Potentiation of immunosuppressive effects of cyclosporin A by 1α,25-dihydroxyvitamin D 3

Abstract

Both cyclosporin A (CsA) and 1α,25-dihydroxyvitamin D 3 (vitamin D 3) inhibit T-cell functions. Because CsA has a dose-related systemic toxicity, there is a need for approaches by which the dosage of CsA could be reduced while maintaining the required immunosuppression. Therefore, we examined for any potentiating effect of vitamin D 3 on CsA-induced suppression of T cell functions in vitro. Peripheral blood mononuclear cells were stimulated with phytohemagglutinin in the presence or absence of various concentrations of CsA (1.6–13.2 μg/ml) or vitamin D 3 (10 −10–10 −7 M) or both together and [ 3H]thymidine incorporation (TdR), interleukin 2 (IL-2) production, IL-2 receptor (IL-2R) expression, and the response to exogenous recombinant IL-2 (rIL-2) on TdR were measured. IL-2 production was measured on CTLL cell line and IL-2R expression with anti-Tac monoclonal antibody using FACScan. There was a dose-dependent inhibition of TdR, IL-2 production, and IL-2R expression by CsA. Vitamin D 3 inhibited TdR and IL-2 production in a dose-dependent manner but had no significant ( P > 0.1) effect on IL-2R expression. Recombinant IL-2 had no effect on CsA-induced inhibition of TdR, whereas rIL-2 completely reversed the vitamin D 3-induced inhibition of TdR. A significantly ( P < 0.05) increased inhibition of TdR and IL-2 production was observed when two agents were used together as compared to expected inhibition by the addition of each agent separately. A consistent synergism was observed between all concentrations of CsA used and vitamin D 3 (10 −8 and 10 −7 M). This study shows that the potentiation of immunosuppressive effects of CsA by vitamin D 3 could be used as an approach to reduce the dosage of CsA in clinical use without compromising immunosuppression, thus preventing or minimizing the dose-related toxic effects of CsA.