Differential inhibition of cutaneous T-cell-mediated reactions and epidermal cell proliferation by cyclosporin 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 only suppressed the erythema response when given systemically. The inhibition of normal human keratinocyte growth by the drugs was 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 than cyclosporin A in inhibiting their proliferation. The future benefit of these drugs in dermatology may ultimately lie in their combined use.
Duncan
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JI
D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology*
D016895:Culture Media, Serum-Free; D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus