Immunobiology of EAU Recovery Through the Melanocortin-Adenosinergic Pathway

 描述（由申请人提供）：自身免疫性葡萄膜炎是一种使人衰弱和潜在致盲的炎症性疾病，每年影响10万美国人中的93人。目前的治疗策略是用包括类固醇在内的免疫抑制药物来控制炎症，这反过来又有严重的副作用，如白内障、青光眼、消化性溃疡、骨脱钙和全身感染易感性。人类自身免疫性葡萄膜炎的小鼠模型，实验性自身免疫性葡萄膜炎（EAU）已被用于更好地了解这种疾病。与慢性人葡萄膜炎相反，EAU无需干预即可消退，并且小鼠由于脾脏中发现的调节性免疫而对葡萄膜炎复发具有抗性。这种调节性免疫需要EAU后Treg细胞被EAU后抗原呈递细胞（APC）激活。我们已经表明，黑皮质素5受体（MC 5 r）是EAU后脾脏中出现调节性APC所必需的，并且该调节性APC是通过腺苷2A受体（A2 Ar）激活EAU后Treg细胞的腺苷的来源。这是一个有趣的发现，因为这两种途径已经被证明可以单独调节免疫力，但我们的观察是第一次将这两种途径联系起来。刺激这种黑皮质素-腺苷能途径的结果是抑制EAU的自身抗原特异性Treg细胞。该提案的重点是这些Treg细胞如何发挥功能以抑制炎症（具体目标1），如果再活化需要接触依赖性因子，以及Treg细胞的持续时间（具体目标2）。在EAU期间刺激MC 5 r或A2 Ar有效地抑制疾病并诱导调节性免疫。因此，有可能刺激这些途径诱导调节性免疫，抑制人类自身免疫性葡萄膜炎。在本提案中，我们将通过测定在黑皮质素-腺苷能途径刺激后对来自慢性葡萄膜炎患者的人PBMC的调节性免疫的诱导来将我们的小鼠发现转化为临床（特异性目的3）。我们的假设是黑皮质素-腺苷能通路诱导有效和长期的调节性免疫。我们建议将联合收割机小鼠研究与转化研究相结合，以回答关于眼部自身抗原特异性Treg细胞的重要机制问题，并将这些发现带入临床，以开发提供持久缓解的葡萄膜炎治疗。

 DESCRIPTION (provided by applicant): Autoimmune uveitis is a debilitating and potentially blinding inflammatory disease that affects 93 in 100,000 Americans annually. The current treatment strategy is to control the inflammation with immunosuppressive medication that include steroids, which in turn have serious side effects, such as cataracts, glaucoma, peptic ulcers, bone decalcification, and systemic susceptibility to infection. A mouse model of human autoimmune uveitis, experimental autoimmune uveitis (EAU) has been used to better understand this disease. In contrast to chronic human uveitis, EAU resolves without intervention and mice are resistant to recrudescence of uveitis because of regulatory immunity found in the spleen. This regulatory immunity requires post-EAU Treg cells to be activated by post-EAU antigen presenting cells (APC). We have shown that the melanocortin 5 receptor (MC5r) is required for the emergence of a regulatory APC in the post- EAU spleen, and this regulatory APC is a source of adenosine that activates the post-EAU Treg cell through the adenosine 2A receptor (A2Ar). This is an interesting finding, because these two pathways have been shown to individually regulate immunity, but our observation is the first to link the two pathways. The result of stimulating this melanocortin-adenosinergic pathway is an autoantigen specific Treg cell that suppresses EAU. This focus of this proposal is how these Treg cells function to suppress inflammation (Specific Aim 1), if reactivation requires contact dependent factors, and how long-lasting the Treg cells are (Specific Aim 2). Stimulation of MC5r or A2Ar during EAU effectively suppresses disease and induces regulatory immunity. Therefore, it may be possible to stimulate these pathways to induce regulatory immunity and suppress human autoimmune uveitis. In this proposal we will translate our mouse findings into the clinic by assaying for the induction of regulatory immunity on human PBMC from chronic uveitis patients following stimulation of the melanocortin-adenosinergic pathway (Specific Aim 3). Our hypothesis is that the melanocortin-adenosinergic pathway induces effective and long-term regulatory immunity. We propose to combine murine studies with a translational study to answer important mechanistic questions about ocular autoantigen specific Treg cells and to bring these findings into the clinic to develop a uveitis treatment that provides lasting remission.