Role of IL-12 family cytokines in human autoimmune Uveitis

IL-12家族细胞因子在人类自身免疫性葡萄膜炎中的作用

• 批准号: 8149139
• 负责人: Charles E Egwuagu
• 金额: $ 35.9万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149139
• 关键词: Family; Human; Interleukin-12; Role; autoimmune uveitis; cytokine

The IL-12 family is comprised of three types of heterodimeric cytokines, IL-12, IL-23 and IL-27. Prior to the discovery of IL-23 and IL-27, IL-12 was thought to be the cause of several chronic inflammatory diseases because of its unique ability to induce differentiation of naive T-cells towards IFNg-secreting Th1 phenotype. However, IL-23 promotes differentiation and/or maintenance of the highly pathogenic ThIL-17 subtype and is now thought to be the primary etiologic agent in several chronic inflammatory diseases. IL-27 promotes the differentiation of naive T cells into Th1 cells but its role in host defense and immune-mediated diseases is largely unknown. Discovery of antagonism between these cytokines have led to increased interest in the roles played by these cytokines in the etiology and treatment of several chronic inflammatory diseases including uveitis. Recent reports have implicated ThIL17 cells in the pathogenesis of a number of immune-mediated diseases including experimental allergic encephalomyelitis (EAE), collagen-induced arthritis (CIA) and colitis. However, most of these studies have been in inbred mouse strain and involvement of ThIL17 cells in human diseases has not been firmly established. In this study, we examined whether ThIL17 cells are involved in two human ocular inflammatory diseases (uveitis and scleritis) and have also investigated the role of this T-cell subtype in the mouse model of human uveitis, experimental uveitis model (EAU). Uveitis is a T-cell mediated intraocular inflammatory disease of presumed autoimmune etiology. Although inhibiting the formation of high affinity IL-2 receptor (IL-2R) by a humanized anti-Tac antibody (Daclizumab) is effective therapy in treatment of these potentially binding ocular diseases, pathogenic T-cell subtypes that cause uveitis or mechanism of IL-2R action remain known. We show that a major difference between mice and "men" in this study is that ThIL17 cells are detected in normal peripheral blood mononuclear cells (PBMC) of humans but not mice. However, IL-17 is elevated in uveitis, scleritis and EAU and we show that its induction of TNFa expression in retinal cells may contribute to the pathology of chronic inflammatory disease of the eye. We further show that IL-27 is constitutively expressed in retinal ganglion and photoreceptor cells, is upregulated by IFNg and inhibits proliferation of ThIL-17-cells. IL-27 is also elevated in serum of patients with sarcoidosis. These findings suggest a novel mechanism by which Th1-cells may mitigate uveitis by antagonizing ThIL17-phenotype through IFNg-mediated induction of IL-27 in target tissue. This study showing that IL-2 promotes ThIL17-cells expansion provides explanations for efficacy of anti-IL2R therapy in uveitis and suggests that antagonism of ThIL17-cells by IFNg/IL-27 maybe exploited in treating chronic inflammation.

IL-12家族由三种类型的异二聚体细胞因子IL-12，IL-23和IL-27组成。在发现IL-23和IL-27之前，IL-12被认为是几种慢性炎症性疾病的原因，因为它具有诱导幼稚T细胞分化IFNG分泌Th1表型的独特能力。但是，IL-23促进了高度致病的Thil-17亚型的分化和/或维持，现在被认为是几种慢性炎性疾病的主要病因学剂。 IL-27促进了幼稚T细胞向Th1细胞的分化，但其在宿主防御和免疫介导的疾病中的作用在很大程度上尚不清楚。这些细胞因子之间拮抗作用的发现导致对这些细胞因子在病因和治疗几种慢性炎症性疾病（包括葡萄膜炎）中发挥的作用的兴趣增加。最近的报道已暗示了Thil17细胞在许多免疫介导的疾病的发病机理中，包括实验性过敏性脑脊髓炎（EAE），胶原蛋白诱导的关节炎（CIA）和结肠炎。然而，这些研究大多数都是在近交小鼠菌株中，而Thil17细胞在人类疾病中的参与尚未牢固确定。在这项研究中，我们检查了Thil17细胞是否参与了两种人眼炎性疾病（葡萄膜炎和硬化症），还研究了该T细胞亚型在人葡萄膜炎小鼠模型中的作用，实验性葡萄膜炎模型（EAU）。葡萄膜炎是一种T细胞介导的假定自身免疫性病因的眼内炎症性疾病。尽管抑制人源化的抗TAC抗体（Daclizumab）抑制高亲和力IL-2受体（IL-2R）是有效治疗这些潜在结合的眼部疾病的治疗，但致病性T细胞亚型，导致葡萄膜炎或机械性IL-2R作用的机制仍然是已知的。我们表明，在这项研究中，小鼠和“男性”之间的主要区别在于，在人类的正常外周血单核细胞（PBMC）中检测到Thil17细胞，而不是小鼠。但是，IL-17在葡萄膜炎，硬化症和EAU中升高，我们表明其在视网膜细胞中诱导TNFA表达可能有助于眼睛的慢性炎性疾病。我们进一步表明，IL-27在视网膜神经节和感光细胞中组成型表达，被IFNG上调并抑制了Thil-17细胞的增殖。在结节病患者的血清中，IL-27也升高。这些发现表明了一种新的机制，通过IFNG介导的IL-27在靶组织中，Th1细胞可以通过拮抗Thil17-表型来减轻葡萄膜炎。这项研究表明，IL-2促进Thil17细胞的扩张为抗IL2R疗法在葡萄膜炎中的疗效提供了解释，并表明可能在治疗慢性炎症时利用了IFNG/IL-27对Thil17细胞的拮抗作用。