Function and Targeting of CCR6/CCL20 in Autoimmune Psoriasiform Skin Disease

描述（由申请人提供）：th17相关细胞和信号通路在多种自身免疫过程的发展中显然是重要的，包括类风湿关节炎、多发性硬化症和牛皮癣。il - 23是th17介导炎症的典型驱动因素，我们和其他人已经证明，在小鼠皮肤中反复注射重组il - 23会在短短5天内导致银屑病样皮炎，模仿人类银屑病的许多特征。在大约20种已知的趋化因子受体中，CC趋化因子受体-6 （CCR6）对Th17导向的免疫活性尤其重要，因为它既是表达Th17表型的T细胞的标记物，也是多种自身免疫性疾病小鼠模型的关键参与者，包括自身免疫性脑炎、胶原诱导的关节炎和牛皮癣。我们之前的研究表明，注射il - 23后，ccr6缺陷小鼠的皮肤不会出现牛皮癣样皮炎。目前的模型表明，树突状细胞（dc）产生的il - 23可以维持表达Th17细胞的真皮CC趋化因子受体-6 (CCR6)， Th17细胞随后产生il - 22作为主要的下游效应物，通过STAT3介导的机制刺激人体皮肤表皮增生。表皮和真皮分泌ccr20 （CCR6配体）提供了积极反馈，可能会招募更多的CCR6+ T细胞或CCR6+抗原呈递细胞进入发炎的银屑病皮肤。虽然人类研究数据刚刚开始涉及牛皮癣和其他自身免疫性疾病中的γδT细胞，但我们发表的数据表明，与常住树突状表皮γδT细胞（DETC）不同，CCR6+， v γ γ3- T细胞受体(TCR) γδ低（GDL） T细胞在暴露于il - 23后在小鼠表皮中积累，并且是小鼠表皮中il - 22和il - 17的主要产生者。我们假设1)皮肤中的CCR6+ GDL T细胞可能是传递il - 22和其他细胞因子的关键先天免疫细胞，这些细胞因子调节牛皮癣等皮肤病中的表皮增生和炎症；2)CCR6或CCL20的拮抗剂可能是几种Th17介导的自身免疫过程（包括牛皮癣）的有效治疗药物，因为它们对CCR6表达细胞的运输和/或功能有影响。基于这一假设，我们试图更好地定义CCR6和γδ T细胞在il - 23和咪喹莫特诱导的小鼠银屑病样皮炎模型中的作用，并使用新的计算方法来鉴定拮抗CCR6或其配体CCL20功能的小分子先导化合物。我们的结果将在SCID-hu牛皮癣皮肤异种移植模型中得到验证。

DESCRIPTION (provided by applicant): Th17-associated cells and signaling pathways are clearly important in the development of multiple autoimmune processes, including rheumatoid arthritis, multiple sclerosis, and psoriasis. IL23 is a prototypical driver of Th17-mediated inflammation, and we and others have shown that repeated injections of recombinant IL23 in mouse skin result in a psoriasiform dermatitis that mimics many of the features of human psoriasis in as little as 5 days. Among the ~20 known chemokine receptors, CC chemokine receptor-6 (CCR6) is particularly important for Th17-directed immune activity since it is both a marker for T cells that express the Th17 phenotype and a critical participant in several mouse models of autoimmune disease, including autoimmune encephalitis, collagen-induced arthritis, and psoriasis. We have previously shown that CCR6-deficient mice fail to develop psoriasiform dermatitis in skin following IL23 injection. Current models suggest that IL23 produced by dendritic cells (DCs) act to sustain dermal CC chemokine receptor-6 (CCR6)-expressing Th17 cells which then produce IL22 as a major downstream effector that stimulates epidermal hyperplasia through STAT3- mediated mechanisms in human skin. Positive feedback is provided by epidermal and dermal production of CCL20, the CCR6 ligand, potentially recruiting more CCR6+ T cells or CCR6+ antigen-presenting cells into inflamed psoriatic skin. While data from human studies are just beginning to implicate γδT cells in psoriasis and other autoimmune disease, our published data demonstrate that a novel population of CCR6+, Vγ3- T cell receptor (TCR) γδ low (GDL) T cells, distinct from resident dendritic epidermal γδ T cells (DETC), accumulates in murine epidermis following exposure to IL23 and is a major producer of IL22 and IL17 in murine epidermis. We hypothesize that 1) CCR6+ GDL T cells in skin may be critical innate immune cells for the delivery of IL22 and other cytokines that regulate epidermal hyperplasia and inflammation in skin in conditions such as psoriasis and 2) that antagonists of CCR6 or CCL20 would be effective therapeutic agents in several Th17- mediated autoimmune processes, including psoriasis, because of their effects on the trafficking and/or function of CCR6-expressing cells. Based on this hypothesis, we seek to better define the roles of CCR6 and γδ T cells in an IL23- and imiquimod-induced models of psoriasisform dermatitis in mice and to use novel computational methods to identify small molecule lead compounds that antagonize the function of either CCR6 or its ligand, CCL20. Our results will be validated with a SCID-hu psoriasis skin xenotransplant model.