Manipulation of Immuity to Treat Uveitis

操纵免疫力治疗葡萄膜炎

• 批准号: 10356073
• 负责人: Andrew W Taylor
• 金额: $ 40.01万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356073
• 关键词: Affect; Agonist; Animal Model; Anti-Inflammatory Agents; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Arrestins; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Binding; Biological Assay; Biological Products; Blindness; Cells; Data; Differentiation Antigens; Eye; Goals; Grant; Immune; Immune Cell Suppression; Immune response; Immunity; Immunologic Memory; Immunosuppression; Inflammation; Injections; MHC Class II Genes; MSH receptor; Mediating; Microglia; Molecular; Mus; Neuropeptides; Pathway interactions; Patients; Peptide Receptor; Phagocytes; Process; Publishing; Regulation; Regulatory T-Lymphocyte; Retina; Role; Steroids; Structure; Structure of retinal pigment epithelium; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Uveitis; Vision; Work; activity marker; alpha-Melanocyte stimulating hormone; antigen processing; autoimmune uveitis; base; cytokine; effector T cell; human model; macrophage; melanocortin receptor; monocyte; novel strategies; preservation; programs; receptor; receptor expression; side effect; uptake

The goal of this proposal is to further understand how the neuropeptide alpha-melanocyte stimulating hormone (α-MSH) regulates immunity, and how it can be used to suppress uveitis to reestablish immune privilege. Previously published work, and the progress of our past grant-period demonstrated that α-MSH-treatment during uveitis can restore immunosuppressive activity of retinal pigment epithelial cells (RPE). In addition, we have demonstrated that part of immune privilege is suppression of the phagocytic/antigen-processing pathway within macrophages by healthy RPE. This suppression is mediated by α-MSH produced by RPE and is dependent on expression of the α-MSH-receptor, melanocortin 5 receptor (MC5r), in the retina. Therefore, suppression of EAU, and the induction of regulatory T cells by α-MSH-therapy is possibly associated with regulating antigen presenting cell activity within the uveitic eye. This would be mediated through α-MSH binding specific melanocortin-receptors on the RPE and APC of the retina. Therefore, we hypothesize that α- MSH regulates the processing and presentation of antigen within the immune privileged microenvironment, and that α-MSH-therapy acts through this mechanism to suppress autoimmune uveitis. We will demonstrate this regulation by assessing the role of α-MSH to regulate the phagocytic pathway in macrophages and microglial cells; by determining the ability of α-MSH-treated APC to antigen-activate effector T cells; and assess the potential for α-MSH to mediate innate-immune memory tolerance in macrophages. The α-MSH- therapy will involve treating EAU with whole neuropeptide and specific melanocortin-receptor-agonists. The regulation of antigen uptake, processing, and presentation will be assayed on both tissue macrophages, and retinal microglial cells. Also, we will examine retinal microglial cells and α-MSH-treated macrophages for expression of markers and activity associated with innate-immune memory tolerance. We will examine changes in this regulation in the initial stages of EAU as suggested by our preliminary data. Our proposed work will have a meaningful impact, because the results will provide new information about the molecular mechanisms of uveitis, and α-MSH anti-inflammatory-activity. Also, it will define how melanocortin-based therapy can regulate antigen presentation and T cell activation by suppressing the central drivers of autoimmune disease.

该提案的目标是进一步了解神经肽α-黑素细胞刺激激素如何 (α-MSH) 调节免疫力，以及如何使用它来抑制葡萄膜炎以重建免疫特权。 之前发表的工作以及我们过去资助期的进展表明，α-MSH 治疗 葡萄膜炎期间可以恢复视网膜色素上皮细胞（RPE）的免疫抑制活性。此外，我们 已证明免疫特权的一部分是抑制吞噬/抗原加工途径 健康的 RPE 位于巨噬细胞内。这种抑制是由 RPE 产生的 α-MSH 介导的， 依赖于视网膜中 α-MSH 受体、黑皮质素 5 受体 (MC5r) 的表达。所以， EAU 的抑制以及 α-MSH 疗法诱导调节性 T 细胞可能与 调节葡萄膜眼内的抗原呈递细胞活性。这将通过 α-MSH 介导 结合视网膜 RPE 和 APC 上的特异性黑皮质素受体。因此，我们假设α- MSH 调节免疫特权微环境中抗原的加工和呈递， α-MSH 疗法通过这种机制发挥作用，抑制自身免疫性葡萄膜炎。我们将展示 通过评估 α-MSH 在调节巨噬细胞吞噬途径中的作用来进行这种调节 小胶质细胞；通过确定 α-MSH 处理的 APC 抗原激活效应 T 细胞的能力；和 评估 α-MSH 介导巨噬细胞先天免疫记忆耐受的潜力。 α-MSH- 治疗将包括用完整的神经肽和特定的黑皮质素受体激动剂治疗 EAU。这 将在组织巨噬细胞和组织巨噬细胞上测定抗原摄取、加工和呈递的调节，以及 视网膜小胶质细胞。此外，我们还将检查视网膜小胶质细胞和 α-MSH 处理的巨噬细胞 与先天免疫记忆耐受相关的标记物和活性的表达。我们将检查 正如我们的初步数据所示，EAU 初始阶段该规定发生了变化。我们提议的工作 将产生有意义的影响，因为结果将提供有关分子的新信息 葡萄膜炎的机制和 α-MSH 抗炎活性。此外，它将定义基于黑皮质素的 疗法可以通过抑制抗原呈递和 T 细胞激活的核心驱动因素来调节 自身免疫性疾病。