DIAGNOSIS AND TREATMENT OF OCULAR INFLAMMATORY DISEASE

该项目的目标是开发改进的 诊断和治疗眼部炎性疾病的方法 并且包括葡萄膜炎的实验室和临床研究， 眼恶性肿瘤、眼变态反应和炎症性疾病 眼表 临床分支实验室重点关注 确定抗炎治疗的靶点， 将这些治疗药物输送到眼睛的新方法。我们有 开发了一种豚草诱导的过敏性小鼠模型， 结膜炎在过去的一年里，我们调查了 细胞因子在过敏性眼病发展中的作用我们 显示眼部炎症加重， 干扰素-γ和IL-12敲除小鼠。相反，IL-4 敲除小鼠对发生眼变态反应具有抗性， 这表明缺乏Th 1会加剧眼结膜炎 Th 2细胞因子的缺乏可抑制Th 2细胞因子的表达。 我们有 继续研究葡萄膜炎的发病机制。在过去的一年里， 我们通过相互作用研究了共刺激的作用， CD 40和CD 40配体对实验性自身免疫性葡萄膜炎的影响。 早期使用抗CD 40配体的单克隆抗体治疗 完全阻止了葡萄膜炎的发展。延迟 用抗CD 40配体抗体治疗也抑制疾病。 抗CD 40配体抗体也可降低淋巴细胞 增殖反应对免疫抗原和减少 ICAM-1在眼内的表达。这些数据表明，早期 通过CD 40配体的共刺激是发病所必需的 并且可能是抗炎治疗的靶点。 临床研究集中在诊断和治疗 葡萄膜炎和眼内淋巴瘤。NEI一直在调查 口服给予抗原作为抗肿瘤药物的安全性和有效性 治疗葡萄膜炎。II型胶原蛋白可能是一种自身免疫性 类风湿性关节炎的治疗方法有哪些我们 正在进行一项I/II期、开放标签试验， 幼年型类风湿关节炎伴眼关节 疾病这项研究的招募工作将于1998年完成。 肿瘤坏死因子-α是一种细胞因子，被认为参与了 成人和青少年类风湿关节炎发病机制 儿童类风湿性关节炎最近，一项协议 研究肿瘤融合蛋白的作用 坏死因子-α对眼和关节疾病的发展 儿童类风湿性关节炎 虽然 皮质类固醇仍然是治疗眼内 炎症，许多患者对类固醇有抵抗力或不耐受 疗法其他免疫抑制剂用于治疗 威胁视力的眼部炎性疾病，但这些药物 也与显著的不良反应有关。临床分支 正在研究将药物局部输送到眼睛中的方法， 全身副作用国家眼科临床分支 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， 严重葡萄膜炎患者植入环孢素。 缓释植入物，释放其他免疫抑制剂 代理商也在开发中。 临床分支也是 眼内麻醉剂局部给药的研究 淋巴瘤以前的研究是与 国家癌症研究所表明， 淋巴瘤常见于接受全身和全身化疗的患者， 鞘内化疗临床研究正在调查 玻璃体内注射甲氨蝶呤与 眼周皮质类固醇治疗复发性眼内淋巴瘤。 玻璃体腔内缓释植入剂的研究 计划使用眼恶性肿瘤的化疗药物。最后在 与药物开发科合作， 临床中心药房，我们正在开发缓释 血管抑制药物的植入物，包括沙利度胺 治疗眼睛的新血管形成。毒性测试和 疗效研究正在进行中。这些设备可以用于 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 will be 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 and intrathecal 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 malignancy are 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 treatment of neovascularization of the eye. Both toxicity testing and efficacy studies are in progress. These devices may be useful for treating diseases such as age-related macular degeneration.