A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations

Background: Retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) has critical roles in the development, maintenance and function of interleukin (IL)-17-producing cells and is a highly attractive target for the treatment of IL-17-mediated autoimmune disease, particularly psoriasis. On the other hand, ROR gamma t is also critical for controlling apoptosis during thymopoiesis, and genetic ROR gamma t ablation or systematic ROR gamma t inhibition cause progressive thymic aberrations leading to T cell lymphomas. Objective: We investigated whether topical administration of our novel ROR gamma t inhibitor, S18-000003 has therapeutic potential for psoriasis with low risk of thymic aberrations. Methods: We evaluated the effect of topical S18-000003 on psoriasis-like skin inflammation and influence on the thymus in a 12-O-tetradecanoylphorbol-13-acetate-induced K14.Stat3C mouse psoriasis model. Results: S18-000003 markedly inhibited the development of psoriatic skin inflammation via suppression of the IL-17 pathway. In the skin, S18-000003 suppressed all subsets of IL-17-producing cells that we previously identified in this psoriasis model: Th17 cells, Tc17 cells, dermal gamma delta T cells, TCR- cells that probably included innate lymphoid cells, and CD4(-)CD8(-) double-negative alpha beta T cells. Notably, neither reduction of CD4(+)CD8(+) double-positive thymocytes nor dysregulation of cell cycling was observed in S18-000003-treated mice, even at a high dose. Conclusion: Our topically administered ROR gamma t inhibitor is a potential therapeutic agent for psoriasis with low risk of thymic lymphoma. (C) 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.