Immune-mediated Neuroprotection of Retinal Ganglion Cells

视网膜神经节细胞的免疫介导的神经保护

基本信息

批准号：
8323404
负责人：
DALE Sannes GREGERSON
金额：
$ 42.41万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323404
关键词：
Affect Age Age related macular degeneration Aging Alzheimer&apos s Disease Antigen-Presenting Cells Antigens Attention Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity Axon CD4 Positive T Lymphocytes CD80 gene Cell Communication Cell Death Cell Survival Cells Cessation of life Chronic Disease Communicable Diseases Contralateral Crush Injury Dendritic Cells Dendritic cell activation Diabetes Mellitus Diabetic Retinopathy Disease Eye Glaucoma Health Homeostasis Human Immune Immune Tolerance Immune response Immune system Immunity Infection Inflammation Injury Interleukin-6 Interruption Kinetics Knockout Mice Lead Literature MHC Class II Genes Macular degeneration Mediating Microglia Modeling Mus Myeloid Cells Natural Immunity Nature Nerve Crush Nerve Degeneration Nerve Fibers Nervous system structure Neurodegenerative Disorders Neurons Optic Nerve Optics Outcome Pathology Phenotype Play Population Process Property Recovery Recruitment Activity Relative (related person)Retina Retinal Retinal Ganglion Cells Role Signal Transduction Specificity Sterility Stroke T-Cell Immunologic Specificity T-Lymphocyte Testing Time Tissues Transgenic Mice Validation activity marker adaptive immunity arm base injured macrophage nerve injury neuroprotection neuroregulation relating to nervous system research study response response to injury

项目摘要

PROJECT SUMMARY/ABSTRACT The innate immune system is comprised of cells and molecules that make up non-antigen specific responses to injury and infection, and includes macrophages, dendritic cells, and PMNs. Innate immune responses in the CNS, represented in part by microglia, have been shown to affect the outcome of neural injuries based on evidence for neuroprotective roles, as well as roles in neurodegeneration and pathology. It is likely that innate immunity plays similar roles in retina. The innate immune response promotes adaptive immune responses, and can be regulated by the adaptive, antigen specific arm of immunity, raising the possibility that these two facets of immunity could be exploited to control the neural tissue response to injury. The possibility of producing more favorable outcomes to neural injuries has received significant attention since the late 1990s when it was proposed that T cells with specificity for neural self-antigens were an important part of neuroprotection. The idea is attractive for several reasons, including the possibility to promote neuroprotection in chronic diseases of the eye that have enormous health impacts on the retina (glaucoma, macular degeneration, diabetes, etc.). However, definitive evidence on how the immune system and nervous system interface remains elusive, and key hypotheses still require experimental validation. Further, new hypotheses are being developed that may change these paradigms. We have been using transgenic and knockout mice for studies related to retinal autoimmunity and immunologic tolerance, and found a new component in the response to retinal injury. These mice and strategies could be rapidly applied to the study of neuroprotection, and used to examine the role of immunity in retinal homeostasis and response to injury, separate from experimental autoimmune disease. The mice bring a fresh opportunity to define the role of immunity in neuroprotection/neurodegeneration. The questions in this proposal are based on preliminary results that suggest the early participation of dendritic cells following injury to retinal ganglion cells. The experiments concentrate on the possible contributions of dendritic cells of innate immunity to neurodegenerative disease/protection, and test their role in focusing retinal antigen specific T cells on neuroprotection, rather than disease. Using the optic nerve crush model for retinal ganglion cell death in glaucoma, the first Aim tests our hypothesis that dendritic cells contribute to retinal homeostasis. We ask: 1) if dendritic cells, rather than microglia, are the first critical responders to retinal injury, 2) do they contribute to neuroprotection, and 3) how they communicate with injured retinal ganglion cells. Since dendritic cells are important antigen presenting cells, the second Aim examines recruitment of an adaptive immune response into neuroprotection, and asks: 1) do the dendritic cells recruit T cells to the injury, 2) what population of T cells is important to retinal ganglion cell survival or loss, and 3) does the Ag- specificity of the T cells matter.

项目摘要/摘要先天免疫系统由构成非抗原的细胞和分子组成对损伤和感染的特定反应，包括巨噬细胞，树突状细胞和PMN。中枢神经系统中的先天免疫反应部分由小胶质细胞代表，已被证明会影响基于神经保护作用的证据以及在神经变性和病理学。先天免疫力可能在视网膜中起着相似的作用。这先天免疫反应会促进适应性免疫反应，并可以由适应性调节，抗原特定的免疫力，提高了这两个免疫力方面的可能性利用以控制神经组织对损伤的反应。产生更有利的可能性自1990年代后期以来，神经损伤的结局受到了极大的关注提出对神经自我抗原具有特异性的T细胞是神经保护。这个想法有吸引力，原因有几个，包括促进的可能性眼睛慢性疾病的神经保护对视网膜具有巨大的健康影响（青光眼，黄斑变性，糖尿病等）。但是，关于如何免疫的明确证据系统和神经系统界面仍然难以捉摸，关键假设仍然需要实验验证。此外，正在开发可能改变这些范式的新假设。我们一直在使用转基因和基因敲除小鼠进行与视网膜自身免疫有关的研究和免疫耐受性，并在对视网膜损伤的反应中发现了一个新成分。这些老鼠策略可以迅速应用于神经保护的研究，并用于检查角色视网膜稳态的免疫力和对损伤的反应，与实验自身免疫分开疾病。老鼠有一个新的机会来定义免疫的作用神经保护/神经变性。本提案中的问题基于初步结果这表明在视网膜神经节细胞损伤后，树突状细胞的早期参与。这实验集中于先天免疫的树突状细胞对神经退行性疾病/保护，并测试其在聚焦视网膜抗原特异性T细胞上的作用神经保护，而不是疾病。使用视网膜神经节细胞在青光眼中使用视神经挤压模型，这是第一个目的测试了我们的假设，即树突状细胞有助于视网膜稳态。我们问：1）如果树突状细胞，而不是小胶质细胞，是对视网膜损伤的第一个关键反应者，2）它们有助于神经保护作用，以及3）它们如何与受伤的视网膜神经节细胞进行通信。自树突状细胞是重要的抗原呈递细胞，第二个目的检查了适应性的募集对神经保护的免疫反应，并提出：1）树突状细胞会募集T细胞损伤， 2）哪些T细胞群对于视网膜神经节细胞的存活或丧失很重要，3）Ag- T细胞的特异性很重要。