Manipulation of Immunity to Treat Uveitis

 描述（由申请人提供）：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有另一次葡萄膜炎发作，约18%的患者会继续患有慢性葡萄膜炎。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方面做出重大承诺，以找到最有效和耐受的生物制剂。与类固醇治疗一样，生物制剂也有严重的副作用。这些疗法的目标是抑制炎症足够长的时间，希望一旦撤销疗法，一种不确定的调节机制将抑制炎症。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内的免疫调节，积极促进免疫耐受，并重建眼部免疫豁免。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豁免而在健康眼睛中发挥核心作用。使用α-MSH肽治疗的初步研究表明，这种治疗可抑制啮齿动物模型的自身免疫性葡萄膜炎。此外，α-MSH处理似乎导致RPE细胞免疫调节活性的恢复。α-MSH通过三种黑皮质素受体抑制炎症，并通过诱导调节性T细胞诱导免疫系统进行自我调节。我们的初步数据表明，MC 1 r和MC 5 r的受体特异性激动剂都抑制EAU;然而，α-MSH通过MC 5 r介导免疫调节的诱导。提示MC 5 r的刺激可能是α-MSH抑制EAU的必要条件，并可能重新激活眼免疫赦免。因此，本研究旨在验证神经肽α-MSH在葡萄膜炎眼中的治疗用途将操纵免疫应答以抑制自身并恢复抗炎性眼部微环境的假设。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的预期免疫豁免机制的重新表达？2)特异性黑皮质素受体是否是抑制EAU的α-MSH以及眼免疫赦免预期抗炎活性的再表达或增强所必需的？这项工作的结果将产生重大影响，显示了一个新的治疗方向葡萄膜炎 新的研究方向是利用神经肽α- MSH抑制炎症、诱导免疫耐受、重建眼免疫赦免。

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enough in the hope that an undefined regulating mechanism will take hold to suppress inflammation once the therapy is withdrawn.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