Oral administration of a novel RORγt antagonist attenuates psoriasis-like skin lesion of two independent mouse models through neutralization of IL-17

Publication date: Available online 3 October 2016
Source:Journal of Dermatological Science
Author(s): Mikiro Takaishi, Masayuki Ishizaki, Keisuke Suzuki, Takashi Isobe, Takaichi Shimozato, Shigetoshi Sano
BackgroundTargeting the IL-17 pathway represents a highly effective strategy for the treatment of psoriasis, using antibodies against IL-17A and IL-17 receptor, suggesting that Th17 cells essentially contribute to development of psoriasis. Th17 differentiation depends on the key transcription factor, RORγt.ObjectiveTo develop a novel RORγt antagonist which is effective on psoriasis via oral administration.MethodsA chemical library was screened using cell-based high-throughput methods, luciferase reporter assay, competitive binding assay, and T cell differentiation assay. To evaluate in vivo effects of a novel RORγt antagonist, A213, we orally administrated it to two independent mouse models of psoriasis; IL-23-injection model and K5.Stat3C transgenic mouse.ResultsOral administration of A213 resulted in attenuation of skin inflammation in the both mouse models. At the same time, increased levels of IL-17A expression were significantly reduced in the skin lesions and skin-draining lymph nodes.ConclusionThese results implicate a new therapeutic application of RORγt antagonist for the treatment of psoriasis.



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