Pathogenicity of memory Th17 cells in chronic autoimmune uveitis

记忆性Th17细胞在慢性自身免疫性葡萄膜炎中的致病性

基本信息

批准号：
10216752
负责人：
YIHE CHEN
金额：
$ 29.55万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216752
关键词：
Acute Acute Disease Address Adoptive Transfer Adrenal Cortex Hormones Affect Animal Experimentation Animal Model Animals Antigens Antimetabolites Autoimmune Diseases Biological Products Blindness CCL20 gene CCR6 gene CD4 Positive T Lymphocytes CD44 gene Cells Chronic Chronic Disease Clinical Clinical Course of Disease Clinical Management Clinical Trials Cyclosporine Cytotoxic agent Development Diabetic Retinopathy Disease Disease Resistance Economic Burden Electroretinography Experimental Autoimmune Encephalomyelitis Eye diseases Failure Foundations Frequencies Future Health Care Costs High Prevalence Human IL2RA gene Immune Immune response Immunologic Memory In Vitro Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-17 Laboratories Legal Blindness Lymphoid Tissue Maintenance Mediating Medical Memory Modeling Molecular Mouse Strains Mus Pathogenesis Pathogenicity Patients Phenotype Play Population Process Production Progressive Disease Rag1 Mouse Research Resistance Resistance Process Resolution Rest Retina Role SELL gene Series Severity of illness Solid Supplementation T memory cell T-Lymphocyte Therapeutic Tissues Uveitis Virulence Factors Visual impairment Work aging population autoimmune uveitis cytokine efficacious treatment experience immunomodulatory strategy improved in vivo interleukin-15 receptor migration mouse model novel novel therapeutic intervention ocular surface productivity loss response side effect socioeconomics targeted treatment translational study

项目摘要

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.

项目概要/摘要慢性自身免疫性葡萄膜炎通常是一种难治性疾病，会导致不可逆的视力丧失。大量患者因此受到影响，并且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%，并由于以下原因增加了巨大的社会经济负担：由此产生的医疗费用和生产力损失估计与糖尿病视网膜病变的费用接近。先前调查自身免疫性葡萄膜炎的研究主要集中在急性葡萄膜炎上。使用流行的急性葡萄膜炎小鼠模型来确定疾病的阶段，这实际上很少导致与慢性葡萄膜炎相比，人类的视力严重丧失，因此，我们目前的治疗方法存在重大缺陷。对慢性自身免疫性葡萄膜炎的确切致病机制的了解存在缺陷。与最近几项临床试验的意外失败有关，这些试验曾有希望作为从患有急性葡萄膜炎的动物到人类患者的治疗策略的转化潜力我们的实验室现已开发并验证了慢性自身免疫性小鼠模型。野生型动物的葡萄膜炎 (CAU)，其表现为缓慢发作、进行性的病程，观察持续时间为 3 个月，复制了观察到的慢性进行性葡萄膜炎的临床特征我们希望利用这种动物模型来更深入地了解免疫发病机制。为葡萄膜炎慢性阶段的优先发展奠定坚实的基础。针对人类患者的新的靶向治疗。我们在 CAU 模型中的初步工作检测到了一个突出的记忆 T 辅助细胞 17 (mTh17)，这种来自 CAU 的独特细胞群已表现出对葡萄膜抗原的强烈反应记忆 T 细胞是具有抗原经验的长寿命 T 淋巴细胞介导。越来越多的证据表明免疫记忆起着至关重要的作用。因此我们了解到记忆 Th17 细胞在自身免疫性疾病和慢性炎症中的作用。特定的葡萄膜炎效应物并介导葡萄膜炎的慢性病程。该项目旨在 (i) 精确表征 CAU 中 mTh17 的表型和功能；以及 (ii) 确定 CAU 中 mTh17 的表型和功能； mTh17 在维持葡萄膜炎慢性性中的功能为了实现这些目标，有两个具体的目标。目标已制定：目标 1：mTh17 是否具有“效应记忆”T 细胞的特征，能够诱导目标 2：补充或消耗 mTh17 是否会影响已确定的病程分别是急性或慢性葡萄膜炎？该项目的成功完成将为以下问题提供一个框架：开发新的治疗方法，精确针对慢性疾病的根本原因 – 对当前可用治疗产生抵抗并导致严重视力障碍的过程。