We have used an optimized, physiologically relevant in vitro assay system to show that in a concentration-dependent fashion the immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin), as well as the glucocorticoid dexamethasone, inhibit allergen-driven T-cell proliferation and IL-5 production in PBMCs from allergen-sensitized atopic asthmatic individuals at physiologic concentrations. This effect of cyclosporin A might at least partially account for its established clinical efficacy in sparing systemic glucocorticoid therapy while improving lung function in chronic, severe, glucocorticoid-dependent asthma. The data are also compatible with the hypothesis that the newer immunomodulatory drugs mycophenolate mofetil and sirolimus exert similar effects, perhaps with a more favorable benefit/risk ratio.