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

描述(由申请人提供)：ITK：T细胞介导的自身免疫性疾病治疗的新兴靶点淋巴细胞介导的自身免疫性疾病源于自我耐受性的崩溃。调节自身耐受性的关键蛋白质之一是抑制性T细胞蛋白CTLA-4。当缺乏CTLA-4时，小鼠会死于一种快速而致命的多器官自身免疫性疾病，并在三周大时死亡。我们实验室最近的研究表明，CTLA-4在预防自身免疫方面具有两个不同的功能。首先，CTLA-4是FOXP3调节性T细胞维持T细胞耐受所必需的。其次，CTLA-4是传统T细胞所必需的，可以在非炎症条件下阻止异常激活的自身反应性T细胞在组织中积聚。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，使其免受组织的渗透和破坏。基于Tec激酶ITK零突变阻止CTLA4-/-小鼠活化的T细胞迁移和自身免疫病理的观察，我们认为ITK激活在T细胞介导的自身免疫性疾病中起关键作用。我们推测，ITK是协同激活Vav1和Vav1下游导致肌动蛋白聚合和细胞骨架重组的途径所必需的。此外，我们认为ITK通过磷酸化和激活Src家族的激酶FYN来激活Vav1，FYN进而磷酸化并激活Vav1。我们将通过检测来自ITK-/-小鼠的自身反应性T细胞在体外和体内的迁移行为来检验这一假设，以确定ITK控制T细胞向非淋巴组织移动的分子机制。我们还将确定ITK是否通过激活FYN来调节原始T细胞的细胞骨架重组，FYN是否是原始T细胞肌动蛋白聚合和细胞骨架重组所必需的，以及是否有助于自身免疫性疾病的进展。最后，我们将研究ITK小分子抑制剂在动物体内抑制I型糖尿病的疗效和机制，以开始探索靶向ITK阻断在临床治疗各种器官特异性自身免疫性疾病的作用。

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.