Local Control and Regulation of Retinal Autoimmunity

视网膜自身免疫的局部控制和调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要效应 T 细胞、调节性 T 细胞和无能 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) 会导致自身抗原介导的自身免疫特异性效应 T 细胞，其靶标可包括眼睛组织。尽管大多数 Tregs 起源于胸腺，我们之前的研究表明，响应视网膜自身抗原，Tregs可以在局部产生视网膜中的传统 CD4+ T 细胞，我们将这一过程称为“按需”Treg 生成。 T细胞在没有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 T 细胞无反应，这是一种功能无反应和不增殖的状态。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个重要机制。体内平衡。我们观察到少量 T 细胞和一群髓样细胞（小胶质细胞），其中的子集可以充当视网膜内的传统树突状细胞。因此，我们假设存在一个局部的、视网膜内不断产生视网膜自身抗原特异性 Tregs 和无能 T 细胞，从而有助于视网膜免疫稳态以及 T 细胞、视网膜小胶质细胞和可能的非细胞之间的相互作用髓性视网膜细胞决定视网膜T细胞的性质和命运。这个假设将分三部分进行探讨旨在将自发性视网膜自身免疫的 R161H 小鼠模型与转基因小鼠结合使用允许跟踪和消耗树突状细胞、小胶质细胞和 Tregs。目标 1：该目标将定义视网膜小胶质细胞，特别是树突状细胞亚群，在抗原中发挥的作用导致视网膜自身免疫发病机制的表现。目标 2：该目标将定义和区分常驻视网膜小胶质细胞与非髓样胶质细胞的作用视网膜细胞在视网膜内产生无能和调节性 T 细胞。目标 3：该目标将是利用视网膜小胶质细胞或其他细胞的局部治疗操作进行转化研究。抗原呈递细胞限制 T 细胞共刺激并促进无能和调节性 T 细胞的生成以限制视网膜的炎症损伤。