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虚弱并可能致盲的炎症性疾病，每年在10万美国人中有93人患病。目前的治疗策略是通过包括类固醇在内的免疫抑制药物来控制炎症，类固醇反过来会产生严重的副作用，如白内障、青光眼、消化性溃疡、骨脱钙和全身感染易感性。实验性自身免疫性葡萄膜炎(EAU)是一种人类自身免疫性葡萄膜炎的小鼠模型，已被用于更好地了解这种疾病。与慢性人类葡萄膜炎不同，EAU在没有干预的情况下就会消失，小鼠对葡萄膜炎的复发具有抵抗力，因为在脾中发现了调节免疫。这种调节免疫需要EAU后Treg细胞被EAU后抗原提呈细胞(APC)激活。我们已经证明，黑素皮质素5受体(MC5r)是在EAU后脾中出现调节性APC所必需的，这种调节性APC是腺苷的来源，通过腺苷2A受体(A2Ar)激活EAU后Treg细胞。这是一个有趣的发现，因为这两条途径已经被证明分别调节免疫，但我们的观察是第一次将这两条途径联系起来。刺激这种黑素皮质素-腺苷能途径的结果是一种自身抗原特异性的Treg细胞，它抑制EAU。这项建议的重点是这些Treg细胞如何发挥作用来抑制炎症(特定目标1)，如果重新激活需要接触依赖因素，以及Treg细胞的持续时间(特定目标2)。在EAU过程中刺激MC5r或A2Ar可有效抑制疾病并诱导调节性免疫。因此，有可能刺激这些途径来诱导调节性免疫和抑制人类自身免疫性葡萄膜炎。在这项提案中，我们将把我们的小鼠发现转化到临床上，通过分析在刺激黑素皮质素-腺苷能通路(特定目标3)后，慢性葡萄膜炎患者对人PBMC的调节性免疫诱导。我们的假设是，黑素皮质素-腺苷能途径诱导有效和长期的调节性免疫。我们建议将小鼠研究与翻译研究相结合，以回答有关眼睛自身抗原特异性Treg细胞的重要机制问题，并将这些发现应用于临床，开发一种可提供持久缓解的葡萄膜炎治疗方法。

 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.