Manipulation of Immunity to Treat Uveitis

操纵免疫来治疗葡萄膜炎

• 批准号: 9126076
• 负责人: Andrew W Taylor
• 金额: $ 41.06万
• 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 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126076
• 关键词: Adverse effects; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Aqueous Humor; Autoimmune Diseases; Autoimmune Process; Blindness; Cells; Chronic; Data; Development; Disease; Eye; Family; Goals; Health; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Life; Ligation; Mediating; Metabolism; Mus; Neuropeptides; Organism; Pathway interactions; Patients; Peptide Receptor; Peptides; Physicians; Pigmentation physiologic function; Publishing; Quality of life; Recovery; Regulation; Regulatory T-Lymphocyte; Replacement Therapy; Resources; Retinal; Rodent Model; Role; Serous; Site; Skin tanning; Steroid therapy; Steroids; Structure; Testing; Therapeutic; Therapeutic Uses; Time; Uveitis; Vision; Weight maintenance regimen; Work; alpha-Melanocyte stimulating hormone; autoimmune uveitis; cytokine; in vivo; melanocortin receptor; member; mouse model; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; receptor; restoration; uveoretinitis

 DESCRIPTION (provided by applicant): Uveitis is the third leading cause of blindness in the US. Generally, the standard therapy for the past 60 years is to treat uveitis with cortical steroid; however, 60% of uveitis patients will have at least another episode of uveitis, and about 18% will continue to suffer chronic uveitis. Steroid replacement therapy with biologics demands a significant commitment in resources and time by patients and physicians to find the most effective and tolerated biologic. As like with steroid therapy, biologics carry their own serious side-effects. The goal of these therapies is to suppress the inflammation long enough in the hope that an undefined regulating mechanism will take hold to suppress inflammation once the therapy is withdrawn. Therefore, development of a therapeutic approach that clearly does this has a great promise. This new therapeutic approach must activate immune regulation within the eye, actively promote immune tolerance, and reestablish ocular immune privilege. The endogenous neuropeptide alpha-Melanocyte Stimulating Hormone (α-MSH), a member of the highly conserved melanocortin family of peptides and receptors, is a potent suppressor of inflammation. Also, α-MSH holds a central role in healthy eyes by helping to maintain ocular immune privilege. Preliminary studies using α-MSH peptide therapy have shown that this treatment suppresses rodent models of autoimmune uveitis. Also, α-MSH treatment appears to led to RPE cell recovery of immune regulating activity. It is through three melanocortin receptors that α-MSH suppresses inflammation, and induces the immune system to regulate itself though induction of regulatory T cells. Our preliminary data show that receptor specific agonists to MC1r and MC5r both suppress EAU; however, it is through MC5r that α-MSH mediates induction of immune regulation. This suggests a strong possibility that MC5r stimulation is the necessary for α-MSH suppression of EAU, and the possibly of reactivating ocular immune privilege. Therefore, this proposal is to test the hypothesis that the therapeutic use of the neuropeptide α-MSH in uveitic eyes will manipulate the immune response to suppress itself and restore the anti-inflammatory ocular microenvironment. This will be approached by answering two questions. 1) Is the suppression of EAU seen by α-MSH therapy because of re-expression of the expected immune privilege mechanisms of aqueous humor and RPE? 2) Are specific melanocortin receptors required for α-MSH suppression of EAU, and the re-expression or enhancement of the expected anti-inflammatory activity of ocular immune privilege? The results of this work will have a significant impact by showing that a new therapeutic direction for uveitis is possible, and that the new direction is to suppress inflammation, induce immune tolerance, and reestablish ocular immune privilege using the neuropeptide α- MSH.

 描述（由申请人提供）：葡萄膜炎是美国第三大失明原因。一般来说，过去60年的标准疗法是用皮质类固醇治疗葡萄膜炎；然而，60%的葡萄膜炎患者至少会再次发作葡萄膜炎，约18%将继续患有慢性葡萄膜炎。使用生物制剂进行类固醇替代疗法需要患者和医生投入大量资源和时间来寻找最有效和耐受性最高的生物制剂。与类固醇疗法一样，生物制剂也有其严重的副作用。这些疗法的目标是抑制炎症足够长的时间，希望一旦治疗撤回，不确定的调节机制将发挥作用来抑制炎症。因此，开发一种能够明确做到这一点的治疗方法具有很大的前景。这种新的治疗方法必须激活眼内的免疫调节，积极促进免疫耐受，并重建眼部免疫特权。内源性神经肽 α-黑素细胞刺激激素 (α-MSH) 是高度保守的黑皮质素肽和受体家族的成员，是一种有效的炎症抑制剂。此外，α-MSH 通过帮助维持眼部免疫特权，在健康眼睛中发挥着核心作用。使用 α-MSH 肽疗法的初步研究表明，这种疗法可抑制啮齿动物模型的自身免疫性葡萄膜炎。此外，α-MSH 治疗似乎导致 RPE 细胞恢复免疫调节活性。 α-MSH 通过三个黑皮质素受体抑制炎症，并通过诱导调节性 T 细胞诱导免疫系统自我调节。我们的初步数据表明，MC1r 和 MC5r 受体特异性激动剂均能抑制 EAU；然而，α-MSH 正是通过 MC5r 介导免疫调节的诱导。这表明 MC5r 刺激很可能是 α-MSH 抑制 EAU 所必需的，并且可能是重新激活眼部免疫特权所必需的。因此，本提案旨在检验神经肽α-MSH在葡萄膜眼中的治疗用途将操纵免疫反应以抑制自身并恢复抗炎眼部微环境的假设。这将通过回答两个问题来解决。 1) α-MSH 治疗对 EAU 的抑制是否是由于房水和 RPE 预期免疫豁免机制的重新表达？ 2) α-MSH 抑制 EAU 以及重新表达或增强眼部免疫特权的预期抗炎活性是否需要特定的黑皮质素受体？这项工作的结果将产生重大影响，表明葡萄膜炎的新治疗方向 是可能的，新的方向是利用神经肽α-MSH抑制炎症、诱导免疫耐受并重建眼部免疫特权。