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Mixed hematopoietic chimerism is a reliable means of tolerance induction, but its utility has not been demonstrated in discordant xenogeneic combinations because of the difficulty in achieving lasting hematopoietic engraftment. Miniature swine are likely to be suitable organ donors for humans. To evaluate the ability of mixed chimerism to induce swine-specific tolerance in widely disparate xenogeneic recipients, this study aimed to achieve long-lasting chimerism in a pig to mouse combination.Immunodeficient transgenic mice were developed by crossing transgenic founders carrying porcine interleukin-3, granulocyte macrophage-colony stimulating factor, and stem cell factor genes with severe combined immunodeficient mice or non-obese diabetic /severe combined immunodeficient mice. Swine bone marrow transplantation was performed in these mice, and porcine chimerism was followed for 20 weeks.Whereas swine cells became undetectable in all non-Tg littermates by 7 weeks, high levels of porcine hematopoietic chimerism, including the presence of porcine class II+ cells in the host thymus were maintained in Tg mice for >20 weeks. Colony-forming assays revealed the presence of large numbers of swine hematopoietic progenitor cells in the marrow of these mice at 20 weeks after bone marrow transplantation.These transgenic mice demonstrate for the first time that spontaneous migration of marrow donor antigen-presenting cells to an intact recipient thymus can occur and that porcine stem cells can persist in this highly disparate species combination. These data therefore support the feasibility of the eventual goal of tolerance induction by mixed chimerism in discordant xenogeneic combinations.