THE EFFECT OF DEXAMETHASONE, CYCLOSPORINE, AND RAPAMYCIN ON T-LYMPHOCYTE PROLIFERATION IN-VITRO - COMPARISON OF CELLS FROM PATIENTS WITH GLUCOCORTICOID-SENSITIVE AND GLUCOCORTICOID-RESISTANT CHRONIC ASTHMA

Inhibition of T-lymphocyte activation may provide a useful approach to the treatment of chronic severe asthma. We compared rapamycin, a nove l immunosuppressive drug, with cyclosporine and dexamethasone for its effects in inhibiting proliferation of T lymphocytes from patients wit h glucocorticoid-resistant and glucocorticoid-sensitive asthma. Phytoh emagglutinin-stimulated peripheral blood T lymphocytes from 11 patient s with clinically glucocorticoid-resistant and 8 patients with glucoco rticoid-sensitive chronic asthma were tested for sensitivity to these drugs in a highly reproducible proliferation assay. All drugs inhibite d proliferation in a dose-dependent manner (10(-6) to 10(-10) mol/L). T lymphocytes from the patients with glucocorticoid-resistant asthma w ere significantly less sensitive (p < 0.01) to dexamethasone than thos e of patients with glucocorticoid-sensitive asthma over a wide concent ration range. In contrast, cyclosporine and rapamycin inhibited cells from both patient groups to an equivalent extent. The presence of exog enous interleukin-2 abrogated the inhibitory effect of dexamethasone b ur not that of cyclosporine or rapamycin, suggesting that dexamethason e may act principally by inhibition of interleukin-2 production, where as the latter drugs exert distinct or additional inhibitory effects. S timulation of peripheral blood T lymphocytes with phytohemagglutinin f or 24 hours before addition of the drugs abolished the inhibitory effe ct of dexamethasone and significantly reduced that of cyclosporine. Th e Inhibitory effect of rapamycin was, however unaltered These data sug gest that dexamethasone and cyclosporine evert their effects only at a n early stage of T-lymphocyte activation whereas rapamycin is able to inhibit lymphoblasts. The fact that the inhibitory mechanisms of these drugs are different might explain why cyclsoporine and rapamycin are effective in inhibiting T lymphocytes from both patients with glucocor ticoid-sensitive and those with glucocorticoid-resistant asthma. The d ata further suggest that cyclosporine and rapamycin may be effective f or the therapy of glucocorticoid-resistant asthma.