Immune-mediated Neuroprotection of Retinal Ganglion Cells

描述(申请人提供)：先天免疫系统由细胞和分子组成，构成对损伤和感染的非抗原特异性反应，包括巨噬细胞、树突状细胞和中性粒细胞。根据神经保护作用的证据，部分以小胶质细胞为代表的中枢神经系统的先天免疫反应，以及在神经退行性变和病理学中的作用，已被证明影响神经损伤的结果。与生俱来的免疫很可能在视网膜中扮演着类似的角色。先天免疫反应促进获得性免疫反应，并可由适应性的、抗原特异性的免疫臂调节，增加了这两个免疫方面被利用来控制神经组织对损伤的反应的可能性。自20世纪90年代末提出具有神经自身抗原特异性的T细胞是神经保护的重要组成部分以来，神经损伤产生更有利结果的可能性受到了极大的关注。这个想法之所以有吸引力，有几个原因，包括有可能促进对视网膜有巨大健康影响的慢性眼部疾病(青光眼、黄斑变性、糖尿病等)的神经保护。然而，关于免疫系统和神经系统如何相互作用的确凿证据仍然难以捉摸，关键假设仍然需要实验验证。此外，正在开发新的假设，可能会改变这些范式。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耐受相关的研究，并在视网膜损伤的反应中发现了一个新的成分。这些小鼠和策略可以迅速应用于神经保护的研究，并用于检测免疫在视网膜动态平衡和损伤反应中的作用，独立于实验性自身免疫性疾病。这些小鼠带来了一个新的机会来定义免疫在神经保护/神经退化中的作用。这项建议中的问题是基于初步结果，这些结果表明树突状细胞在视网膜神经节细胞损伤后早期参与。这些实验集中在先天免疫的树突状细胞对神经退行性疾病/保护的可能贡献，并测试它们在将视网膜抗原特异性T细胞集中在神经保护而不是疾病上的作用。利用青光眼视网膜神经节细胞死亡的视神经挤压模型，第一个目的是检验我们的假设，即树突状细胞有助于视网膜内稳态。我们问：1)如果树突状细胞，而不是小胶质细胞，是视网膜损伤的第一关键反应者，2)它们是否有助于神经保护，3)它们如何与受损的视网膜神经节细胞沟通。由于树突状细胞是重要的抗原提呈细胞，第二个目的是检查适应性免疫反应在神经保护中的招募，并询问：1)树突状细胞是否招募T细胞到损伤处，2)什么T细胞群对视网膜神经节细胞的存活或丧失重要，以及3)T细胞的抗原特异性是否重要。 公共卫生相关性：导致神经变性的伤害和疾病困扰着越来越多的人类人口。这些神经退化过程的结果从轻度衰弱到致命，包括青光眼、老年性黄斑变性、糖尿病视网膜病变、阿尔茨海默病、中风、创伤、传染病和许多其他不常见的原因。由于老龄化是许多此类疾病的一个因素，随着人口平均年龄的增加，其影响将会增加。在了解神经保护的基本机制方面取得进展至关重要。

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.