Induced Tolerance to Rat Liver Allografts Involves the Apoptosis of Intragraft T Cells and the Generation of CD4+CD25+FoxP3+ T Regulatory Cells

Posttransplant total lymphoid irradiation is a nonmyeloablative regimen that has been extensively studied in rodent models for the induction of tolerance to bone marrow and solid organ allografts. Previous studies of experimental models and clinical transplantation have used total lymphoid irradiation in combination with anti-lymphocyte-depleting reagents and donor cell infusion to promote graft acceptance. In a rat model of orthotopic liver transplantation, we demonstrated that total lymphoid irradiation alone induced long-term graft survival. Apoptotic T cells were detected in markedly higher numbers in the livers of the total lymphoid irradiation-treated group in comparison with the control group of liver allograft recipients. Intragraft CD4(+)CD25(+)FoxP3(+) cells were increased in the total lymphoid irradiation group in the first week post-transplant and remained elevated in the graft and in the spleen. Importantly, the adoptive transfer of splenocytes from recipients that received posttransplant total lymphoid irradiation prolonged the survival of donor heart grafts, but not third-party heart grafts, whereas the depletion of CD4(+)CD25(+) cells from transferred splenocytes abrogated this prolongation. We conclude that posttransplant total lymphoid irradiation significantly increases the apoptosis of T cells in the liver graft and allows the accumulation of CD4(+)CD25(+)FoxP3(+) T regulatory cells, which facilitate the generation of donor-specific tolerance. Liver Transpl 16:147-154, 2010. (C) 2010 AASLD.