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

• 批准号: 10394923
• 负责人: YIHE CHEN
• 金额: $ 23.89万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394923
• 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 potential; translational study

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.

项目总结/摘要 慢性自身免疫性葡萄膜炎通常是一种难治性疾病，导致患者不可逆转的视力丧失。 有相当数量的患者受到影响。由于在工作年龄人口中发病率特别高， 它占美国法律的失明的10-15%，并增加了大量的社会经济负担， 由此产生的医疗费用和生产力损失，估计接近糖尿病视网膜病变。 以往研究自身免疫性葡萄膜炎的优势集中在急性 使用流行的急性葡萄膜炎的鼠模型，这实际上不常见地导致疾病的早期阶段。 与慢性葡萄膜炎相比，人类严重的视力丧失。因此，我们目前的一个主要缺陷是， 了解慢性自身免疫性葡萄膜炎的确切致病机制。这一缺陷 与最近几项临床试验的意外失败有关，这些试验有希望 作为从急性葡萄膜炎动物到人类葡萄膜炎患者的治疗策略的转化潜力 慢性葡萄膜炎我们的实验室现在已经开发并验证了慢性自身免疫性小鼠模型 葡萄膜炎（CAU）在野生型动物中表现为缓慢发作的进行性病程， 观察持续时间为3个月，复制了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，以发展更深入的了解免疫发病机制 葡萄膜炎在慢性阶段，从而提供了一个坚实的基础，优先发展 人类患者的新靶向治疗。 我们的初步工作在CAU模型中检测到了一个突出的记忆性T辅助细胞-17（mTh 17）， 这种来自CAU的独特细胞群对葡萄膜原性抗原表现出强烈的反应 体外刺激。记忆性T细胞是一种具有抗原感受性的长寿命T淋巴细胞， 免疫记忆越来越多的证据表明，免疫记忆在免疫系统中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，我们假设记忆性Th 17细胞是 特异性的葡萄膜原效应物，并介导葡萄膜炎的慢性病程。的主要目标 本项目旨在（i）精确表征CAU中mTh 17的表型和功能;（ii）确定 mTh 17在维持葡萄膜炎慢性化中的作用。为了实现这些目标，两个具体的 目的1：mTh 17是否具有“效应记忆”T细胞的特征，能够诱导 葡萄膜炎目的2：补充或消耗mTh 17是否会影响已建立的疾病病程？ 急性或慢性葡萄膜炎，分别？该项目的成功完成将为 开发精确针对疾病慢性化根本原因的新型治疗方法 - 这是一种对目前可用的治疗有抵抗力并导致严重视力损害的过程。