Diagnosis and treatment of ocular inflammatory disease

该项目的目标是开发用于诊断和治疗所有年龄段的人类患者的眼部炎性疾病的改进方法，包括葡萄膜炎、巩膜炎、眼表炎性疾病如干眼综合征和眼内恶性肿瘤。在过去的一年中，临床研究集中在检查新治疗药物的有效性，这些药物通过阻断已知在眼睛炎症发展中起作用的特定分子来发挥作用。其中一种药物是依那西普（Enbrel）。依那西普是一种通过皮下注射给予的合成蛋白质，其结合肿瘤坏死因子（TNF），肿瘤坏死因子是可能导致儿童和成人关节炎的重要分子之一。 我们目前正在招募一项研究，以确定依那西普治疗青少年类风湿性关节炎（JRA）儿童葡萄膜炎的安全性和有效性，这些儿童容易发生眼部慢性炎症。 另一种新的药物，人源化抗Tac单克隆抗体（Zenepax，Daclizumab），也简称为HAT，是NEI免疫学实验室进行的翻译实验室到旁边研究的产物。 通过静脉注射，HAT与活化的T细胞结合，在几种被认为是自身免疫性疾病的眼睛中引起炎症和损伤。 到目前为止，大多数接受HAT治疗的患者已经能够减少其他免疫抑制药物的数量和剂量，如泼尼松，环孢素和甲氨蝶呤，以控制他们的葡萄膜炎，并经历了稳定或改善的视力。 由于HAT的成功，我们已经开始了白塞病患者的第二个方案，并计划在未来的研究中使用HAT治疗葡萄膜炎儿童。 另一个从实验室到旁边的转化研究的例子是在葡萄膜炎动物模型中观察到怀孕和雌性激素雌激素和孕激素可以影响疾病的严重程度。 这一发现与传闻中的观察结果相关，即女性葡萄膜炎可能在怀孕期间改善，并随月经周期而变化。 根据这些信息，制定了一项临床方案，以确定妊娠对葡萄膜炎患者的影响。干眼症是一种影响数百万美国人的疾病。 在NEI中进行的调查局部环孢素治疗干眼效果的重要研究表明，眼表炎症在这种疾病的发展中起着关键作用。 因此，一种治疗干眼症的新药有望很快问世。 对原发性眼内淋巴瘤发病机制的持续研究最近揭示了从眼内取出的淋巴瘤细胞中存在来自人疱疹病毒8型（HHV-8）和EB病毒（EBV）的DNA。 这些发现表明，病毒因子可能在这种眼部恶性肿瘤的发展中发挥作用。已知与恶性肿瘤和眼部炎症相关的另一种病毒因子是人T细胞嗜淋巴细胞病毒I型（HTLV-1）。 在NEI中对HTLV-1感染患者的检查揭示了新的角膜发现的存在。一项进一步研究HTLV-1引起的眼病自然史的方案正在进行中。

The goal of this project is to develop improved methods for the diagnosis and treatment of ocular inflammatory diseases in human patients of all ages including uveitis, scleritis, inflammatory diseases of the ocular surface such as the dry eye syndrome, and intraocular malignancies. Over the past year clinical studies have focused on examining the effectiveness of new therapeutic agents which act by blocking specific molecules known to play a role in the development of inflammation in the eye. One such medication is etanercept (Enbrel). Etanercept is a synthesized protein given by subcutaneous injection that binds to tumor necrosis factor (TNF) one of the important molecules that may cause arthritis in children and adults. We are currently recruiting for a study to determine the safety and efficacy of etanercept for the treatment of uveitis in children with juvenile rheumatoid arthritis (JRA) that are prone to develop chronic inflammation in the eye. Another new agent, the Humanized Anti-Tac monoclonal antibody (Zenepax, Daclizumab), also called HAT for short, is the product of translational bench-to-beside research performed in the NEI Laboratory of Immunology. Given by intravenous injection, HAT binds to activated T-cells that cause inflammation and damage in the eye in several diseases that are thought to be autoimmune in origin. Thus far, the majority of patients treated with HAT have been able to decrease the number and dose of other immunosuppressive medications such as prednisone, cyclosporine and methotrexate required to control their uveitis and have experienced stable or improved vision. Because of the success with HAT we have started a second protocol for patients with Behcet's disease and have plans for a future study to treat children with uveitis using HAT. Another example of translational bench-to-beside research resulted from the observation that pregnancy and the female hormones estrogen and progesterone can influence the severity of disease in an animal model of uveitis. The findings correlate with anecdotal observations that uveitis in women may improve during pregnancy and vary with the menstrual cycle. Based on this information a clinical protocol to determine the effect of pregnancy on patients with uveitis was developed. Dry eye is a condition that affects millions of Americans. Important studies performed in the NEI investigating the effect of treatment with topical cyclosporine for dry eye have revealed that inflammation on the ocular surface plays a key role in the development of this disease. As a result a new medication to treat dry eye is expected soon. Continuing studies on the pathogenesis of primary intraocular lymphoma have recently revealed the presence of DNA from human herpes virus type 8 (HHV-8) and the Epstein-Barr virus (EBV) in the lymphoma cells removed from the eye. These findings suggest that a viral agent may play a role in the development of this ocular malignancy. Another viral agent known to be associated with malignancy and ocular inflammation is the human T-cell lymphotrophic virus type I (HTLV-1). Examination of HTLV-1 infected patients in the NEI has revealed the presence new corneal findings. A protocol to further investigate the natural history of eye disease caused by HTLV-1 is in progress.