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: 10339488
• 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/10339488
• 关键词: Affect; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Arrestins; Autoantigens; Autoimmune; Autoimmunity; Blindness; CD4 Positive T Lymphocytes; Cell Communication; Cells; 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; Local Therapy; MHC antigen; Mediating; Microglia; Modeling; Mus; Myeloid Cells; Nature; Neuraxis; 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; cell type; 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.

项目总结/摘要 效应T细胞、调节T细胞和无能T细胞的平衡和功能对于维持免疫功能至关重要。 免疫稳态缺乏调节性T细胞（Tcells）导致自身抗原介导的自身免疫 特异性效应T细胞，其靶可包括眼组织。虽然大多数的Tibetan起源于 我们以前的研究表明，在对视网膜自身抗原的反应中，TdR可以在局部产生， 在视网膜中从传统的CD 4 + T细胞中产生Treg，我们称之为“按需”Treg生成的过程。T细胞 在不存在共刺激信号或存在共刺激信号的情况下识别抗原-MHC-II复合物， 抑制信号可诱导无反应性，即T细胞中功能性无反应性和不增殖的状态。 因此，无反应性T细胞的产生可能是维持视网膜免疫的另一重要机制 体内平衡我们已经观察到少量的T细胞和髓样细胞（小胶质细胞）， 其亚群可以作为视网膜内的常规树突细胞。因此，我们假设有一个本地的， 视网膜内持续产生视网膜自身抗原特异性T细胞和无反应性T细胞， 视网膜免疫稳态之间的相互作用，视网膜小胶质细胞，并可能非- 髓样视网膜细胞决定视网膜T细胞的性质和命运。这一假设将在三个方面进行探讨。 目的利用R161 H小鼠自发性视网膜自身免疫模型结合转基因小鼠， 它允许追踪和消除树突细胞、小胶质细胞和Tcells。 目的1：明确视网膜小胶质细胞，特别是树突状细胞亚群在抗原表达中的作用， 在视网膜中的自身免疫性发病机制。 目的2：该目的将定义和区分视网膜小胶质细胞与非髓样细胞的作用， 视网膜细胞在视网膜内产生无反应性和调节性T细胞中起作用。 目标3：该目标将是使用视网膜小胶质细胞或其他局部治疗操作的转化研究 抗原呈递细胞，以限制T细胞共刺激并促进无反应性和调节性T细胞的产生 以限制视网膜的炎症损伤。