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

• 批准号: 9533571
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9533571
• 关键词: Adenosine; Adrenal Cortex Hormones; Adverse effects; Affect; Alkylating Agents; American; Antigen-Presenting Cells; Antigens; Antimetabolites; Autoantigens; Autoimmune Process; Autoimmunity; 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; success; targeted treatment; translational study; treatment strategy; uveoretinitis

 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（由适用提供）：自身免疫性葡萄膜炎是一种令人衰弱的炎症性疾病，每年影响100,000名美国人中有93个。当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感染，这些药物反过来又具有严重的副作用，例如白内障，青光眼，肽溃疡，骨骼脱钙化和全身感染。实验性自身免疫性葡萄膜炎（EAU）的小鼠自身免疫性葡萄膜炎模型已用于更好地理解这种疾病。与慢性人葡萄膜炎相反，由于脾脏中发现的调节性免疫学，EAU在没有干预的情况下消失了，小鼠对葡萄膜炎的复发性具有抵抗力。该调节性免疫学要求在OEAT抗原呈递细胞（APC）激活OEF后Treg细胞。我们已经表明，黑色素皮质5受体（MC5R）是在sleen后的调节性APC出现所必需的，并且该调节性APC是通过腺苷2A受体（A2AR）激活后Treg细胞（A2AR）的腺苷的来源。这是一个有趣的发现，因为这两种途径已被证明可以单独调节免疫史，但是我们的观察结果是第一个连接这两种途径的途径。刺激这种黑色皮质素 - 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细胞如何抑制注射（特定的目标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期间，MC5R或A2AR的刺激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诱导调节性免疫和抑制人类自身免疫性葡萄膜炎。在此提案中，我们将通过主张在刺激黑色素质素 - 辅助途径后，将小鼠的发现转化为慢性葡萄膜炎患者的人类PBMC的调节性免疫（特定AIM 3）。我们的假设是，黑色皮质素 - 腺苷能途径可引起有效和长期的调节免疫。我们建议将鼠研究与翻译研究相结合，以回答有关眼部自身抗原特异性特雷格细胞的重要机械问题，并将这些发现带入诊所，以开发葡萄膜炎治疗，可提供持久的缓解。