Role of IL-12 family cytokines in human autoimmune Uveit

IL-12家族细胞因子在人类自身免疫性Uveit中的作用

• 批准号: 7321809
• 负责人: Charles E Egwuagu
• 金额: --
• 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/7321809
• 关键词: Role; IL; 12; family; cytokines

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 IFN?-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 TNF? 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 IFN? and inhibits proliferation of ThIL-17-cells. These findings suggest a novel mechanism by which Th1-cells may mitigate uveitis by antagonizing ThIL17-phenotype through IFN?-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 IFN?/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性疾病的原因，因为它具有诱导幼稚T细胞向IFN？分化的独特能力。分泌Th 1表型。然而，IL-23促进高致病性蒂尔-17亚型的分化和/或维持，并且现在被认为是几种慢性炎性疾病的主要病原体。IL-27促进幼稚T细胞分化为Th 1细胞，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是未知的。这些细胞因子之间的拮抗作用的发现导致了对这些细胞因子在包括葡萄膜炎在内的几种慢性炎性疾病的病因学和治疗中所起的作用的兴趣增加。最近的报道表明ThIL 17细胞参与了许多免疫介导的疾病的发病机制，包括实验性过敏性脑脊髓炎（EAE）、胶原诱导的关节炎（CIA）和结肠炎。然而，这些研究中的大多数都是在近交系小鼠品系中进行的，并且ThIL 17细胞在人类疾病中的参与还没有被牢固地确立。在这项研究中，我们检查了ThIL 17细胞是否参与了两种人类眼部炎症性疾病（葡萄膜炎和巩膜炎），并且还研究了这种T细胞亚型在人类葡萄膜炎小鼠模型、实验性葡萄膜炎模型（EAU）中的作用。葡萄膜炎是一种T细胞介导的眼内炎症性疾病，推测为自身免疫性病因。虽然通过人源化抗Tac抗体（Daclizumab）抑制高亲和力IL-2受体（IL-2 R）的形成是治疗这些潜在结合性眼部疾病的有效疗法，但引起葡萄膜炎的致病性T细胞亚型或IL-2 R的机制？行动仍然是已知的。我们表明，在这项研究中，小鼠和“人”之间的主要区别是，ThIL 17细胞在人的正常外周血单核细胞（PBMC）中检测到，而不是小鼠。然而，IL-17升高葡萄膜炎，巩膜炎和EAU，我们表明，其诱导的TNF？在视网膜细胞中的表达可能导致眼睛的慢性炎性疾病的病理学。我们进一步表明，IL-27是组成性表达在视网膜神经节和感光细胞，上调IFN？并抑制蒂尔-17-细胞的增殖。这些发现提示了一种新的机制，Th 1细胞通过IFN？介导的靶组织中IL-27的诱导。这项研究表明，IL-2促进ThIL-17-细胞扩增，为抗IL-2 R治疗葡萄膜炎的疗效提供了解释，并表明IFN-γ对ThIL-17-细胞的拮抗作用。IL-27可能用于治疗慢性炎症。