Local Control and Regulation of Retinal Autoimmunity

视网膜自身免疫的局部控制和调节

• 批准号: 10551909
• 负责人: Scott W McPherson
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551909
• 关键词: Acceleration; Affect; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Arrestins; Autoantigens; Autoimmune; Autoimmunity; Blindness; CD4 Positive T Lymphocytes; Cell Communication; Cells; Central Nervous System; Chronic; Complex; Dendritic Cells; Disease; Equilibrium; Eye; Eye diseases; Generations; Graves' Disease; Homeostasis; ITGAX gene; Immune; Immune Tolerance; Immune response; Immunocompetence; Inflammatory; Injury; Insulin-Dependent Diabetes Mellitus; Knowledge; Learning; Local Therapy; Mediating; Microglia; Modeling; Mus; Myeloid Cells; Nature; Organ; Peptides; Phenotype; Play; Population; Process; Production; Property; Regulation; Regulatory T-Lymphocyte; Retina; Rheumatoid Arthritis; Role; Sarcoidosis; Severities; Signal Transduction; Systemic Lupus Erythematosus; Systemic Therapy; T cell anergy; T-Lymphocyte; Testing; Therapeutic; Therapeutic Uses; Thymus Gland; Tissue Grafts; Tissues; Transgenic Mice; Visual; Visual impairment; anergy; antigen-specific T cells; autoimmune pathogenesis; cytokine; effector T cell; immune function; mouse model; prevent; response; side effect; translational study; uveoretinitis

Project Summary/Abstract The balance and function of effector T cells, regulatory T cells, and anergic T cells are critical for maintaining immune homeostasis. Lack of regulatory T cells (Tregs) leads to autoimmunity mediated by self-antigen specific effector T cells whose targets can include tissues of the eye. Although most Tregs originate in the thymus, our previous studies suggest that in response to retinal self-antigens, Tregs can be generated locally in the retina from conventional CD4+ T cells, a process we refer to as "on-demand" Treg generation. T cell recognition of antigen-MHC-II complexes in the absence of costimulatory signals or in the presence of inhibitory signals can induce anergy, a state of functional unresponsiveness and non-proliferation in T cells. Thus, generation of anergic T cells may be another important mechanism for maintaining retinal immune homeostasis. We have observed a small number of T cells and a population of myeloid cells (microglia), a subset of which can act as conventional dendritic cells within the retina. Thus, we hypothesize there is a local, continual generation of retinal self-antigen specific Tregs and anergic T cells within the retina that contributes to retinal immune homeostasis and that the interaction between T cells, retinal microglia, and possibly non- myeloid retinal cells determines the nature and fate of retinal T cells. This hypothesis will be explored in three aims using the R161H mouse model of spontaneous retinal autoimmunity in conjunction with transgenic mice that allow for the tracking and depletion of dendritic cells, microglia, and Tregs. Aim 1: This aim will define the role that retinal microglia, particularly the dendritic cell subset, plays in antigen presentation that leads to autoimmune pathogenesis in the retina. Aim 2: This aim will define and distinguish the roles that resident retinal microglia versus the non-myeloid retinal cells play in production of anergic and regulatory T cells within the retina. Aim 3: This aim will be translational studies using local therapeutic manipulation of retinal microglia or other antigen presenting cells to limit T cell co-stimulation and promote generation of anergic and regulatory T cells to limit inflammatory injury to the retina.

项目摘要/摘要 效应T细胞，调节性T细胞和厌食T细胞的平衡和功能对于维持 免疫稳态。缺乏调节性T细胞（TREG）导致自身免疫性由自我抗原介导 特定效应T细胞的靶标可以包括眼睛的组织。虽然大多数treg都起源于 胸腺，我们以前的研究表明，在对视网膜自我抗原的响应中，可以在局部生成Tregs 在常规CD4+ T细胞的视网膜中，我们称之为“按需” Treg的生成。 T细胞 在没有共刺激信号的情况下或在存在的情况下，识别抗原MHC-II复合物 抑制信号可以诱导Anergy，T细胞中功能性无反应性和不变状态。 因此，厌食T细胞的产生可能是维持视网膜免疫的另一种重要机制 稳态。我们观察到少数T细胞和髓样细胞群（小胶质细胞），A 其子集可以充当视网膜内的常规树突状细胞。因此，我们假设有一个本地 视网膜中的视网膜自我抗原特异性Treg和视网膜中的无抗T细胞的持续生成有助于 视网膜免疫稳态以及T细胞，视网膜小胶质细胞，可能是非 - 髓样视网膜细胞确定视网膜T细胞的性质和命运。该假设将在三个 使用自发性视网膜自身免疫的R161H小鼠模型与转基因小鼠结合 这允许树突状细胞，小胶质细胞和Treg的跟踪和耗竭。 AIM 1：此目标将定义视网膜小胶质细胞（尤其是树突状细胞）在抗原中发挥作用的作用 导致视网膜自身免疫发病机理的表现。 AIM 2：此目标将定义和区分居民视网膜小胶质细胞与非乳状细胞的角色 视网膜细胞在视网膜内的厌食和调节性T细胞的产生中发挥作用。 AIM 3：此目的是使用视网膜小胶质细胞或其他视网膜的局部治疗操作进行翻译研究 抗原呈现细胞以限制T细胞共刺激并促进厌食和调节性T细胞的产生 限制对视网膜的炎症伤害。