IMMUNOLOGIC MECHANISMS OF OCULAR DISEASE

这个项目的目标是研究免疫机制。 参与眼部炎症和眼部病变的发病机制 并根据这些数据开发和测试治疗方法。 最近，我们集中在细胞黏附分子的作用上。 细胞黏附分子和细胞因子在眼部炎症发展中的作用 疾病。CaM是对抗原致敏很重要的表面蛋白 以及白细胞向炎症部位的迁移。我们是 目前正在研究阻断CAM的化合物作为治疗 葡萄膜炎等眼部炎症性疾病。我们之前展示了 抗淋巴细胞功能的单抗与 抗原-1(LFA-1)、细胞间黏附分子(ICAM-1)和Mac-1 能有效抑制两种动物模型的眼部炎症 葡萄膜炎：内毒素诱导的葡萄膜炎和实验性自身免疫 葡萄膜炎。在过去的一年里，我们展示了 抗E-选择素和P-选择素的单抗显著 减少内毒素诱导的葡萄膜炎的眼部炎症。再说一次，一个 抗LFA-1的单抗也有类似的抑制作用。我们 也在研究将血清中的CaM用作疾病的标志 活动。在临床研究中，我们证明了高水平的 葡萄膜炎患者血清中可溶性细胞间黏附分子-1的比较 年龄和性别匹配的对照组没有葡萄膜炎。此外， 葡萄膜炎患者的sICAM-1水平最高 与潜在的系统性疾病有关。这些数据表明 血清可溶性ICAM-1水平可用于确定 葡萄膜炎患者将接受潜在全身疾病的评估。 我们对研究细胞因子在眼部的作用也很感兴趣。 炎症性疾病。对10例虹膜切除标本进行检查 葡萄膜炎患者。缺乏转化生长因子-β 在样本中与炎症增加有关， 提示这种细胞因子可能对血管生成有抑制作用 葡萄膜炎。 该项目还包括开发和测试新的 眼部炎症的免疫抑制疗法。环孢素A 环孢素A(CsA)是一种有效的免疫抑制剂，但全身 给药与显著的毒性有关。我们检查了 环孢素A外用制剂治疗青光眼的安全性和有效性 治疗眼部炎症。外用环孢素A显著抑制 肥大细胞介导的小鼠结膜炎模型。相比之下， 局部应用环孢素A对大鼠眼部炎症影响有限。 内毒素引起的葡萄膜炎。这些数据表明，外用CsA可能是 对治疗人类过敏性结膜炎很有用；然而，其 治疗前葡萄膜炎的有效性尚不清楚。镓 硝酸盐对实验性糖尿病的发展有抑制作用 自身免疫性葡萄膜炎，可用于治疗 葡萄膜炎。最后，我们实验室以前的研究表明，MDL 28,842，一种有效的S-腺苷-L-同型半胱氨酸的不可逆抑制剂 水解酶，抑制小鼠实验性自身免疫性葡萄膜炎。超过了 在过去的一年里，我们证明了可以使用较低剂量的药物 有效联合糖皮质激素治疗慢性阻塞性肺疾病 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.