Manipulation of Immunity to Treat Uveitis

 描述(申请人提供)：葡萄膜炎是美国第三大致盲原因。一般来说，过去60年的标准治疗方法是用皮质类固醇治疗葡萄膜炎；然而，60%的葡萄膜炎患者将至少再发作一次葡萄膜炎，约18%的患者将继续遭受慢性葡萄膜炎。使用生物制剂的类固醇替代疗法需要患者和医生在资源和时间上做出重大承诺，以找到最有效和最耐受的生物制剂。就像类固醇疗法一样，生物制品本身也有严重的副作用。这些疗法的目标是抑制炎症足够长的时间，希望一旦停止治疗，一种未知的调节机制将会控制住炎症。因此，开发一种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睛内的免疫调节，积极促进免疫耐受，并重新建立眼睛免疫豁免权。内源性神经肽α-黑素细胞刺激素(α-MSH)是高度保守的黑素皮质素多肽和受体家族的成员，是一种有效的炎症抑制因子。此外，α-MSH通过帮助维持眼睛免疫豁免权，在健康的眼睛中发挥着核心作用。使用α-MSH多肽疗法的初步研究表明，这种疗法可以抑制自身免疫性葡萄膜炎的啮齿动物模型。同时，α-MSH处理后的视网膜色素上皮细胞似乎恢复了免疫调节活性。α-MSH通过三种黑素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。我们的初步数据显示，受体特异性激动剂MC1R和MC5R均抑制EAU；然而，α-MSH正是通过MC5R介导免疫调节的诱导。提示刺激MC5r很可能是α-MSH抑制EAU所必需的，也可能是重新激活眼免疫赦免的可能。因此，这一建议是为了验证一种假说，即在葡萄膜眼治疗中使用神经肽α-MSH将操纵免疫反应，抑制自身，恢复抗炎的眼部微环境。我们将通过回答两个问题来解决这一问题。1)α-MSH治疗对EAU的抑制是否是由于房水和RPE的预期免疫赦免机制的重新表达？2)α-MSH抑制EAU所需的特异性黑素皮质素受体，以及眼免疫赦免预期的抗炎活性的重新表达或增强？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 这是可能的，新的方向是抑制炎症，诱导免疫耐受，并重新建立眼部免疫豁免权使用神经肽α-msh。

 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enough in the hope that an undefined regulating mechanism will take hold to suppress inflammation once the therapy is withdrawn.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.