IMMUNOLOGIC MECHANISMS OF OCULAR DISEASE

本项目的目的是研究免疫学机制 参与眼部炎症的发病机制， 恶性肿瘤，并开发和测试基于这些数据的疗法。 最近，我们集中在细胞粘附分子的作用 细胞间粘附分子（CAMs）和细胞因子在眼部炎症发展中的作用 疾病CAM是抗原致敏的重要表面蛋白 以及白细胞向炎症部位的迁移。我们 目前正在研究阻断CAM的化合物， 葡萄膜炎和其它眼部炎性疾病。we previously showed 针对淋巴细胞功能相关的单克隆抗体 抗原-1（LFA-1）、细胞间粘附分子（ICAM-1）和Mac-1 在两种动物模型中， 葡萄膜炎：内毒素诱导的葡萄膜炎和实验性自身免疫性葡萄膜炎 葡萄膜炎在过去的一年里，我们表明， 抗E-选择素和P-选择素单克隆抗体的表达与对照组相比， 减少内毒素诱导的葡萄膜炎的眼部炎症。再次 抗LFA-1单克隆抗体具有类似的抑制作用。我们 还在研究使用血清中的细胞粘附分子作为疾病标志物 活动在临床研究中，我们证明了 葡萄膜炎患者血清中可溶性ICAM-1， 年龄和性别匹配的无葡萄膜炎的对照组。而且 葡萄膜炎患者可溶性ICAM-1水平最高 与潜在的系统性疾病相关。这些数据表明 血清可溶性ICAM-1水平可用于确定 将评估葡萄膜炎患者潜在的全身性疾病。 我们也有兴趣研究细胞因子在眼内 炎症性疾病。对10例虹膜切除标本进行了检查， 葡萄膜炎患者。缺乏转化生长因子-β（TGF-β） 与炎症增加有关， 这表明这种细胞因子可能具有抑制作用， 葡萄膜炎 该项目还涉及开发和测试新的 用于眼部炎症的免疫抑制疗法。环孢素a (CsA)是一种有效的免疫抑制剂，但全身 给药与显著的毒性相关。我们研究 CsA局部制剂用于 治疗眼部炎症。局部CsA显著抑制 小鼠模型中肥大细胞介导的结膜炎。与此相反， 局部CsA对眼部炎症的作用有限， 内毒素诱导的葡萄膜炎这些数据表明，局部CsA可能是 用于治疗人类过敏性结膜炎;然而， 用于治疗前葡萄膜炎的效用尚不清楚。镓 硝酸盐被证明可以抑制实验性 自身免疫性葡萄膜炎，并可用于治疗 葡萄膜炎最后，我们实验室以前的研究表明，MDL 28，842，S-腺苷-L-同型半胱氨酸的强效不可逆抑制剂 水解酶，抑制小鼠实验性自身免疫性葡萄膜炎。来 去年，我们证明了较低剂量的药物可以用于 有效地与皮质类固醇组合用于治疗 实验性葡萄膜炎

The goals of this project are to study the immunologic mechanisms involved in the pathogenesis of ocular inflammation and ocular malignancy and to develop and test therapies based on these data. Recently, we have concentrated on the role of cell adhesion molecules (CAMs) and cytokines in the development of ocular inflammatory disease. CAMs are surface proteins important for antigen sensitization and the migration of leukocytes to sites of inflammation. We are currently investigating compounds that block CAMs as a treatment for uveitis and other ocular inflammatory diseases. We previously showed that monoclonal antibodies against lymphocyte function-associated antigen-1 (LFA-1), intercellular adhesion molecule (ICAM-1), and Mac-1 could effectively inhibit ocular inflammation in two animal models of uveitis: endotoxin-induced uveitis and experimental autoimmune uveitis. During the past year, we showed that the combination of monoclonal antibodies against E-selectin and P-selectin significantly reduced ocular inflammation in endotoxin-induced uveitis. Again, a monoclonal antibody against LFA-1 had a similar inhibitory effect. We are also studying the use of CAMs in the serum as a marker for disease activity. In clinical studies, we demonstrated elevated levels of soluble-ICAM-1 in the serum of patients with uveitis when compared with age- and sex-matched controls without uveitis. Furthermore, the highest soluble-ICAM-1 levels were found in patients with uveitis associated with an underlying systemic disease. These data suggest that serum soluble-ICAM-1 levels may be used to determine which uveitis patients would be evaluated for underlying systemic disease. We are also interested in studying the role of cytokines in ocular inflammatory disease. Iridectomy specimens were examined from 10 uveitis patients. A lack of transforming growth factor-beta (TGF-beta) in the specimens was associated with increased inflammation, suggesting that this cytokine may have an inhibitory effect on uveitis. This project also involves the development and testing of new immunosuppressive therapies for ocular inflammation. Cyclosporine A (CsA) is an effective immunosuppressive agent, but systemic administration is associated with significant toxicity. We examined the safety and efficacy of a topical preparation of CsA for the treatment of ocular inflammation. Topical CsA significantly inhibited mast-cell-mediated conjunctivitis in a murine model. In contrast, topical CsA had limited effect on the ocular inflammation in endotoxin-induced uveitis. These data suggest that topical CsA may be useful for treating allergic conjunctivitis in humans; however, its utility for the treatment of anterior uveitis is unclear. Gallium nitrate was shown to inhibit the development of experimental autoimmune uveitis and may be useful for treating patients with uveitis. Finally, previous studies from our laboratory showed that MDL 28,842, a potent irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase, inhibited experimental autoimmune uveitis in mice. Over the past year, we showed that lower doses of the drug could be used effectively in combination with corticosteroids for the treatment of experimental uveitis.