Role of IL-17+ Autoreactive T Cells in Experimental Autoimmune Uveitis (EAU)

IL-17 自身反应性 T 细胞在实验性自身免疫性葡萄膜炎 (EAU) 中的作用

基本信息

批准号：
8128485
负责人：
Deming Sun
金额：
$ 38.73万
依托单位：
DOHENY EYE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8128485
关键词：
Adoptive Transfer Animals Antigens Autoimmune Diseases Autoimmune Process CD4 Positive T Lymphocytes Cell Communication Cells Chronic Phase Development Disease Disease Progression Event Experimental Models Exposure to Eye Generations Goals Growth Factor Health Human IL17 gene Immune Immunization Infectious Agent Inflammatory Interferon Type II Interferons Interleukin-17 Interleukin-2 Interleukin-4 Laboratories Lead Lymphoid Measures Molecular Mus Organ Pathogenesis Pathway interactions Peripheral Play Production Proteins Research Research Personnel Role Severity of illness T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Therapeutic Uveitis Vision autoimmune uveitis autoreactive T cell base cytokine design effective therapy environmental agent human disease immunoregulation improved interest interstitial retinol-binding protein microbial novel therapeutics prevent response

项目摘要

DESCRIPTION (provided by applicant): Over the past two decades, studies on pathogenic T cells have been guided by the dogma that these are mostly CD4+ Th1-type T cells and produce interferon-? (IFN-?). This concept has been revised recently because of studies showing that induction of many autoimmune diseases is not abolished in the absence of Th1 cells and that autoreactive T cells producing IL-17, but not IFN-?, play an important role in autoimmune diseases. Our preliminary studies determining the role of IL-17+ autoreactive T cells in EAU have shown that IL-17-expressing T cells can be readily identified in EAU-susceptible mice and that both IFN-? + and IL-17+ IRBP-specific T cells are uveitogenic. The observation that growth factors required for activation of IFN-?+ and IL-17+ IRBP-specific T cells IRBP-specific T cells are different and that ?? T cells play a major role in the activation of IL-17+ cells, but that they are not as important for IFN-? response, prompts us to place our emphasis on determining whether dominance of one type of pathogenic T cell is determined by the immune conditions under which T cells become activated. We will determine the activation requirements of IFN-? + and IL-17+ IRBP-specific T cells in the periphery and inside the inflamed eye and determine whether activation of two uveitogenic T cell subsets relies on different APCs and co-stimulatory molecules (Aim 1). In terms of determining the factors that are important for the activation and expansion of IL-17+ autoreactive T cells (Aims 2&3), our preliminary studies have shown that increased activation of IL-17+ T cells is frequently associated with activation of ?? TCR cells and that depletion of ?? T cells reduces induction of EAU. We will now determine whether depletion of ?? T cells prevent the Th17 uveitogenic T cells to acquire pathogenic activity and whether ?? -/- recipients will generate increased numbers of Th17-type uveitogenic T cells, if such mice are injected with a small number of ?? T subset (Aim2). We have observed that interaction between ??? and ?? T cell subsets results in the production of increased amount of IL-17. We will now determine the mechanisms that lead to reciprocal stimulation between ?? and ?? T cells and determine the role of ?? T cell subsets in immunoregulation on generation of IL17+ uveitogenic T cells. Our hypothesis is that "exposure to infectious agents, such as microbial proteins, may promote ?? T cell activation. Activation of specific ?? subset(s) promotes the generation of IL17+ uveitogenic T cell; activated??? T cells may further promote the activation of ?? T cells, leading to augmented Th17 response." The continuation of this study and the clarification of the pathogenic role of, and relationship between, IFN-?+ and IL-17+ autoreactive T cells in EAU should contribute to our understanding of the mechanism of autoimmune disease pathogenesis. PUBLIC HEALTH RELEVANCE: Uveitis is a sight-threatening, inflammatory disease. Mice can be induced for similar disease, either by immunization of the animals with a pathogenic antigen or by adoptive transfer with uveitogenic T cells. These experimental models have been extensively used for determination of the pathogenic mechanisms that is not possible to be directly approached in humans. Our laboratory has been interested in the characterization of pathogenic T cells that cause this disease. We have developed a range of expertise in determining the cellular and molecular events crucial to the development of autoimmune disease. In this application, we propose to determine a new pathogenic T cell subset expressing interleukin-17 (IL-17).

描述（由申请人提供）：在过去的二十年中，对致病性 T 细胞的研究一直遵循这样的教条：这些细胞大多是 CD4+ Th1 型 T 细胞，并产生干扰素-？（干扰素-？）。这一概念最近得到了修订，因为研究表明，在缺乏 Th1 细胞的情况下，许多自身免疫性疾病的诱发并不会消失，并且产生 IL-17（而非 IFN-γ）的自身反应性 T 细胞在自身免疫性疾病中发挥着重要作用。我们的初步研究确定了 EAU 中 IL-17+ 自身反应性 T 细胞的作用，结果表明，在 EAU 易感小鼠中可以很容易地识别表达 IL-17 的 T 细胞，并且 IFN-α + 和 IL-17+ IRBP 特异性 T 细胞具有葡萄膜致性。观察到激活 IFN-α+ 和 IL-17+ IRBP 特异性 T 细胞所需的生长因子与 IRBP 特异性 T 细胞不同，并且 ?? T 细胞在 IL-17+ 细胞的激活中发挥着重要作用，但它们对于 IFN-α 的作用并不那么重要。反应，促使我们将重点放在确定一种致病性 T 细胞的优势是否由 T 细胞被激活的免疫条件决定。我们将确定 IFN-α 的激活要求。 + 和 IL-17+ IRBP 特异性 T 细胞位于发炎的眼睛周围和内部，并确定两个致葡萄膜 T 细胞亚群的激活是否依赖于不同的 APC 和共刺激分子（目标 1）。在确定对 IL-17+ 自身反应性 T 细胞的激活和扩增至关重要的因素（目标 2 和 3）方面，我们的初步研究表明，IL-17+ T 细胞的激活增加通常与 ?? 的激活相关。 TCR 细胞和 ?? 的耗尽T 细胞减少 EAU 的诱导。我们现在将确定 ?? 是否耗尽T 细胞阻止 Th17 致葡萄膜 T 细胞获得致病活性，是否 ?? -/- 如果给这些小鼠注射少量 ??，受者将产生更多数量的 Th17 型葡萄膜致 T 细胞。 T 子集（目标 2）。我们观察到 ??? 之间的相互作用和？？ T 细胞亚群导致 IL-17 的产生量增加。我们现在将确定导致 ?? 之间相互刺激的机制。和？？ T细胞的作用及决定?? T 细胞亚群对 IL17+ 致葡萄膜 T 细胞生成的免疫调节作用。我们的假设是，“接触传染源，例如微生物蛋白，可能会促进 ??T 细胞激活。特定 ?? 亚群的激活促进 IL17+ 致葡萄膜 T 细胞的生成；激活的 ??T 细胞可能进一步促进T 细胞的激活，导致 Th17 反应增强。”这项研究的继续进行以及对 EAU 中 IFN-α+ 和 IL-17+ 自身反应性 T 细胞的致病作用及其关系的澄清，应有助于我们了解自身免疫性疾病发病机制。公共卫生相关性：葡萄膜炎是一种威胁视力的炎症性疾病。通过用致病性抗原对动物进行免疫接种或用致葡萄膜 T 细胞进行过继转移，可以诱导小鼠患上类似的疾病。这些实验模型已广泛用于确定人类无法直接接近的致病机制。我们的实验室一直对引起这种疾病的致病性 T 细胞的特征感兴趣。我们在确定对自身免疫性疾病发展至关重要的细胞和分子事件方面积累了一系列专业知识。在此应用中，我们建议确定表达白细胞介素 17 (IL-17) 的新致病性 T 细胞亚群。