Local Retinal Antigen Presentation

局部视网膜抗原呈现

• 批准号: 7473797
• 负责人: DALE Sannes GREGERSON
• 金额: $ 35.57万
• 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/7473797
• 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; Numbers; 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.

描述：免疫反应取决于抗原表现，这是免疫力中的中心事件。能够在淋巴组织中执行该功能的细胞是强烈研究的主题，并且越来越多地发现是树突状细胞。相反，在非淋巴组织中呈现抗原的细胞，尤其是包括视网膜和中枢神经系统在内的神经组织的细胞，并未充分表征。这些细胞功能的基本知识对于理解这些敏感组织中的炎症至关重要。我们以前对视网膜中免疫细胞抗原表现出能力的体外测定几乎没有活性。在体内，我们发现证据表明抗原表现会导致视网膜炎症，可由循环中募集的细胞提供。我们还发现，将少量分离的树突状细胞接种到眼睛中，显着增加了自动反应性T细胞对视网膜抗原的致病反应强度。结果，我们建议在视网膜中引发CD4 T细胞介导的免疫反应所需的抗原表现取决于从循环中募集的细胞而不是局部细胞。该假设与视网膜和中枢神经系统中抗原表现的当前范式有显着不同，这断言周围细胞是呈现抗原的抗原，负责诱导CD4 T细胞介导的神经系统免疫反应。因此，需要检查视网膜免疫生物学的基本方面。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炎所需的抗原表现取决于从循环中募集的抗原呈现的细胞，而不是居民小胶质细胞，或骨髓衍生的骨膜上血管周围细胞，这些细胞会缓慢转移。 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扮演了减弱视网膜炎症的调节作用。为了解决这些假设，将对视网膜抗原特异的自动反应性CD4 T细胞接种到具有或缺乏的小鼠中：1。树突状细胞；或2。在视网膜中免疫细胞子集的MHC II类。将测试循环抗原呈递细胞或其前体替代抗原表现中这些缺陷的能力。