Inhibiting accelerated rejection mediated by alloreactive CD4(+) memory T cells and prolonging allograft survival by 1α,25-dihydroxyvitamin D(3) in nude mice

Abstract

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 D(3) [1,25(OH)(2)D(3)] 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)(2)D(3) 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)(2)D(3) 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)(2)D(3) 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)(2)D(3) treatment when compared with the control group. Our data suggests that 1,25(OH)(2)D(3) 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)(2)D(3) as a novel immunosuppressant targeting CD4(+) memory T cells.