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（包括类风湿性关节炎、多发性硬化症和银屑病）的发展中显然很重要。IL 23是Th17介导的炎症的原型驱动因子，我们和其他人已经表明，在小鼠皮肤中重复注射重组IL 23导致银屑病样皮炎，其在短短5天内模仿了人类银屑病的许多特征。在约20种已知的趋化因子受体中，CC趋化因子受体-6（CCR6）对于Th17导向的免疫活性特别重要，因为它既是表达Th17表型的T细胞的标志物，也是几种自身免疫性疾病小鼠模型（包括自身免疫性脑炎、胶原诱导的关节炎和银屑病）的关键参与者。我们先前已经表明，CCR6缺陷小鼠在IL 23注射后不能在皮肤中发展银屑病样皮炎。目前的模型表明，由树突状细胞（DC）产生的IL 23的作用，以维持皮肤CC趋化因子受体-6（CCR6）表达的Th17细胞，然后产生IL 22作为一个主要的下游效应，刺激表皮增生，通过STAT3介导的机制在人类皮肤。正反馈由CCL20（CCR6配体）的表皮和真皮产生提供，潜在地将更多的CCR6 + T细胞或CCR6+抗原呈递细胞募集到发炎的银屑病皮肤中。虽然来自人类研究的数据刚刚开始暗示银屑病和其他自身免疫性疾病中的γ δ T细胞，但我们已发表的数据表明，与常驻树突状表皮γ δ T细胞（DETC）不同的CCR6+，V γ 3-T细胞受体（TCR）γ δ低（GDL）T细胞的新群体，在暴露于IL 23后在鼠表皮中积累，并且是鼠表皮中IL 22和IL 17的主要产生者。我们假设：1）皮肤中的CCR6 + GDL T细胞可能是递送IL 22和其他细胞因子的关键先天免疫细胞，所述细胞因子在诸如银屑病的病症中调节皮肤中的表皮增生和炎症，和2）CCR6或CCL20的拮抗剂将是几种Th17介导的自身免疫过程（包括银屑病）中的有效治疗剂，因为它们对表达CCR6的细胞的运输和/或功能有影响。基于这一假设，我们试图更好地定义CCR6和γ δ 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。我们的研究结果将与SCID-hu银屑病皮肤异种移植模型进行验证。

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.