xenografts through mixed chimerism. We previously showed that NOD/SCID-Tg mice expressing porcine cytokine transgenes permit the induction of durable porcine hematopoietic chimerism. In this study we achieved human T-cell development in these mice by engrafting human fetal thymus/liver tissues. In porcine hematopoietic chimeras, human thymus grafts were populated with porcine class II high cells in addition to human cells, and human T cells were tolerant of the porcine hematopoietic donor as measured by mixed lymphocyte reaction assay and skin grafting. This study proves the principle that porcine chimerism induces tolerance of xenoreactive human T cells. IntroductionThe severe shortage of allogeneic organ donors currently limits the number of transplantations performed. 1,2 This supply-demand disparity could be corrected by the ability to use organs from other species (xenografts). In view of the ethical issues and impracticalities associated with the use of nonhuman primates, interest has focused on other species, in particular the pig, as the most suitable organ donor species for humans. In addition to organ size and physiologic similarities to humans, the ability to rapidly breed and inbreed pigs makes them particularly amenable to genetic modifications that could improve their ability to function as organ donors to humans. [3][4][5][6][7] However, organ transplantations across discordant species barriers are subject to vigorous immunologic rejection. 1,8 One might, therefore, expect the amount of nonspecific immunosuppression that would be required to overcome xenograft rejection to be so great that recipients would succumb to infections. Thus, it would be highly desirable to eliminate the immune response to xenografts through the induction of tolerance.Mixed chimerism has been proven to be a powerful and reliable approach for tolerance induction across allogeneic and closely related xenogeneic barriers. 9-14 Our recent studies showed that this approach also induces tolerance in a pig-to-mouse, highly disparate xenogeneic combination. 15 However, the ability of mixed chimerism to induce human T-cell tolerance to porcine xenografts has yet to be explored because of the lack of a suitable model system. It has been unclear whether or not genetic incompatibilities in immune cytokines, 16,17 accessory molecules, [17][18][19] and other unknown molecules between the 2 species might impede the induction of human T-cell tolerance to porcine xenografts through mixed chimerism. To address these questions, we have developed a murine model that permits the induction of both sustained porcine hematopoietic chimerism and active human thymopoiesis. Our results demonstrate...

These results demonstrate that porcine T-cell function is severely impaired in the xenogeneic murine microenvironment.