ITK: an emerging target for treatment of T cell-mediated autoimmune disease

描述（由申请人提供）：ITK：治疗T细胞介导的自身免疫性疾病的新兴靶标淋巴细胞介导的自身免疫性疾病由自身耐受性的破坏引起。调节自身耐受性的关键蛋白之一是抑制性T细胞蛋白CTLA-4。当CTLA-4缺失时，小鼠会死于快速和致命的多器官自身免疫性疾病，并在三周龄时死亡。我们实验室最近的研究表明，CTLA-4在预防自身免疫中具有两种不同的功能。首先，CTLA-4是FOXP 3+调节性T细胞在维持T细胞耐受性中的功能所必需的。其次，CTLA-4是常规T细胞所必需的，以阻断非炎症条件下组织中异常活化的自身反应性T细胞积累。目前尚不清楚共刺激分子如何控制异常激活的自身反应性T细胞浸润和损伤组织。基于Tec激酶Itk的无效突变阻止Ctla 4-/-小鼠的活化T细胞迁移和自身免疫病理学的观察，我们提出ITK活化对于T细胞介导的自身免疫性疾病是至关重要的。我们假设ITK是协同激活VAV 1和VAV 1下游途径所必需的，从而导致肌动蛋白聚合和细胞骨架重组。此外，我们提出ITK通过磷酸化和激活Src家族激酶FYN激活VAV 1，而Src家族激酶FYN反过来磷酸化和激活VAV 1。我们将通过检查来自Itk-/-小鼠的自身反应性T细胞在体外和体内的迁移行为来测试这一假设，以确定ITK控制T细胞运动到非淋巴组织中的分子机制。我们还将确定ITK是否通过激活FYN调节原代T细胞中的细胞骨架重组，FYN是否是原代T细胞中肌动蛋白聚合和细胞骨架重组所需的，并有助于自身免疫性疾病的进展。最后，我们将研究ITK小分子抑制剂抑制动物I型糖尿病的疗效和机制，开始探索靶向ITK阻断剂在临床上治疗各种器官特异性自身免疫性疾病的效用。 公共卫生相关性：ITK：当个体的免疫系统攻击他/她自己的细胞和器官时，出现治疗T细胞介导的自身免疫疾病的新兴靶点。该提案解决了防止自身免疫在健康个体中发生的基本机制之一。更好地了解这一机制可能会提供机会，以防止易感个体的自身免疫过程的发生，并治疗和治愈这些疾病的患者。

DESCRIPTION (provided by applicant): ITK: an emerging target for treatment of T cell-mediated autoimmune diseases Lymphocyte-mediated autoimmune diseases arise from a breakdown of self-tolerance. One of the key proteins regulating self-tolerance is the inhibitory T cell protein, CTLA-4. When CTLA-4 is absent, mice succumb to a rapid and fatal multi-organ autoimmune disease, and die by three weeks of age. Recent studies from our labs have demonstrated that CTLA-4 has two distinct functions in preventing autoimmunity. First, CTLA-4 is required for the function of FOXP3+ regulatory T cells in maintaining T cell tolerance. Second, CTLA-4 is required in conventional T cells, to block aberrantly activated self-reactive T cell accumulation in tissues under non-inflammatory conditions. It is unknown how costimulatory molecules control aberrantly activated self-reactive T cells from infiltrating and damaging tissues. Based on the observation that the null mutation of the Tec kinase Itk prevents activated T cell migration and autoimmune pathology of Ctla4-/- mice, we propose that ITK activation is critical for T cell-mediated autoimmune diseases. We hypothesize that ITK is required for the synergistic activation of VAV1 and the pathways downstream of VAV1 leading to actin polymerization and cytoskeletal reorganization. Further, we propose that ITK activates VAV1 by phosphorylating and activating the Src family kinase, FYN, which in turn phosphorylates and activates VAV1. We will test this hypothesis by examining the migratory behavior of self-reactive T cells from Itk-/- mice in vitro and in vivo to determine the molecular mechanism by which ITK controls T cell movement into non-lymphoid tissues. We will also determine whether ITK regulates cytoskeletal reorganization in primary T cells by activating FYN, whether FYN is required for actin polymerization and cytoskeletal reorganization in primary T cells and contribute to autoimmune disease progression. Finally, we will investigate the efficacy and mechanism of suppression of Type I diabetes in animals by small molecule inhibitors of ITK, to begin to explore the utility of targeted ITK blockade in clinics to treat various organ-specific autoimmune diseases. PUBLIC HEALTH RELEVANCE: ITK: an emerging target for treatment of T cell-mediated autoimmune diseases occur when an individual's immune system attacks his/her own cells and organs. This proposal addresses one of the basic mechanisms that prevent autoimmunity from occurring in healthy individuals. A better understanding of this mechanism may provide opportunities to prevent the onset of autoimmune processes in susceptible individuals and to treat and cure patients with these diseases.