Potentiation of immunosuppressive effects of cyclosporin A by 1 alpha,25-dihydroxyvitamin D3.
Both cyclosporin A (CsA) and 1 alpha,25-dihydroxyvitamin D3 (vitamin D3) 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 D3 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 micrograms/ml) or vitamin D3 (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 D3 inhibited TdR and IL-2 production in a dose-dependent manner but had no significant (P greater than 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 D3-induced inhibition of TdR. A significantly (P less than 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 D3 (10(-8) and 10(-7) M). This study shows that the potentiation of immunosuppressive effects of CsA by vitamin D3 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.
Gupta
S
S
Division of Basic and Clinical Immunology, University of California, Irvine 92717.
Fass
D
D
Shimizu
M
M
Vayuvegula
B
B
D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000032:analysis
D003524:Cyclosporins; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D004247:DNA; D002117:Calcitriol