Regulatory T cells induced by 1α,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance

1 alpha ,25-Dihydroxyvitamin D-3, the active form of vitamin D3, and mycophenolate mofetil, a selective inhibitor of T and B cell proliferation, modulate APC function and induce dendritic cells (DCs) with a tolerogenic phenotype. Here we show that a short treatment with these agents induces tolerance to fully mismatched mouse islet allografts that is stable to challenge with donor-type spleen cells and allows acceptance of donor-type vascularized heart grafts. Peritransplant macrophages and DCs from tolerant mice express down-regulated CD40, CD80, and CD86 costimulatory molecules. In addition, DCs from the graft area of tolerant mice secrete, upon stimulation with CD4(+) cells, 10-fold lower levels of IL-12 compared with DCs from acutely rejecting mice, and induce a CD4(+) T cell response characterized by selective abrogation of IFN-gamma production. CD4(+) but not CD8(+) or class II+ cells from tolerant mice, transferred into naive syngeneic recipients, prevent rejection of donor-type islet grafts. Graft acceptance is associated with impaired development of IFN-gamma -producing type 1 CD4(+) and CD8(+) cells and an increased percentage of CD4(+)CD25(+) regulatory cells expressing CD152 in the spleen and in the transplant-draining lymph node. Transfer of CD4(+)CD25(+) cells from tolerant but not naive mice protects 100% of the syngeneic recipients from islet allograft rejection. These results demonstrate that a short treatment with immunosuppressive agents, such as 1 alpha ,25-dihydroxyvitamin D-3/mycophenolate mofetil, induces tolerance to islet allografts associated with an increased frequency of CD4(+)CD25(+) regulatory cells that can adoptively transfer transplantation tolerance.