Immunopathogenic mechanisms of dry eye disease

干眼病的免疫致病机制

• 批准号: 9129776
• 负责人: Reza Dana
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129776
• 关键词: Acute; Adult; Affect; Age related macular degeneration; American; Antigen-Presenting Cells; Automobile Driving; Blindness; CD4 Positive T Lymphocytes; Cell Maturation; Cell physiology; Cells; Cellular Immunity; Chronic; Clinical; Data; Disease; Elements; Epithelial; Epithelium; Expenditure; Eye; Eye diseases; Frequencies; Functional disorder; Generations; Grant; Health; High Prevalence; Homeostasis; Immune; Immunity; Immunologic Memory; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Interleukin-15; Interleukin-17; Interleukin-2; Interleukin-6; Interleukin-7; Knowledge; Laboratories; Lead; Maintenance; Mediating; Memory; Molecular; PDCD1LG1 gene; Pathogenesis; Performance at work; Phenotype; Prevalence; Principal Investigator; Productivity; Regulatory T-Lymphocyte; Research; Role; Series; Severities; Severity of illness; Stress; T-Cell Proliferation; T-Lymphocyte; Thrombospondin 1; Time; Topical application; United States; Vision; Visual; Work; aging population; base; corneal epithelium; corneal scar; cytokine; effective therapy; eye dryness; in vivo; insight; interleukin-15 receptor; interleukin-23; novel; ocular surface; pigment epithelium-derived factor; research study; response; restoration; therapeutic target; treatment effect

DESCRIPTION (provided by applicant): Dry eye disease (DED), a chronic immune-mediated disorder of the ocular surface, is characterized by sustained ocular surface inflammation and disruption of the ocular surface epithelium, which in severe cases can lead to corneal scarring and blindness. DED has a very high prevalence, almost triple that of age-related macular degeneration, affecting many millions of individuals in the United States alone, and its prevalence is set to increase considerably with the aging of the population. Current expenditures for treating DED surpass $2 billion dollars annually, and because it often affects visual function in working adults, it leads to lost productivity by impacting job performance. While the role of immunity in amplifying DED severity has been known for some time, it is only recently that we have gained insights into the immunopathogenic mechanisms that drive DED. Evidence from several laboratories, including the Principal Investigator's, has established strong evidence for the critical role of T helper-17 (Th17) cells, in driving immune-mediated damage to the ocular surface in DED. More recent evidence from the PI's lab shows that DED can be maintained chronically for months, even after termination of desiccating stress to the eye, by memory Th17 cells, which are distinct from the effector T cells that mediate disease after acute ocular desiccating stress. In addition, data from the PI's lab demonstrate that in DED the regulatory T cells (Tregs), which are normally highly effective in suppressing T cell-mediated inflammation, are particularly defective in suppressing the Th17 response. While these data provide new insights into DED immunopathogenesis, numerous important questions remain unanswered. We hypothesize that DED is characterized by a microenvironment that promotes the generation and maintenance of Th17 immunity, which in turn leads to suppressed function of Tregs that normally maintain immune quiescence. The principal objectives of this project are to (i) define the factors that influence the generation and maintenance of immunologic memory, and characterize precisely the dysfunction of (ii) the corneal epithelium and (iii) Tregs in maintaining immune homeostasis in DED. To achieve these major objectives, three specific aims have been defined to answer the following questions: Aim 1: What are the critical cytokine mechanisms that lead to induction and maintenance of Th17 immunological memory in chronic dry eye disease? Aim 2: How does epithelial damage affect the immunomodulatory function of the corneal epithelium in DED? And, Aim 3: Which among the Th17- associated cytokines interact directly with Tregs to suppress their regulatory function? It is anticipated that this research will have significant translational impact given the high prevalence of DED, the still limited knowledge we have regarding its precise immunopathogenesis, and the relative dearth of effective treatments.

描述（由申请人提供）：干眼症（DED），一种慢性免疫介导的眼表面疾病，其特征是眼表炎症持续性和眼表上皮的破坏，在严重的情况下，这会导致角膜疤痕和失明。 DED的患病率很高，几乎是与年龄相关的黄斑变性的三倍，仅在美国就影响了数百万个人，并且随着人口的衰老，其患病率将大大增加。当前用于处理DED的支出每年超过20亿美元，并且由于它通常会影响工作成年人的视觉功能，因此它会通过影响工作绩效而导致生产力失去。 虽然免疫力在扩大DED严重性中的作用已知一段时间，但直到最近，我们才能深入了解驱动DED的免疫发病机制。来自包括主要研究者在内的几个实验室的证据已经为T Helper-17（Th17）细胞的关键作用建立了有力的证据，在驱动免疫介导的DED中对眼表面的损害。 PI实验室的最新证据表明，即使通过记忆Th17细胞终止了对眼睛的干燥压力，DED也可以长期维持数月，这些细胞与急性眼干燥应激后介导疾病的效应T细胞不同。此外，来自PI实验室的数据表明，在DED中，通常在抑制T细胞介导的炎症方面非常有效的DED T细胞（TREG）在抑制TH17反应方面尤为有缺陷。尽管这些数据为DED免疫发病发生提供了新的见解，但许多重要的问题仍未得到解决。 我们假设DED的特征是微环境促进了Th17免疫的产生和维持，这反过来又导致了通常保持免疫静止的Treg的抑制功能。该项目的主要目标是（i）定义影响免疫记忆产生和维持的因素，并精确地表征（ii）（ii）角膜上皮和（iii）Treg的功能障碍，以维持DED中的免疫稳态。为了实现这些主要目标，已经定义了三个特定目标来回答以下问题：目标1：导致慢性干眼病中Th17免疫记忆的诱导和维持的关键细胞因子机制是什么？目标2：上皮损伤如何影响DED中角膜上皮的免疫调节功能？并且，AIM 3：TH17相关的细胞因子中的哪个直接与Treg相互作用以抑制其调节功能？预计，鉴于DED的高度流行，我们对其精确的免疫发病发生的知识以及有效治疗的相对缺乏，这项研究将产生重大的翻译影响。