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: 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
• 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

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.

项目摘要 /摘要 慢性自身免疫性葡萄膜炎通常是一种耐药性疾病，导致不可逆转的视力丧失 如此受影响的大量患者。在工作年龄人口中的患病率特别高， 它占美国法律失明的10-15％，并增加了大量的社会经济伯恩。 因此，医疗保健成本和生产力损失估计接近糖尿病性视网膜病。 先前研究自身免疫性葡萄膜炎的先前研究重点是急性 疾病的阶段使用流行的急性葡萄膜炎模型，实际上很少会导致 与慢性葡萄膜炎相比，人类严重的视力丧失。那就是我们当前的主要缺陷 了解慢性自身免疫性葡萄膜炎的精确致病机制。这种缺陷有 与最近有承诺的几项临床试验的最近出乎意料的失败有关 转化潜力是从患有急性葡萄膜炎的动物到人类患者的治疗策略 慢性葡萄膜炎。我们的实验室现已开发并验证了慢性自身免疫的鼠标模型 野生型动物中的葡萄膜炎（CAU），该动物呈现出缓慢发育的进行性疾病病程 观察到3个月的持续时间，复制在 人类。我们希望使用这种动物模型来深入了解免疫病变 慢性阶段的葡萄膜炎，因此为优先考虑发展提供了坚实的基础 人类患者的新目标治疗。 我们在CAU模型中的初步工作已检测到一个突出的内存t辅助辅助17细胞（MTH17）， CAU的这种独特的细胞种群表现出对葡萄蛋白抗原的剧烈反应 体外刺激。记忆T细胞是抗原经验的，长寿命的T淋巴细胞介导的 免疫记忆。越来越多的证据表明，免疫记忆起着关键 在自身免疫性疾病和慢性注射中的作用。因此，我们假设记忆Th17细胞是 特定的葡萄象作用并介导葡萄膜炎的慢性疾病病程。的主要目标 该项目是（i）精确表征Cau中MTH17的表型和功能； （ii）确定 MTH17在维持葡萄膜炎的维持方面的功能。为了实现这些目标，两个特定的目标 已经开发了目的：目标1：MTH17是否为“效应器记忆” T细胞，能够诱导 葡萄膜炎？目标2：将补充或耗尽MTH17在既定 急性还是慢性葡萄膜炎？成功完成该项目将为 精确针对疾病的根本原因的新型治疗方法的发展 - 对当前可用治疗的抗性过程，并导致严重的视觉障碍。