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Durable tolerance can be reliably achieved by inducing engraftment of allogeneic or xenogeneic hematopoietic cells in recipients initially depleted of T lymphocytes. Engraftment of pluripotent hematopoietic stem cells (PPHSC) provides a constant supply of donor antigen to ensure the ongoing central deletion of donor-reactive T cell clones, resulting in a permanent state of donor-specific tolerance. Because of the toxicity of myeloablative therapy used to achieve allogeneic PPHSC engraftment, this approach has not yet been applied in humans. However, a non-myeloablative, relatively non-toxic conditioning regimen allowing allogeneic or concordant xenogeneic bone marrow engraftment and tolerance induction has recently been developed in a murine model. Host pre-treatment with depleting doses of anti-CD4 and anti-CD8 mAbs (and in the xenogeneic combination, anti-Thy 1.2 and anti-NK 1.1 mAbs), followed by 3 Gy whole body irradiation (WBI) and 7 Gy of thymic irradiation (TI) allows engraftment of allogeneic or xenogeneic rat bone marrow cells with mixed, multilineage lymphohematopoietic chimerism and donor-specific skin graft tolerance. TI can be omitted from the regimen if additional mAb treatments are given. Engraftment of allogeneic PPHSC is associated with early migration of donor bone marrow-derived cells to the host thymus, resulting in deletion of developing thymocytes with reactivity to donor antigens. Maintenance of long-term tolerance is purely due to this deletional mechanism. In the xenogeneic rat→mouse species combination, mixed chimerism is also associated with deletional T cell tolerance, and also leads to tolerance at the level of B cells that make natural antibodies. In the discordant pig→mouse species combination, we have found that physiologic preference for host hematopoiesis is a major barrier to achieving donor hematopoietic reconstitution. Pig-specific hematopoietic cytokines can at least partially overcome this barrier. Furthermore, if normal, immunocompetent mice are thymectomized, then receive T- and NK-cell-depleting mAbs, and a fetal swine thymus is grafted, murine CD4 T cells recover in the swine thymus, and demonstrate specific tolerance to the xenogeneic swine donor. These T cells appear to be able to recognize antigen in the context of host MHC, and demonstrate immunocompetence. Our studies have demonstrated for the first time that donor-specific skin graft tolerance can be induced across a discordant species barrier.