The role of interleukin (IL)-10 in the pathogenesis of autoimmune uveitis in mice and man

白细胞介素 (IL)-10 在小鼠和人自身免疫性葡萄膜炎发病机制中的作用

• 批准号: 268732935
• 负责人: Professor Dr. Rafael Grajewski
• 金额: --
• 依托单位: Augenzentrum am St. Franziskus Hospital Münster
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/268732935?language=en
• 关键词: role; interleukin; IL; 10; pathogenesis

Intraocular inflammation (uveitis) is a common cause of blindness. Etiologically, uveitis can be divided into infectious and autoimmune forms, with some associations between both forms, as in the case of HLA-B27 positive uveitis. Since there is a release of self antigens during every infection, the body prevents the development of subsequent autoimmune reactions by peripheral tolerance mechanisms including regulatory cell populations and cytokines such as interleukin (IL)-10. Failure of this network may explain the known association between autoimmune disorders and preceding infections. Our preliminary work in the murine model of human uveitis, experimental autoimmune uveitis (EAU), has shown that pre-exposure with bacterial products (analogous to a preceding infection) in form of complete freund´s adjuvant (CFA) ameliorates EAU. This protective feature critically depends on IL-10 and is associated with an expansion of myeloid derived suppressor cells (MDSC). The aim of this project now is to elucidate the mechanisms of this protective effect, particularly the role of MDSC and the cellular source of IL-10. Based on these findings we want to explore the hypothesis that dysregulation of IL-10 production, especially during infections, predisposes to subsequent autoimmune uveitis. Our initial findings support that in the EAU model, uveitis develops in IL-10 deficient mice after pre-exposure with bacterial products followed by EAU induction, but not in wild-type mice that are protected through bacteria-induced IL-10. In addition to peripheral MDSC, resident macrophages in the retina are present as microglia and aquire an activated state during EAU. The contribution of this population to immunoregulation of EAU via IL-10 will be analyzed. Local delivery by intravitreal application of IL-10 will be evaluated in EAU as a novel therapeutical means for uveitis, enabling a local immunosuppression without potential systemic side-effect due to the pleiotropic profile of this cytokine. Finally, secretion patterns of IL-10 in serum and peripheral blood monocytes and lymphocytes as putative markers of susceptibility for developing uveitis will be examined in patients with HLA-B27 positive uveitis.

眼内炎症(葡萄膜炎)是导致失明的常见原因。病因学上，葡萄膜炎可分为感染性和自身免疫性葡萄膜炎，两种类型之间有一定的联系，如人类白细胞抗原B27阳性葡萄膜炎。由于在每次感染过程中都会释放自身抗原，人体通过外周耐受机制来防止随后的自身免疫反应的发展，包括调节细胞群和细胞因子，如白细胞介素10。这个网络的失败可能解释了已知的自身免疫性疾病和先前感染之间的联系。我们在人葡萄膜炎小鼠模型-实验性自身免疫性葡萄膜炎(EAU)中的初步工作表明，预先接触完全弗氏S佐剂(CFA)形式的细菌产品(类似于先前的感染)可以改善EAU。这一保护功能严重依赖于IL-10，并与髓系抑制细胞(MDSC)的扩张有关。目前该项目的目的是阐明这种保护作用的机制，特别是MDSC的作用和IL-10的细胞来源。基于这些发现，我们想要探索一种假设，即IL-10产生的失调，特别是在感染期间，容易导致随后的自身免疫性葡萄膜炎。我们的初步发现支持，在EAU模型中，IL-10缺乏的小鼠在预先暴露于细菌产品后继而诱导EAU后发生葡萄膜炎，但在通过细菌诱导的IL-10保护的野生型小鼠中不发生葡萄膜炎。除了外周MDSC外，视网膜中驻留的巨噬细胞以小胶质细胞的形式存在，并在EAU期间处于激活状态。将分析这一人群通过IL-10对EAU免疫调节的贡献。通过玻璃体内应用IL-10的局部给药将作为葡萄膜炎的一种新的治疗手段在EAU中进行评估，使局部免疫抑制不会由于这种细胞因子的多效性而产生潜在的全身副作用。最后，在人类白细胞抗原B27阳性的葡萄膜炎患者中，将检测血清和外周血单核细胞和淋巴细胞中IL-10的分泌模式，作为发展为葡萄膜炎的可能的易感性标记。