银屑病
CD8型
医学
免疫学
RAR相关孤儿受体γ
T细胞
癌症研究
免疫系统
FOXP3型
作者
Chihiro Imura,Azumi Ueyama,Yasutaka Sasaki,Masaya Shimizu,Yoko Furue,Nobuyuki Tai,Kenichiro Tsujii,Kazufumi Katayama,Takayuki Okuno,Michitaka Shichijo,Kiyoshi Yasui,Mina Yamamoto
标识
DOI:10.1016/j.jdermsci.2019.03.002
摘要
Background Retinoic acid receptor-related orphan receptor gamma t (RORγt) 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, RORγt is also critical for controlling apoptosis during thymopoiesis, and genetic RORγt ablation or systematic RORγt inhibition cause progressive thymic aberrations leading to T cell lymphomas. Objective We investigated whether topical administration of our novel RORγt 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 γδ T cells, TCR− cells that probably included innate lymphoid cells, and CD4−CD8− double-negative αβ 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 RORγt inhibitor is a potential therapeutic agent for psoriasis with low risk of thymic lymphoma.
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