Departments of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
Am J Pathol. 2010 Dec;177(6):2912-20. doi: 10.2353/ajpath.2010.100353. Epub 2010 Oct 15.
Uveitis is a major and common cause of visual disability. Recent studies have shown that Th17 cells are implicated in the pathogenesis of this serious intraocular disorder. Activated T cells express an inducible costimulatory molecule called OX40, and OX40 in turn promotes the activation and proliferation of these lymphocytes. Nevertheless, it is unclear whether OX40 plays a vital role in enhancing the effector function of Th17 cells as well as the severity of uveitis. In this study, we demonstrated an increase of OX40 transcription in ovalbumin-induced uveitis, whereas anti-OX40L antibody substantially inhibited the antigen-specific ocular inflammation. Next, results from flow cytometry showed that activated Th17 cells expressed OX40, and OX40-activating antibody significantly augmented the production of Th17 cytokines in vitro. To validate the impact of OX40 in vivo, we stimulated ovalbumin-specific T cells with the OX40-activating antibody. Compared to donor cells without OX40 activation, adoptive transfer of OX40-stimulated lymphocytes elicited more severe ocular inflammation. Furthermore, an interleukin-17-neutralizing antibody attenuated OX40-mediated uveitis. In conclusion, our findings suggest that activation of OX40 augments Th17 cell function and thereby contributes to ocular inflammation. This study thus enhances our knowledge of costimulatory molecule-mediated immunopathological mechanisms of uveitis and suggests a future therapeutic strategy to treat uveitis by the targeting of OX40.
葡萄膜炎是一种主要且常见的致盲原因。最近的研究表明，Th17 细胞参与了这种严重的眼内疾病的发病机制。活化的 T 细胞表达一种称为 OX40 的可诱导共刺激分子，而 OX40 反过来又促进这些淋巴细胞的激活和增殖。然而，尚不清楚 OX40 是否在增强 Th17 细胞的效应功能以及葡萄膜炎的严重程度方面发挥重要作用。在这项研究中，我们证明了卵清蛋白诱导的葡萄膜炎中 OX40 转录增加，而抗-OX40L 抗体则显著抑制了抗原特异性眼内炎症。接下来，流式细胞术的结果表明，活化的 Th17 细胞表达 OX40，而 OX40 激活抗体显著增强了体外 Th17 细胞因子的产生。为了验证 OX40 在体内的影响，我们用 OX40 激活抗体刺激卵清蛋白特异性 T 细胞。与未经 OX40 激活的供体细胞相比，过继转移 OX40 刺激的淋巴细胞引起了更严重的眼内炎症。此外，白细胞介素-17 中和抗体减弱了 OX40 介导的葡萄膜炎。总之，我们的研究结果表明，OX40 的激活增强了 Th17 细胞的功能，从而导致眼内炎症。因此，这项研究增加了我们对共刺激分子介导的葡萄膜炎免疫病理机制的认识，并为通过靶向 OX40 治疗葡萄膜炎提供了一种未来的治疗策略。
