DIAGNOSIS AND TREATMENT OF OCULAR INFLAMMATORY DISEASE

这个项目的目标是开发改进的方法来 诊断和治疗眼部炎症性疾病，包括 葡萄膜炎、眼部恶性肿瘤、 眼部过敏和眼表炎症性疾病。这个 临床分部实验室专注于确定目标 抗炎治疗和开发新的方法来提供这些 对眼睛的治疗。我们已经培育出一种豚草诱导的小鼠 过敏性结膜炎模型。在过去的一年里，我们 探讨细胞因子在过敏性眼病发生发展中的作用 疾病。我们证实了眼部炎症的加重 干扰素-γ和IL-12基因敲除小鼠。相比之下，IL-4敲打- Out小鼠对眼睛过敏具有抵抗力，这表明 缺乏Th1细胞因子会加重眼球结膜炎 并因缺乏Th2细胞因子而受到抑制。我们一直在继续研究 葡萄膜炎的发病机制。在过去的一年里，我们对 CD40与CD40相互作用的共刺激效应 配体对实验性自身免疫性葡萄膜炎的影响。早期治疗使用一种 抗CD40配体的单抗可完全阻止 葡萄膜炎的发展。抗CD40配体的延迟治疗 抗体也能抑制疾病。抗CD40配体抗体也 降低淋巴细胞对免疫的增殖反应 ICAM-1在眼内的表达降低。这些数据 提示早期通过CD40配体的共刺激作用是必要的 葡萄膜炎的发病机制并可能成为抗葡萄膜炎的靶点 炎症疗法。临床研究主要集中在诊断上。 以及葡萄膜炎和眼内淋巴瘤的治疗。NEI一直是 复方丹参口服液的安全性和有效性研究 用于治疗葡萄膜炎的抗原。II型胶原是一种可能的 不同类型类风湿患者的自身免疫抗原 关节炎。我们正在进行一项I/II阶段的开放式标签试验 II型胶原治疗幼年类风湿性关节炎的临床研究 关节和眼部疾病都有。该研究的招募工作已经完成 在1998年。肿瘤坏死因子-α是一种被认为是 参与成人类风湿性关节炎的发病机制 儿童幼年类风湿性关节炎。最近有一项协议 被开发来研究一种融合蛋白的作用 肿瘤坏死因子-α在眼关节发育中的作用 儿童幼年类风湿性关节炎的疾病。虽然 皮质类固醇仍是眼内治疗的主要药物 炎症，许多患者对类固醇耐药或不耐受 心理治疗。其他免疫抑制剂被用来治疗视力- 威胁眼部炎症性疾病，但这些制剂也 与显著的不良反应有关。临床科是 开发局部给药进入眼睛的方法，以避免 全身副作用。国家眼科临床分会 该研究所与杜克大学合作，目前正在 进行玻璃体内缓释药物的I期研究 环孢素植入剂治疗重症葡萄膜炎。持续有效- 释放其他免疫抑制剂的植入物有 也在开发中。临床科也在研究当地的 眼内淋巴瘤的抗肿瘤药物应用。 之前的研究是与国家癌症研究所合作进行的 研究所显示，眼部复发的淋巴瘤常见于 接受全身和鞘内化疗的患者。 临床研究目前正在调查玻璃体内植入 甲氨蝶呤注射联合眼周注射 皮质类固醇治疗复发性眼内淋巴瘤。的研究 玻璃体内缓释植入物的抗肿瘤作用 治疗眼部恶性肿瘤的药物也在计划之中。最后，在协作方面 与临床中心药物开发科合作 药房，我们正在开发缓释植入物 抗血管药物，包括沙利度胺，用于治疗 眼部新生血管。毒性试验和疗效 研究正在进行中。这些设备可能对治疗 老年性黄斑变性等疾病。

The goal of this project is to develop improved methods for diagnosing and treating ocular inflammatory disease and encompasses both laboratory and clinical studies of uveitis, ocular malignancy, ocular allergy, and inflammatory diseases of the ocular surface. The Clinical Branch laboratory has focused on identifying targets for anti-inflammatory therapy and developing novel ways to deliver these treatments to the eye. We have developed a ragweed-induced murine model of allergic conjunctivitis. Over the past year, we investigated the role of cytokines in development of allergic ocular disease. We demonstrated an exacerbation of ocular inflammation in interferon-gamma and IL-12 knock-out mice. In contrast, IL-4 knock- out mice were resistant to developing ocular allergy, suggesting that ocular conjunctivitis is exacerbated by a lack of Th1 cytokines and inhibited by a lack of Th2 cytokines. We have continued to study the pathogenesis of uveitis. Over the past year, we investigated the effect of costimulation through the interaction of CD40 and CD40 ligand on experimental autoimmune uveitis. Early treatment with a monoclonal antibody against CD40 ligand completely prevented the development of uveitis. Delayed treatment with the anti-CD40 ligand antibody also inhibited disease. Antibody against CD40 ligand also reduced the lymphocyte proliferative response against the immunizing antigen and decreased expression of ICAM-1 in the eye. These data suggest that early costimulation through CD40 ligand is required for the pathogenesis of uveitis and may be a target for anti- inflammatory therapy. Clinical studies have focused on the diagnosis and treatment of uveitis and intraocular lymphoma. The NEI has been investigating the safety and efficacy of oral administration of antigens as a treatment for uveitis. Type II collagen is a possible autoimmune antigen in patients with various forms of rheumatoid arthritis. We are conducting a Phase I/II, open label trial of type II collagen for patients with juvenile rheumatoid arthritis with both joint and eye disease. Recruitment for the study was completed in 1998. Tumor necrosis factor-alpha is a cytokine thought to be involved in the pathogenesis of rheumatoid arthritis in adults and juvenile rheumatoid arthritis in children. A protocol has recently been developed to investigate the effect of a fusion protein of tumor necorisis factor-alpha on the development of eye and joint disease in children with juvenile rheumatoid arthritis. Although corticosteroids remain the mainstay of therapy for intraocular inflammation, many patients are resistant or intolerant of steroid therapy. Other immunosuppressive agents are used to treat sight- threatening ocular inflammatory disease, but these agents are also associated with prominent adverse effects. The Clinical Branch is developing ways to locally deliver drugs into the eye to avoid systemic side effects. The Clinical Branch at the National Eye Institute, in collaboration with Duke University, is currently conducting a Phase I study of a sustained-release intravitreal cyclosporine implant for patients with severe uveitis. Sustained- release implants that release other immunosuppressive agents are also being developed. The Clinical Branch is also studying local administration of antineoplastic agents for intraocular lymphoma. Previous studies conducted in collaboration with the National Cancer Institute showed that ocular recurrence of lymphoma is common in patients treated with systemic andintrathecal chemotherapy. Clinical studies are now investigating the use of intravitreal injections of methotrexate in combination with periocular corticosteroids for recurrent intraocular lymphoma. Studies of intravitreal sustained-release implants to deliver antineoplastic agents for ocular malignancyare planned. Finally, in collaboration with the Pharmaceutical Development Section of the Clinical Center Pharmacy, we are developing sustained-release implants for angiostatic drugs, including thalidomide, for the treatmentof neovascularization of the eye. Bothtoxicity testing and efficacy studies arein progress. These devices may be useful for treating diseases such as age-related macular degeneration.