Additive effects of calcium antagonists on cyclosporin A-induced inhibition of T-cell proliferation.

The purpose of this study was to investigate possible additive effects of calcium antagonists on the cyclosporin A (CsA)-induced inhibition of cellular immunity. Human T-cells were isolated using standard methods and stimulated with phytohaemagglutinin (PHA, n = 8), the monoclonal antibody OKT3 (n = 6), or mixed lymphocyte reaction (MLR, n = 5). Verapamil, nifedipine, nimodipine or diltiazem were added (5 x 10(-7) - 5 x 10(-5) M) to the cultures, either alone, or in combination with CsA (62.5, 125, and 250 ng/ml). 3H-thymidine uptake was measured to estimate the proliferative responses and dose response curves were constructed for the Ca antagonists and their combinations with CsA. A 50% inhibition of T-cell proliferation in the different stimulation assays was achieved with 3.2 x 10(-5) - 5.3 x 10(-5) M verapamil, 2.5 x 10(-5) -4.3 x 10(-5) M nifedipine, 3.7 x 10(-6) - 5 x 10(-6) M nimodipine, and greater than 5 x 10(-5) M diltiazem. In combination with CsA a dose-dependent additive inhibitory effect of the Ca antagonists on T-cell proliferation was observed. This effect was less pronounced in the OKT3 assay, intermediate after PHA stimulation and most pronounced in MLR. Even in low concentrations, which correspond to therapeutic serum concentrations, Ca antagonists have an additive inhibitory effect in MLR. We conclude that Ca antagonists exert a dose-dependent inhibitory effect on T-cell proliferation. A combination of CsA with verapamil, nifedipine, nimodipine, or diltiazem is more effective than each drug given alone. This additive effect of Ca antagonists and CsA may possibly contribute to a better graft survival in clinical transplantation.