DIFFERENTIAL INHIBITION OF CUTANEOUS T-CELL-MEDIATED REACTIONS AND EPIDERMAL-CELL PROLIFERATION BY CYCLOSPORINE-A, FK-506, AND RAPAMYCIN

Although cyclosporin A is a highly effective treatment for several skin disorders, particularly psoriasis, its use in dermatology appears limited due to drug-induced hypertension and nephrotoxicity. Newer, similar-acting anti-T-cell agents such as FK-506 and rapamycin may be more effective; therefore a comparison was made with cyclosporin A to assess their inhibitory action on T-cell responses and keratinocyte proliferation. Using a guinea-pig model of delayed-type hypersensitivity to dinitrofluorobenzene (DNFB), drugs were given systemically (25 mg/kg cyclosporin A, rapamycin; 2.5 mg/kg FK-506) and topically (0.02% and 2%) at the time of DNFB challenge or several hours after and were assessed with respect to erythema and the numbers of infiltrating T lymphocytes entering skin-challenge sites. FK-506, at all concentrations, significantly inhibited both T-cell infiltration and skin reddening when used by both routes. Rapamycin displayed no inhibitory effect, whereas cyclosporin A suppressed the erythema given systemically. The inhibition of normal human keratinocyte growth by the drugs assessed using a protein dye-binding assay. After 2 weeks, FK-506 had no effect, whereas cyclosporin A and rapamycin both inhibited keratinocyte growth in a dose-dependent fashion and almost equivalently in serum-containing and serum-free keratinocyte growth medium. The findings showed that in vivo only FK-506 suppressed T-cell involvement in sensitized animals. In contrast, it failed to have any effect on keratinocyte growth, whereas rapamycin was more potent cyclosporin A in inhibiting their proliferation. The future benefit of these drugs in dermatology may ultimately lie in their combined use.