T lymphocytes play a critical part in inflammatory
skin diseases but are targeted by available
therapies that have only partial efficacy, significant side-effects, or both. Because
psoriasis,
atopic dermatitis, and allergic
contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and
cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam
ascomycin analog,
ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple
cytokines in human peripheral blood leukocytes which have been found in human
skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5)
cytokines.
ABT-281 was shown to have potent topical activity (ED50 = 0.6% in
acetone/
olive oil) in a stringent 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 blood levels. Compared with a wide potency range of topical
corticosteroids in clinical formulations, 0.3% and 1%
ABT-281 ointments profoundly inhibited
dinitrochlorobenzene-induced
contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent
steroids such as
clobetasol propionate 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 following uptake into the bloodstream, and its ability to inhibit
cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory
skin diseases, including
psoriasis,
atopic dermatitis, and
allergic contact dermatitis.