Diagnosis And Treatment Of Ocular Inflammatory Disease

该项目的目标是开发改进的方法，用于诊断和治疗所有年龄的人类患者的眼部炎症性疾病，包括葡萄膜炎、巩膜炎、眼表炎症性疾病和眼内恶性肿瘤。在过去的一年里，临床研究继续关注于检查新的治疗药物的有效性，这些药物的安全性比目前可用的标准免疫抑制药物更温和。今年，我们开始了我们的英夫利昔单抗（Remicade）的经验，这是一种嵌合人/鼠单克隆抗体，可中和tnf - α的生物活性，用于治疗Behcet？S病、巩膜炎、后段葡萄膜炎包括视网膜血管炎。虽然英夫利昔单抗似乎是治疗眼部炎症性疾病的有效替代疗法，但潜在的眼部并发症可能限制了该药物的使用。daclizumab （HAT, Zenapax）是一种人源化单克隆抗il -2受体抗体，目前正在对非感染性中间和后葡萄膜炎患者进行临床研究。以前通过静脉输注给予daclizumab治疗的患者现在受益于每2-4周给予一次新的皮下药物配方，同时保持静脉制剂提供的相同治疗效果。目前正在计划未来评估daclizumab治疗活动性葡萄膜炎患者的内部和多中心临床试验。其他正在进行的临床研究包括评估英夫利昔单抗和daclizumab治疗活动性巩膜炎的疗效，以及IL-1受体拮抗剂anakinra （Kineret）治疗儿童和成人前葡萄膜炎的疗效。除了使用皮质类固醇进行全身治疗外，眼部炎症性疾病还可使用皮质类固醇进行局部或眼内或眼周注射治疗。在过去的一年里，我们证实了之前的研究表明，结膜下类固醇可以有效地局部治疗无眼压升高或青光眼病史的非坏死性巩膜炎。我们还证明，选择性T淋巴细胞和B淋巴细胞抑制剂霉酚酸酯可作为活动性硬膜炎患者有效的类固醇保留剂。计划进行动物研究，以评估具有类似环孢素机制但缺乏肾毒性作用的新型免疫抑制剂，并有望转化为人体试验。今年，我们继续利用眼内IL-10和IL-6的评估来诊断和治疗原发性眼内淋巴瘤（PIOL）。我们分析了35例PIOL和64例uvetic患者的玻璃体细胞因子水平，发现PIOL的IL-10 / IL-6比值大于1.0是疾病诊断的临界点。截断规则的灵敏度为74.3%，特异度为75.0%。在1例经玻璃体内甲氨蝶呤治疗的复发性PIOL患者中，眼内IL-10与IL-6比值与临床肿瘤的存在相关，有助于确定患者是否存在肿瘤。s PIOL对甲氨蝶呤产生耐药性。使用免疫组织化学和共聚焦显微镜，我们检查了患者？并确定甲氨蝶呤耐药蛋白的异常表达和叶酸载体蛋白和叶酸结合蛋白的减少表达是淋巴瘤细胞获得性甲氨蝶呤耐药的可能原因。最近开发的PIOL动物模型有望为该病的发病机制和治疗提供新的见解。最后，使用免疫病理技术，我们能够证明视网膜变性的原因在两个病人。在第一个患者中，对视网膜反应的自身抗体显示出对患者成熟畸胎瘤的细胞成分的反应，这是在系统性工作过程中发现的。在第二例已知诊断为华登斯特罗姆巨球蛋白血症的患者中，我们能够证明抗体对视网膜光感受器有反应，这可能是导致她视网膜变性的原因。

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, and intraocular malignancies. Over the past year clinical studies have continued to focus on examining the effectiveness of new therapeutic agents with a milder safety profile than that offered by currently available standard immunosuppressive medications. This year we have initiated our experience with infliximab (Remicade), a chimeric human/murine monoclonal antibody that neutralizes the biologic activity of TNF-alpha for the treatment of Behcet?s disease, scleritis, and posterior segment uveitis including retinal vasculitis. Although infliximab seems to be an effective alternate therapy for the treatment of ocular inflammatory disease the potential for ocular complications may limit the usage of the agent. Clinical studies with daclizumab (HAT, Zenapax), a humanized monoclonal anti-IL-2 receptor antibody, are ongoing in patients with non-infectious intermediate and posterior uveitis. Previously given by intravenous infusions, patients treated with daclizumab are now benefited from the convenience of a new subcutaneous formulation of the drug given every 2-4 weeks while maintaining the same therapeutic efficacy offered by the intravenous formulation. Future intramural and multicenter clinical trials evaluating daclizumab for the treatment of patients with active uveitis are now being planned. Other clinical studies in development include evaluating the therapeutic efficacy of infliximab and daclizumab for the treatment of active scleritis and anakinra (Kineret), a IL-1 receptor antagonist, for the treatment of anterior uveitis in children and adults. In addition to systemic therapy with corticosteroids, ocular inflammatory disease can be treated with corticosteroids given topically or by injection in or around the eye. In the past year we have verified previous work showing that subconjunctival steroids can be effective local therapy for the treatment of non-necrotizing scleritis in patients without a history of increased intraocular pressure or glaucoma. We also demonstrated that mycophenolate mofetil, a selective inhibitor of T and B lymphocytes can be used as an effective steroid sparing agent in patients with active scleritis. Animal studies to evaluate new immunosuppressive agents with a mechanism similar cyclosporine but lacking the nephrotoxic effects are planned that will hopefully translate into human trials. This year we have continued to exploit the utility of the intraocular assessment of IL-10 and IL-6 for the diagnosis and management of primary intraocular lymphoma (PIOL). We analyzed vitreal cytokine levels from 35 PIOL and 64 uveitic patients and found a cutoff point in disease diagnosis with an IL-10 to IL-6 ratio greater than 1.0 for PIOL. The sensitivity and specificity of the cutoff rule are74.3% and 75.0%, respectively. In a patient with recurrent PIOL treated with intravitreal methotrexate the intraocular IL-10 to IL-6 ratio correlated with the presence of tumor clinically and were helpful in the determination that the patient?s PIOL had become resistant to methotrexate. Using immunoshistochemistry with confocal microscopy we examined the patient?s resistant PIOL cells and determined that aberrant expression of the methotrexate resistant protein and decreased expression of the reduced folate carrier and folate binding proteins on the lymphoma cells we the likely cause of the acquired methotrexate resistance. A recently developed animal model for PIOL holds the promise of offering new insights into the pathogenesis and treatment of this disease. Finally, using immunopathologic techniques we were able to demonstrate the cause of retinal degeneration in two patients. In the first patient autoantibodies reactive against the retina were shown to react against cellular components the patients mature teratoma that was discovered in the process of a systemic work. In the second case of a patient with a known diagnosis of Waldenstrom macroglobulinemia we were able to demonstrate of antibodies reactive against the retinal photoreceptors that were the likely cause of her retinal degeneration.