Immunobiology of EAU Recovery Through the Melanocortin-Adenosinergic Pathway

通过黑皮质素-腺苷能途径恢复 EAU 的免疫生物学

基本信息

批准号：
9752540
负责人：
Darren James Lee
金额：
$ 37万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752540
关键词：
Adenosine Adrenal Cortex Hormones Affect Alkylating Agents American Antigen-Presenting Cells Antigens Antimetabolites Autoantigens Autoimmune Process Autoimmunity Biological Biological Assay Blindness CD4 Positive T Lymphocytes Cataract Cell physiology Cells Chronic Clinic Decalcification Disease Disease remission Eragrostis Experimental Models Glaucoma Human Immune Immune system Immunity Immunobiology Immunosuppressive Agents Individual Infection Inflammation Inflammatory Intervention Lead Link Mediating Mus Non-Steroidal Anti-Inflammatory Agents Pathway interactions Patients Peptic Ulcer Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacology Pharmacotherapy Predisposition Process Proliferating Recovery Recrudescences Regulatory T-Lymphocyte Relapse Resistance Resolution Sampling Source Spleen Steroids T-Lymphocyte Therapeutic immunosuppression Translating Treatment Failure United States Uveitis autoimmune uveitis base bone cytokine disorder later incidence prevention human model immunoregulation mouse model novel strategies prevent public health relevance receptor reduce symptoms side effect success targeted treatment translational study treatment strategy uveoretinitis

项目摘要

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.

描述（由申请人提供）：自身免疫性葡萄膜炎是一种使人衰弱且可能致盲的炎症性疾病，每年影响 10 万分之 93 名美国人，目前的治疗策略是使用包括类固醇在内的免疫抑制药物来控制炎症，而类固醇会产生严重的副作用，例如。如白内障、青光眼、消化性溃疡、骨骼脱钙和系统性感染易感性人类自身免疫小鼠模型。实验性自身免疫性葡萄膜炎 (EAU) 已被用来更好地了解这种疾病，与慢性人类葡萄膜炎相比，EAU 无需干预即可消退，并且由于脾脏中存在调节性免疫，因此小鼠能够抵抗葡萄膜炎的复发。 -EAU Treg 细胞被 EAU 后抗原呈递细胞 (APC) 激活我们已经证明，黑皮质素 5 受体 (MC5r) 是调节性细胞出现所必需的。 EAU 后脾脏中的 APC，这种调节性 APC 是通过腺苷 2A 受体 (A2Ar) 激活 EAU 后 Treg 细胞的腺苷来源。这是一个有趣的发现，因为这两条途径已被证明可以单独调节。免疫，但我们的观察是第一个将这两种途径联系起来的结果，刺激这种黑皮质素-腺苷能途径是抑制 EAU 的自身抗原特异性 Treg 细胞。该提案的主要内容是这些 Treg 细胞如何发挥抑制炎症的作用（具体目标 1）、重新激活是否需要接触因素依赖，以及 Treg 细胞的持续时间有多长（具体目标 2）在 EAU 期间刺激 MC5r 或 A2Ar 可以有效抑制疾病。因此，有可能刺激这些途径来诱导调节性免疫并抑制人类自身免疫性葡萄膜炎。刺激黑皮质素-腺苷能途径后，人类 PBMC 的调节免疫（具体目标 3）我们建议将小鼠研究与转化相结合。这项研究旨在回答有关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，以开发可提供持久缓解的葡萄膜炎治疗方法。