A macrolactam inhibitor of T helper type 1 and T helper type 2 cytokine biosynthesis for topical treatment of inflammatory skin diseases

T lymphocytes play a critical part in inflammatory skin diseases but are ta rgeted by available therapies that have only partial efficacy, significant side-effects, or both, Because psoriasis, atopic dermatitis, and allergic c ontact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respective ly, there is a need for a better broad-based inhibitor, The macrolactam asc omycin analog, ABT-281, was found to inhibit potently T cell function acros s species and to inhibit expression of multiple cytokines in human peripher al blood leukocytes which have been found in human skin disease cells and t issues. These included immunoregulatory Th1 (interleukin-2 and interferon-g amma) and Th2 (interleukin-4 and interleukin-5) cytokines, ABT-281 was show n to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a s tringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/ olive oil over 25% of the body surface in swine resulted in undetectable bl ood levels. Compared with a wide potency range of topical corticosteroids i n clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% an d 90%, respectively, whereas super-potent steroids such as clobetasol propi onate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance fo llowing uptake into the bloodstream, and its ability to inhibit cytokine bi osynthesis of both Th1 and Th2 cell subsets, suggests that it will have a b road therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.