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

基本信息

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
项目类别：
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

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, 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，特别是工作年龄人口，从而增加了大量的社会负担随之而来的医疗费用和生产力损失造成的经济负担。调查自身免疫性葡萄膜炎的研究重点关注该疾病的急性期，使用流行的方法急性葡萄膜炎的小鼠模型，事实上，相比之下，这种模型很少导致人类严重视力丧失因此，我们目前对确切病因的了解存在重大缺陷。我们的实验室最近开发并验证了慢性葡萄膜炎的小鼠模型。野生型动物的慢性自身免疫性葡萄膜炎（CAU），复制了慢性自身免疫性葡萄膜炎的临床特征使用这种独特的 CAU 模型，我们已经证明了在人类中观察到的威胁视力的葡萄膜炎。慢性疾病中的记忆 CD4+ T 细胞寿命较长，而慢性疾病中的效应 CD4+ T 细胞寿命较短这些记忆 T 细胞是抗原特异性、自身反应性效应细胞（“效应记忆”T 细胞）。此外，我们的初步研究表明，CAU 中的眼内炎症长期持续存在。研究揭示了 CAU 发炎视网膜内的局部缺氧微环境，这与缺氧诱导因子 1α (HIF-1α)、糖酵解代谢和 Wnt/β-连环蛋白显着上调转录活性选择性地存在于视网膜浸润性记忆T细胞中，但不存在于其他视网膜细胞中。由此得出HIF-1α通过维持致病记忆促进慢性自身免疫性葡萄膜炎 CD4+ T 细胞库通过调节 T 细胞的代谢和转录重编程来促进该项目的主要目标是 (i) 确定个体的功能和长期生存。 HIF-1α、糖酵解和 Wnt/β-连环蛋白激活对记忆 CD4+ T 细胞的葡萄膜原性的贡献；并进一步 (ii) 确定 HIF-1α 是否通过调节记忆 CD4+ T 细胞和慢性葡萄膜炎激活糖酵解代谢和 Wnt/β-连环蛋白转录途径为了实现这些目标，制定了三个具体目标：目标 1：记忆 T 细胞表达 HIF-1α 是否是其正常运作所必需的？目标 2：糖酵解是否增强？记忆 T 细胞发挥致病功能并由 HIF-1α 驱动？目标 3：Wnt/β- 是否被激活？记忆 T 细胞中的连环蛋白转录途径是其长寿所必需的，并由 HIF-1α 驱动？该项目的成功完成将大大提高我们对分子机制的了解调节致葡萄膜记忆 T 细胞的病理学并提供潜在的治疗新方法方法精确针对慢性自身免疫性葡萄膜炎的根本原因。