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：
10610815
负责人：
Darren James Lee
金额：
$ 45.56万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610815
关键词：
Adenosine Affect American Antigen-Presenting Cells Antigens Autoantigens Autoimmune Blindness CCR6 gene Cataract Cells Cervical lymph node group Chronic Clinic Decalcification Dependence Disease Disease remission Eye Eye Infections Glaucoma Goals Home Homing Human ITIM Immune response Immune system Immunity Immunization Immunobiology Immunoglobulins Immunology Individual Infection Inflammation Inflammatory Intervention Link Lymphoid Tissue Mediating Modeling Mus Pathway interactions Patients Peptic Ulcer Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Population Predisposition Publishing Recovery Recrudescences Regulatory T-Lymphocyte Relapse Resistance Resolution Role Sampling Secondary to Site Source Spleen Steroids T-Lymphocyte Techniques Tissues Translating United States Uveitis Vision research Work autoimmune uveitis bone clinically relevant human model lymph nodes migration mouse model novel strategies prevent programmed cell death protein 1 programs receptor recruit relapse prevention side effect success translational study treatment strategy uveoretinitis

项目摘要

Abstract 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. We have observed A2Ar-dependent Tregs emerge in the eye at the onset of EAU, persist through resolution, and expand in an A2Ar-dependent manner following EAU-reimmunization. Therefore, how these A2Ar- dependent ocular resident Tregs prevent relapse and the mechanism of A2Ar dependency will be answered (Aim 1). We have identified distinct A2Ar-dependent T cell Immunoglobulin and ITIM (TIGIT) TIGIT+ and PD-1+ post-EAU Treg subsets in the spleen. How these distinct Treg subsets are induced, how they suppress EAU, and if each subset has a different activation requirement in uveitis patients will be investigated (Aim 2). The post-EAU Treg cells express CCR7 that homes to secondary lymphoid tissue and CCR6 that homes to the eye, these Tregs are found in both tissue sites when reactivated, and expression of CCR6 and CCR7 induced through stimulation of the adenosinergic-melanocortin pathway on PBMC from uveitis patients is significantly reduced compared to healthy controls. Where and how the adenosinergic-melanocortin induced post-EAU Treg cells home to suppress uveitis will be investigated (Aim 3). Our hypothesis is that the melanocortin- adenosinergic pathway induces effective and long-term regulatory immunity that provides resistance to autoimmune uveitis. We propose to combine murine studies with translational studies to answer important mechanistic questions about ocular autoantigen specific Treg cells with the long-term goal of bringing these findings into the clinic to develop a uveitis treatment that provides lasting remission.

抽象的自身免疫性葡萄膜炎是一种使人衰弱并可能致盲的炎症性疾病，影响 93 每年有 100,000 名美国人。目前的治疗策略是控制炎症包括类固醇在内的免疫抑制药物，这又会产生严重的副作用，例如白内障、青光眼、消化性溃疡、骨质脱钙和全身易受感染。一只老鼠人类自身免疫性葡萄膜炎模型，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。与慢性人类葡萄膜炎相反，EAU 无需干预即可消退，并且小鼠由于脾脏中存在调节免疫，因此可以抵抗葡萄膜炎的复发。此次监管免疫需要 EAU 后 Treg 细胞被 EAU 后抗原呈递细胞 (APC) 激活。我们有表明黑皮质素 5 受体 (MC5r) 是后处理中调节性 APC 的出现所必需的。 EAU 脾脏，这种调节性 APC 是腺苷的来源，可通过以下方式激活 EAU 后 Treg 细胞：腺苷2A受体（A2Ar）。这是一个有趣的发现，因为这两条途径已被显示可以单独调节免疫力，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-腺苷能通路的是抑制 EAU 的自身抗原特异性 Treg 细胞。我们观察到 A2Ar 依赖性 Tregs 在 EAU 开始时出现在眼睛中，并持续存在于消退过程中，并在 EAU 重新免疫后以 A2Ar 依赖性方式扩展。因此，这些 A2Ar- 依赖眼部常驻Tregs预防复发，A2Ar依赖性机制将得到解答（目标 1）。我们已经鉴定出不同的 A2Ar 依赖性 T 细胞免疫球蛋白和 ITIM (TIGIT) TIGIT+ 和 PD-1+ 脾脏中 EAU 后 Treg 亚群。这些不同的 Treg 子集是如何被诱导的，它们是如何抑制 EAU 的，如果每个子集在葡萄膜炎患者中具有不同的激活要求，则将进行研究（目标 2）。这 EAU后Treg细胞表达CCR7和CCR6，CCR7定位于次级淋巴组织，CCR6定位于次级淋巴组织。眼睛中，这些Tregs在重新激活时在两个组织部位都被发现，并诱导CCR6和CCR7的表达通过刺激腺苷能-黑皮质素通路对葡萄膜炎患者的 PBMC 具有显着的作用与健康对照组相比有所减少。腺苷能黑皮质素在何处以及如何诱导 EAU 后将研究抑制葡萄膜炎的 Treg 细胞（目标 3）。我们的假设是黑皮质素腺苷能途径诱导有效且长期的调节免疫，从而提供抵抗力自身免疫性葡萄膜炎。我们建议将小鼠研究与转化研究相结合来回答重要的问题关于眼自身抗原特异性 Treg 细胞的机制问题，长期目标是将这些研究结果进入临床，以开发一种可提供持久缓解的葡萄膜炎治疗方法。