Donor Peripheral Blood Stem Cell Infusion and Apoptosis in Lymphocytes Induces Immunological Tolerance of Kidney Allografts in Rhesus Monkeys

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(Background) We previously demonstrated that a nonmyeloablative, T-cell depleting preparative regimen including whole-body irradiation, thymic irradiation and donor bone marrow infusion induced mixed chimerism and allograft tolerance. Although tolerance has been successfully induced in the majority of recipients treated with this approach, broad clinical application requires simplifying the therapeutic regimen.(Methods) Male rhesus monkeys weighing 4-7 kg were used. T-cell depletion was planned using a combination of cyclophosphamide (CY) and the novel agent, FTY720 without irradiation. A second modification was allotransplantation of granulocyte-colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs), which has been increasingly used clinically as an alternative to allogeneic bone marrow transplantation.(Results) In 3 of 5 recipients in full protocol, renal function remained stable with no evidence of rejection more than 300 days after discontinuing immunosuppressive therapy. Donor-specific hyporesponsiveness was confirmed by sequential in vitro mixed lymphocyte reactions as well as skin transplantation from the original kidney donor in 1 recipient. The donor skin was accepted, while third party skin was rejected.(Conclusions) The mechanisms involved in the long-term immunosuppression-free allograft survival observed here remain to be elucidated. Nevertheless, these encouraging preliminary observations suggest that this approach to tolerance induction is particularly applicable to clinical protocols because of the non-toxic, relatively uncomplicated conditioning regimen required.