Comparison of the inhibition by glucocorticosteroids and cyclosporin A of mitogen-stimulated human lymphocyte proliferation.

We examined the effects of dexamethasone, hydrocortisone and cyclosporin A (CyA), alone and in combination, on tritiated thymidine (3H-TdR) incorporation into human blood mononuclear cells stimulated by phytohaemagglutinin (PHA), pokeweed mitogen (PWM) and phorbol myristic acetate (PMA). Pharmacological concentrations of glucocorticosteroids displaced the PHA and PWM dose-response curves to the right, but the same maximum response was achieved indicating selective inhibition at suboptimal levels of stimulation. In contrast, steroid inhibition of PMA-stimulated cells was not mitogen dose-dependent and the maximum response was clearly depressed. In the case of CyA, the stimulation by all three mitogens was inhibited in the latter fashion, but 10-fold higher concentrations were required to inhibit PMA-stimulated cells compared with PHA- and PWM-stimulated cells. These results suggest that a steroid-sensitive mechanism or lymphocyte sub-population may be selectively activated by PMA and by low doses of PHA and PWM, while the different inhibition profile observed for CyA might be taken to indicate that this drug affects a separate subpopulation and that PMA activation occurs later than the CyA-sensitive stage. Predominantly synergistic effects were obtained when the drugs were used together, thus providing an experimental basis for combination therapy in the treatment of reactions involving multiple lymphocyte activation mechanisms.