Manipulation of Immuity to Treat Uveitis

这项提案的目的是进一步了解神经肽α-黑素细胞刺激激素 （α-MSH）调节免疫力，以及它如何用于抑制葡萄膜炎以重建免疫豁免。 以前发表的工作，以及我们过去资助期的进展表明，α-MSH治疗 在葡萄膜炎期间，可以恢复视网膜色素上皮细胞（RPE）的免疫抑制活性。另外我们 已经证明免疫豁免的一部分是抑制吞噬/抗原加工途径 在巨噬细胞内被健康的视网膜色素上皮所覆盖。这种抑制是由RPE产生的α-MSH介导的， 依赖于α-MSH受体，黑皮质素5受体（MC 5 r）在视网膜中的表达。因此，我们认为， 抑制EAU和α-MSH治疗诱导调节性T细胞可能与 调节葡萄膜炎眼内的抗原呈递细胞活性。这可能通过α-MSH介导 结合视网膜的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疗法通过这种机制抑制自身免疫性葡萄膜炎。我们将演示 通过评估α-MSH调节巨噬细胞吞噬途径的作用， 通过测定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- 治疗将包括用全神经肽和特异性黑皮质素受体激动剂治疗EAU。的 将在组织巨噬细胞上测定抗原摄取、加工和呈递的调节， 视网膜小胶质细胞此外，我们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。我们将研究 我们的初步数据表明，在EAU的初始阶段，这一规定发生了变化。我们建议的工作 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的抗炎活性。此外，它将定义如何黑皮质素为基础的 治疗可以通过抑制抗原呈递和T细胞活化的中心驱动因素来调节抗原呈递和T细胞活化。 自身免疫性疾病

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.