Pathogenicity of memory Th17 cells in chronic autoimmune uveitis

项目摘要/摘要 慢性自身免疫性葡萄膜炎通常是一种耐药疾病，会导致不可逆转的视力丧失。 因此受到影响的患者数量很大。在劳动年龄人口中患病率特别高， 它占美国法律盲人的10%-15%，并因以下原因增加了大量的社会经济负担 随之而来的医疗成本和生产力损失，估计接近糖尿病视网膜病变。 先前对自身免疫性葡萄膜炎的研究主要集中在急性葡萄膜炎。 使用流行的急性葡萄膜炎小鼠模型来判断疾病的发展阶段，这实际上很少见地导致 与慢性葡萄膜炎形成对比的是人类严重的视力丧失。因此，我们目前的一个重大缺陷是 了解慢性自身免疫性葡萄膜炎的确切发病机制。这一缺陷有 与最近几项临床试验的意外失败有关，这些试验有希望 从急性葡萄膜炎动物到人类患者的翻译潜力作为一种治疗策略 慢性葡萄膜炎。我们实验室现在已经开发并验证了一种慢性自身免疫的小鼠模型 野生动物的葡萄膜炎(CAU)，表现为缓慢起病，进展性的疾病过程 观察3个月，复制观察到的慢性进行性葡萄膜炎的临床特征 人类。我们希望利用这种动物模型来加深对免疫发病机制的理解。 在慢性期发生葡萄膜炎，从而为优先发展葡萄膜炎提供坚实的基础 对人类患者进行新的靶向治疗。 我们在CAU模型中的初步工作检测到了一个显著的记忆T辅助细胞(MTh17)， CAU的这种独特的细胞群对葡萄膜生成抗原表现出强烈的反应。 体外刺激。记忆T细胞是经历过抗原的、长寿的T淋巴细胞 免疫记忆。越来越多的证据表明，免疫记忆起着至关重要的作用 在自身免疫性疾病和慢性炎症中的作用。因此我们假设记忆中的Th17细胞是 特异性葡萄膜生成效应因子，并介导葡萄膜炎的慢性病程。的主要目标 本项目的目的是(I)准确地描述mTh17在慢性萎缩性胃炎中的表型和功能；以及(Ii)确定 MTh17在葡萄膜炎慢性维持中的作用为了实现这些目标，有两个具体的目标 已经开发出目标：目标1：mTh17是不是能够诱导 葡萄膜炎？和目标2：补充或耗尽mTh17是否会影响已建立的 分别是急性葡萄膜炎还是慢性葡萄膜炎？该项目的成功完成将为 开发新的治疗方法，精确地针对疾病慢性化的根本原因 -对目前可用的治疗方法产生抵抗力并导致严重视力障碍的过程。

PROJECT SUMMARY / ABSTRACT Chronic autoimmune uveitis is often a treatment-resistant disease, leading to irreversible vision loss in a significant number of patients thus affected. With particularly high prevalence in the working-age population, it accounts for 10-15% of legal blindness in the US, and adds a substantial socio-economic burden due to consequent healthcare costs and productivity loss, estimated to be close to that of diabetic retinopathy. The preponderance of previous studies investigating autoimmune uveitis have focused on the acute stage of the disease using the popular murine models of acute uveitis, which in fact uncommonly leads to severe vision loss in humans in contrast to chronic uveitis. Thus, there is a major deficiency in our current understanding of the precise pathogenic mechanisms in chronic autoimmune uveitis. This deficiency has been associated with the recently unexpected failure of several clinical trials, which had promising translational potential as a therapeutic strategy from animals with acute uveitis to human patients with chronic uveitis. Our laboratory has now developed and validated a mouse model of chronic autoimmune uveitis (CAU) in wild-type animals, which presents with a slow-onset, progressive disease course for an observed duration of 3 months, replicating the clinical features of chronic progressive uveitis observed in humans. We hope to use this animal model to develop a deeper understanding of the immunopathogenesis of uveitis during the chronic stage, and thus provide a solid foundation for prioritizing the development of new targeted treatment in human patients. Our preliminary work in the CAU model has detected a prominent memory T helper-17 cells (mTh17), and this unique cell population from CAU has demonstrated vigorous responses to uveitogenic antigen stimulation in vitro. Memory T cells are antigen-experienced, long-lived T lymphocytes mediating immunological memory. Increasing evidence has demonstrated that immunological memory plays a critical role in autoimmune disorders and chronic inflammation. We thus hypothesize that memory Th17 cells are specific uveitogenic effectors and mediate the chronic disease course of uveitis. The principal objectives of this project are to (i) precisely characterize the phenotype and function of mTh17 in CAU; and (ii) determine the function of mTh17 in the maintenance of chronicity of uveitis. To achieve these objectives, two specific aims have been developed: Aim 1: Are mTh17 featured as `effector memory' T cells capable of inducing uveitis? And Aim 2: Will supplementation or depletion of mTh17 affect the disease course in established acute or chronic uveitis, respectively? Successful completion of this project will provide a framework for the development of novel therapeutic approaches precisely targeting the underlying cause of disease chronicity – a process resistant to the currently available treatment and leading to severe visual impairment.