Mechanisms of immunological memory-mediated pathogenesis in chronic autoimmune uveitis

慢性自身免疫性葡萄膜炎免疫记忆介导的发病机制

• 批准号: 10657851
• 负责人: YIHE CHEN
• 金额: $ 49.25万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657851
• 关键词: Acute; Acute Disease; Address; Adrenal Cortex Hormones; Adult; Age; Animals; Antigens; Apoptosis; Autoimmune Diseases; Biological Assay; Biology; Blindness; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Survival; Cell physiology; Cells; Chronic; Chronic Disease; Clinical; Clinical Management; Data; Dependence; Development; Disease; Disease Resistance; Economic Burden; Electroretinography; Flow Cytometry; Future; Genetic Transcription; Glycolysis; Health Care Costs; Histopathology; Human; Hypoxia; Hypoxia Inducible Factor; Immune response; Immunologic Memory; Immunotherapeutic agent; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Knowledge; Laboratories; Longevity; Mediating; Mediator; Medical; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Oxygen; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Play; Proliferating; Proteins; Public Health; Resistance; Retina; Role; Severity of illness; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Model; Up-Regulation; Uveitis; Viral Cancer; Virus Diseases; Vision; Visual impairment; Western Blotting; Work; aging population; antigen-specific T cells; autoimmune uveitis; autoreactivity; beta catenin; economic impact; efficacious treatment; experimental study; glucose uptake; hypoxia inducible factor 1; improved; in vivo; memory CD4 T lymphocyte; memory recall; mouse model; novel; novel therapeutic intervention; overexpression; productivity loss; response; sensor; side effect; socioeconomics; targeted treatment; transcriptional reprogramming; translational study; young adult

PROJECT SUMMARY / ABSTRACT Chronic autoimmune uveitis is often a treatment-resistant disease, leading to irreversible vision loss in a significant number of patients, particularly in the working-age population, and thus adds a substantial socio- economic burden due to consequent healthcare costs and productivity loss. 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 uveitis. Our laboratory has recently developed and validated a mouse model of chronic autoimmune uveitis (CAU) in wild-type animals, which replicates the clinical features of chronic sight-threatening uveitis observed in humans. Using this unique CAU model, we have demonstrated distinct long-lived memory CD4+ T cells in chronic disease, in contrast to the short-lived effector CD4+ T cells in acute disease. These memory T cells are antigen-specific, autoreactive effectors (`effector-memory' T cells) responsible for the chronic persistence of intraocular inflammation in CAU. Furthermore, our preliminary work reveals a local hypoxic microenvironment within the inflamed retina in CAU, which is associated with prominent up-regulation of hypoxia-inducible factor-1α (HIF-1α), glycolytic metabolism, and Wnt/β-catenin transcriptional activity selectively in the retinal infiltrating memory T cells but not in other retinal cells. We thus hypothesize that HIF-1α promotes chronic autoimmune uveitis via maintaining the pathogenic memory CD4+ T cell pool through regulating metabolic and transcriptional reprogramming of T cells that facilitates their function and long-term survival. The principal objectives of this project are to (i) determine individual contribution of HIF-1α, glycolysis, and Wnt/β-catenin activation to uveitogenicity of memory CD4+ T cells; and further (ii) determine whether HIF-1α modulates memory CD4+ T cells and chronic uveitis through activating glycolytic metabolism and Wnt/β-catenin transcriptional pathway. To achieve these objectives, three specific aims have been developed: Aim 1: Is HIF-1α expression by memory T cells required for their function and long-term survival and maintaining disease chronicity? Aim 2: Is enhanced glycolysis in memory T cells required for their pathogenic function and driven by HIF-1α? And Aim 3: Is activated Wnt/β- catenin transcriptional pathway in memory T cells required for their longevity and driven by HIF-1α? Successful completion of this project will substantially advance our knowledge of molecular mechanisms in modulating pathobiology of uveitogenic memory T cells and provide potentially novel therapeutic approaches precisely targeting the underlying cause of 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难治性疾病，导致患者不可逆转的视力丧失。 大量患者，特别是工作年龄人群，从而增加了大量的社会负担 由于随之而来的医疗保健成本和生产力损失而造成的经济负担。以往的优势 研究自身免疫性葡萄膜炎的研究集中在疾病的急性阶段， 急性葡萄膜炎的小鼠模型，其实际上在人类中不常见地导致严重的视力丧失， 慢性葡萄膜炎因此，我们目前对精确致病性的理解存在重大缺陷。 慢性葡萄膜炎的发病机制我们的实验室最近开发并验证了一种小鼠模型， 慢性自身免疫性葡萄膜炎（CAU）在野生型动物，复制的临床特征的慢性自身免疫性葡萄膜炎 在人类中观察到的威胁视力的葡萄膜炎。使用这种独特的CAU模型，我们已经证明了不同的 慢性疾病中的长寿命记忆性CD4 + T细胞，与慢性疾病中的短寿命效应性CD4 + T细胞相反， 急性病。这些记忆T细胞是抗原特异性的、自身反应性的效应子（"效应子-记忆" T细胞）。 导致CAU中眼内炎症的慢性持续性。此外，我们的初步 这项工作揭示了CAU中发炎视网膜内的局部缺氧微环境， 缺氧诱导因子-1 α（HIF-1 α）、糖酵解代谢和Wnt/β-catenin显著上调 在视网膜浸润性记忆T细胞中选择性地具有转录活性，但在其他视网膜细胞中没有。我们 因此推测HIF-1 α通过维持致病记忆促进慢性自身免疫性葡萄膜炎 通过调节T细胞的代谢和转录重编程促进CD 4 + T细胞库 功能和长期生存。本项目的主要目标是：（一）确定个人 HIF-1 α、糖酵解和Wnt/β-catenin激活对记忆性CD4 + T细胞葡萄膜形成的贡献; 并进一步（ii）确定HIF-1 α是否通过以下途径调节记忆性CD4 + T细胞和慢性葡萄膜炎： 激活糖酵解代谢和Wnt/β-catenin转录途径。为了实现这些目标， 已经开发了三个具体的目标：目标1：记忆T细胞表达HIF-1 α是否是其功能所必需的？ 功能和长期生存和维持疾病慢性化？目的2：增强的糖酵解是否 记忆T细胞是其致病功能所必需的，并由HIF-1 α驱动。目的3：激活Wnt/β- 记忆T细胞寿命所需的连环蛋白转录途径，由HIF-1 α驱动？ 该项目的成功完成将极大地推进我们的分子机制的知识， 调节葡萄膜记忆T细胞的病理生物学，并提供潜在的新的治疗方法， 方法精确地针对慢性自身免疫性葡萄膜炎的根本原因。