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Manipulation of Immuity to Treat Uveitis

操纵免疫力治疗葡萄膜炎

基本信息

批准号：
10570296
负责人：
Andrew W Taylor
金额：
$ 41.25万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
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/10570296
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 Macrophage Mediating Microglia Molecular Mus Neuropeptides Pathway interactions Patients Peptide Hormones Receptors Phagocytes Process Productivity Publishing Regulation Regulatory T-Lymphocyte Retina Role Steroids Structure Structure of retinal pigment epithelium T-Cell Activation Testing Therapeutic Tissues Uveitis Vision Work alpha-Melanocyte stimulating hormone antigen processing autoimmune uveitis cytokine effector T cell hormone therapy human model melanocortin receptor monocyte novel strategies preservation programs receptor receptor expression side effect uptake

项目摘要

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。