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

• 批准号: 8132313
• 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
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132313
• 关键词: Affect; Age; Age related macular degeneration; Aging; Alzheimer' 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; public health relevance; relating to nervous system; research study; response; response to injury

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Injuries and diseases that lead to neurodegeneration afflict an ever-growing portion of the human population. The outcomes of these neurodegenerative processes range from mildly debilitating to deadly and include glaucoma, age-related macular degeneration, diabetic retinopathy, Alzheimer's disease, stroke, traumatic injuries, infectious diseases, and many other less common causes. Since aging is a factor in many of these diseases, their impact will increase, as the average age of the population increases. Progress toward understanding the fundamental mechanisms of neuroprotection is critical.

描述（由申请人提供）：先天免疫系统由构成对损伤和感染的非抗原特异性反应的细胞和分子组成，其中包括巨噬细胞，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表示，已证明基于神经保护作用的证据以及在神经变性和病理学中的作用，会影响神经损伤的结果。先天免疫力可能在视网膜中起着相似的作用。先天免疫反应促进了适应性免疫反应，可以通过免疫的适应性，抗原特异性部门来调节，从而提高了可以利用这两个免疫力来控制神经组织对损伤的反应的可能性。自1990年代后期提出，对神经自我抗原具有特殊性的T细胞是神经保护的重要组成部分，因此产生更有利的神经损伤结果的可能性已受到了极大的关注。该想法具有多种原因很有吸引力，包括促进对视网膜具有巨大健康影响（青光眼，黄斑变性，糖尿病等）的慢性疾病神经保护的可能性。但是，关于免疫系统和神经系统界面如何仍然难以捉摸的明确证据，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和免疫学耐受性有关的研究，并在视网膜损伤的反应中发现了一个新成分。这些小鼠和策略可以迅速应用于神经保护的研究，并用于检查免疫在视网膜稳态中的作用和对损伤的反应，与实验性自身免疫性疾病分开。小鼠有新的机会来定义免疫在神经保护/神经变性中的作用。该提案中的问题基于初步结果，表明在视网膜神经节细胞受伤后树突状细胞的早期参与。该实验集中于先天免疫对神经退行性疾病/保护的树突状细胞的可能贡献，并测试其在聚焦视网膜抗原特异性T细胞对神经保护方面的作用，而不是疾病。 使用视网膜神经节细胞死亡中的视网膜神经节细胞死亡中，第一个目标检验了我们的假设，即树突状细胞有助于视网膜稳态。我们问：1）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）它们是否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。由于树突状细胞是重要的抗原呈现细胞，因此第二个目的检查了适应性免疫反应到神经保护中的募集，并提出：1）树突状细胞是否募集T细胞造成T细胞损伤，2）T细胞的群体对视网膜神经节细胞的存活或损失很重要，以及3）对T细胞的AG-特异性很重要。 公共卫生相关性：导致神经变性的伤害和疾病在人口中不断增长。这些神经退行性过程的结果范围从轻度衰弱到致命，包括青光眼，与年龄相关的黄斑变性，糖尿病性视网膜病变，阿尔茨海默氏病，中风，创伤性损伤，感染性疾病，感染性疾病以及许多其他常见原因。由于衰老是其中许多疾病的一个因素，因此随着人口的平均年龄增长，它们的影响将增加。了解神经保护的基本机制的进展至关重要。