Local Retinal Antigen Presentation

局部视网膜抗原呈现

• 批准号: 7659519
• 负责人: DALE Sannes GREGERSON
• 金额: $ 36.29万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659519
• 关键词: Address; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated; Autoimmune Process; Bite; Blood Circulation; Bone Marrow; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chimera organism; Confocal Microscopy; Dendritic Cells; Dependence; Diphtheria Toxin; Event; Eye; Fluorescent Probes; ITGAX gene; Imagery; Immune; Immune response; Immunity; Immunobiology; Inflammation; Injection of therapeutic agent; Knowledge; Lead; Lymphoid Tissue; MHC Class II Genes; Mediating; Microglia; Modeling; Modification; Mus; Mutant Strains Mice; Nervous system structure; PTPRC gene; Pathogenesis; Pericytes; Play; Population; Predisposition; Process; Radiation; Recruitment Activity; Retina; Retinal; Role; Source; T-Lymphocyte; Testing; Tissues; Uncertainty; autoreactive T cell; cell mediated immune response; in vitro Assay; in vivo; migration; monocyte; relating to nervous system; response; uveoretinitis

DESCRIPTION: Immune responses are dependent on antigen presentation, a central event in immunity. The cells capable of performing this function in lymphoid tissues are the subject of intense study, and are increasingly found to be dendritic cells. Conversely, the cells which present antigen in non-lymphoid tissues, especially neural tissues including retina and CNS, are not well-characterized. Fundamental knowledge of the function of these cells is critical to understanding inflammation in these sensitive tissues. Our previous in vitro assays of the antigen presenting abilities of immune cells in retina found virtually no activity. In vivo, we found evidence that antigen presentation leading to retinal inflammation could be provided by cells recruited from the circulation. We also found that inoculating small numbers of isolated dendritic cells into the eye dramatically increased the strength of the pathogenic response of autoreactive T cells to a retinal antigen. As a result, we propose that the antigen presentation required to initiate CD4 T cell-mediated immune responses in retina is dependent on antigen presenting cells recruited from the circulation, rather than local cells. This hypothesis differs significantly from the current paradigm of antigen presentation in retina and CNS, which asserts that perivascular cells are the antigen presenting cells responsible for induction of CD4 T cell mediated nervous system immune responses. Consequently, basic aspects of retinal immunobiology need to be examined. The hypothesis is divided into two parts. Part A proposes that the antigen presentation required to initiate CD4 T cell-mediated experimental autoimmune uveoretinitis is dependent on antigen presenting cells recruited from the circulation, rather than on the resident microglia, or on bone marrow-derived perivascular cells that turn over slowly. Part B proposes that retinal microglia and perivascular cells play regulatory roles that attenuate retinal inflammation in this model. To address these hypotheses, autoreactive CD4 T cells specific for a retinal antigen will be inoculated into mice that either possess or lack: 1. dendritic cells; or 2. MHC class II on subsets of immune cells in the retina. The ability of circulating antigen presenting cells, or their precursors, to replace these deficiencies in antigen presentation will be tested.

免疫反应依赖于抗原呈递，抗原呈递是免疫的中心事件。在淋巴组织中能够执行这一功能的细胞是研究的重点，并且越来越多地被发现是树突状细胞。相反，在非淋巴样组织，特别是包括视网膜和中枢神经系统在内的神经组织中呈递抗原的细胞没有很好的特征。了解这些细胞的基本功能对于理解这些敏感组织中的炎症至关重要。我们之前对视网膜免疫细胞抗原提呈能力的体外试验几乎没有发现任何活性。在体内，我们发现了导致视网膜炎症的抗原呈递可以由循环细胞提供的证据。我们还发现，将少量分离的树突状细胞接种到眼睛中，可显著增加自身反应性T细胞对视网膜抗原的致病性反应的强度。因此，我们提出在视网膜中启动CD4 T细胞介导的免疫应答所需的抗原呈递依赖于从循环中招募的抗原呈递细胞，而不是局部细胞。这一假设与目前视网膜和中枢神经系统中抗原呈递的范式有很大不同，后者认为血管周围细胞是负责诱导CD4 T细胞介导的神经系统免疫反应的抗原呈递细胞。因此，视网膜免疫生物学的基本方面需要检查。该假设分为两部分。A部分提出，启动CD4 T细胞介导的实验性自身免疫性葡萄膜视网膜炎所需的抗原呈递依赖于从循环中募集的抗原呈递细胞，而不是依赖于常驻的小胶质细胞，也不是依赖于周转缓慢的骨髓源性血管周围细胞。B部分提出视网膜小胶质细胞和血管周围细胞在该模型中发挥调节作用，减轻视网膜炎症。为了解决这些假设，将针对视网膜抗原的自身反应性CD4 T细胞接种到具有或缺乏：1。树突状细胞;或2。视网膜免疫细胞亚群上的MHC II类。循环抗原呈递细胞或其前体取代抗原呈递缺陷的能力将被测试。