DIAGNOSIS AND TREATMENT OF OCULAR INFLAMMATORY DISEASE

这个项目的目标是开发改进的 眼炎性疾病的诊断和治疗方法 包括葡萄膜炎的实验室和临床研究， 眼部恶性肿瘤、眼部过敏和炎症性疾病 眼表。临床分部实验室专注于 确定抗炎治疗的靶点和发展 将这些治疗方法提供给眼睛的新方法。我们有 建立豚草致小鼠过敏模型 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病中的作用。我们 显示眼部炎症加重 干扰素-γ和IL-12基因敲除小鼠。相比之下，IL-4 基因敲除的小鼠对眼睛过敏有抵抗力， 提示Th1缺乏可加重眼结膜炎 细胞因子，缺乏Th2细胞因子而抑制。我们有 继续研究葡萄膜炎的发病机制。在过去一年里， 我们通过相互作用研究了共刺激效应。 CD40及CD40配体对实验性自身免疫性葡萄膜炎的影响 抗CD40配体的单抗早期治疗 完全防止了葡萄膜炎的发展。延迟 使用抗CD40配体抗体的治疗也可以抑制疾病。 抗CD40配体抗体也使淋巴细胞减少 对免疫抗原的增殖反应减弱 ICAM-1在眼组织中的表达。这些数据表明，早期 CD40配体的协同刺激作用在肿瘤发生中起重要作用 葡萄膜炎，并可能成为抗炎治疗的靶点。 临床研究主要集中在诊断和治疗上。 葡萄膜炎和眼内淋巴瘤。NEI一直在调查 口服抗原作为一种治疗的安全性和有效性 葡萄膜炎的治疗。II型胶原可能是一种自身免疫性疾病 各种形式的类风湿性关节炎患者的抗原。我们 正在进行II型胶原的I/II期开放标签试验 幼年类风湿性关节炎合并关节和眼部病变 疾病。这项研究的招募工作将于1998年完成。 肿瘤坏死因子-α是一种被认为参与 成人和青少年类风湿性关节炎的发病机制 儿童类风湿性关节炎。最近有一项协议是 研究一种肿瘤融合蛋白的作用 死亡因子-α与眼部和关节疾病的发展 在幼年类风湿性关节炎的儿童中。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 威胁视力的眼部炎症性疾病，但这些药物 也与显著的不良反应有关。临床科 正在开发将药物局部输送到眼睛内的方法，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。 释放其他免疫抑制药的缓释植入物 代理也在开发中。临床科也是 眼内局部应用抗肿瘤药物的研究 淋巴瘤。先前的研究与 国家癌症研究所的研究表明，眼部复发 淋巴瘤在接受全身和全身化疗的患者中很常见 鞘内化疗。临床研究目前正在调查 玻璃体内注射甲氨蝶呤联合应用 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物的研究 眼科恶性肿瘤的抗肿瘤药物正在计划中。最后，在 与世界卫生组织药物发展科合作 临床中心药房，我们正在开发缓释 包括沙利度胺在内的血管抑制药物植入物 眼部新生血管的治疗。毒性测试和 功效研究正在进行中。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 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.