Inhibiting accelerated rejection mediated by alloreactive CD4+ memory T cells and prolonging allograft survival by 1α,25-dihydroxyvitamin D3 in nude mice

Donor-reactive memory T cells are major barriers to long-term survival of transplanted organs due to their capacity to accelerate rejection. In this study we investigated the ability of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] to inhibit accelerated rejection mediated by alloreactive CD4+ memory T cells and to prolong cardiac allograft survival in an adoptive T cell memory/heart transplant model of nude mice. In vitro, the proliferation of CD4+ memory T cells was significantly inhibited by 1,25(OH)2D3 and was restored following addition of exogenous IL-2. Compared with the control group, the mean survival time of cardiac allografts in the 1,25(OH)2D3 group was prolonged from 6.5 ± 0.3 to 20.2 ± 0.8 days in vivo. Five days after transplantation, the levels of IL-2 and IFN-γ were reduced in the grafts and the recipient sera by 1,25(OH)2D3 treatment, while that of IL-10 increased. The proportions of CD4+ memory T cells and CD4+Foxp3+ T cells, both in recipient spleen and lymph nodes, were lowered by 1,25(OH)2D3 treatment when compared with the control group. Our data suggests that 1,25(OH)2D3 inhibits expansion of CD4+ memory T cells, possibly by inducing clonal anergy and/or clonal deletion, resulting in prolongation of cardiac allograft survival in nude mice. These results may provide a rational basis for exploiting 1,25(OH)2D3 as a novel immunosuppressant targeting CD4+ memory T cells.

► 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] demonstrates immunomodulatory effects. ► 1,25(OH)2D3 induces hyporesponsiveness of alloreactive CD4+ memory T cells in vitro. ► 1,25(OH)2D3 prolongs graft survival of adoptive memory T cell/heart transplanted nude mice. ► 1,25(OH)2D3 inhibits acute rejection caused by alloreactive CD4+ memory T cells. ► 1,25(OH)2D3 enhances function but not proportion of regulatory T cells.