Application of xenogeneic stem cells for induction of transplantation tolerance: present state and future directions.

Xenotransplantation using pig organs provides a possible solution to the severe shortage of allogeneic organ donors, one of the major limiting factors in clinical transplantation. However, because of the greater antigenic differences that exist between different species than within a species, the immune response to xenografts is much more vigorous than to allografts. Thus, tolerance induction is essential to the success of clinical xenotransplantation. Tolerance induced by mixed hematopoietic chimerism across the MHC barrier is remarkably robust, but its ability to induce tolerance across highly disparate xenogeneic barriers remains poorly studied. None of the current available regimens of host conditioning, which permit hematopoietic stem cell engraftment and chimerism induction in allogeneic or closely related (concordant) xenogeneic combinations, has been demonstrated to be effective in establishing porcine hematopoietic chimerism in a discordant xenogeneic species. Unlike bone marrow transplantation within the same species, the innate immune system and the species specificity of cytokines and adhesion molecules essential to hematopoiesis pose formidable obstacles to the establishment of donor hematopoiesis across discordant xenogeneic barriers. The genetic incompatibility between species may also impede xenograft tolerance induction by mixed chimerism. While we remain far from achieving tolerance in clinical xenotransplantation, recent studies using a transgenic mouse model have proven the principle that mixed hematopoietic chimerism may induce mouse and human T cell tolerance to porcine xenografts. This review article focuses on the barriers to porcine hematopoietic engraftment in highly disparate xenogeneic species and the possible application of mixed hematopoietic chimerism to xenograft tolerance induction.