Immune-mediated Neuroprotection of Retinal Ganglion Cells

项目总结/摘要 先天免疫系统由构成非抗原的细胞和分子组成 对损伤和感染的特异性反应，包括巨噬细胞、树突状细胞和中性粒细胞。 CNS中的先天免疫应答，部分由小胶质细胞代表，已显示影响免疫应答。 基于神经保护作用的证据的神经损伤的结果，以及 神经变性和病理学。先天性免疫可能在视网膜中发挥类似的作用。的 先天性免疫应答促进适应性免疫应答，并且可以通过适应性， 免疫的抗原特异性臂，提高了免疫的这两个方面可能是 用来控制神经组织对损伤的反应生产更有利的可能性 自20世纪90年代末以来，神经损伤的结果受到了极大的关注， 提出，对神经自身抗原具有特异性的T细胞是免疫系统的重要组成部分。 神经保护这个想法之所以吸引人，有几个原因，包括可能促进 对视网膜有巨大健康影响的慢性眼部疾病的神经保护 （青光眼、黄斑变性、糖尿病等）。然而，关于免疫系统如何 系统和神经系统的接口仍然难以捉摸，关键的假设仍然需要实验 验证。此外，正在开发的新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视网膜自身免疫相关的研究 和免疫耐受，并发现了视网膜损伤反应的新成分。这些小鼠 和策略可以迅速应用于神经保护的研究，并用于检查作用 免疫在视网膜稳态和损伤反应中的作用，与实验性自身免疫性 疾病这些小鼠为定义免疫在免疫系统中的作用带来了新的机会。 神经保护/神经变性。本提案中的问题基于初步结果 提示视网膜神经节细胞损伤后树突状细胞的早期参与。的 实验集中在先天免疫的树突细胞对 神经退行性疾病/保护，并测试它们在将视网膜抗原特异性T细胞聚焦于 神经保护，而不是疾病。 利用视神经夹伤模型研究青光眼视网膜神经节细胞死亡， 测试我们的假设，树突状细胞有助于视网膜稳态。我们问：1）如果树突细胞， 而不是小胶质细胞，是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，以及3）它们如何与受损的视网膜神经节细胞通信。由于树突状 细胞是重要的抗原呈递细胞，第二个目的是检查适应性细胞的募集。 免疫反应转化为神经保护，并提出：1）树突状细胞是否招募T细胞到损伤处， 2)什么样的T细胞群体对视网膜神经节细胞的存活或丧失是重要的，以及3）Ag- T细胞的特异性很重要。

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.