IMMUNOLOGIC MECHANISMS OF OCULAR DISEASE

这个项目的目标是研究相关的免疫学机制。 在眼部炎症和眼部恶性肿瘤的发病机制中的作用 根据这些数据开发和测试治疗方法。最近，我们有 集中在细胞黏附分子在发育中的作用 葡萄膜炎和眼睛过敏。在过去的一年里，我们证明了 淋巴细胞活化是细胞过继转移的关键 免疫和炎症性眼病转基因动物模型的建立 自身免疫性葡萄膜炎。重要的是，荧光素激活的细胞分选器 (FACS)分析表明，这种激活似乎涉及到 细胞黏附分子表达上调，包括非常晚期 抗原-4(VLA-4)、细胞间黏附分子-1(ICAM-1)和 淋巴细胞功能相关分子1(LFA-1)。此外， 应用抗这些黏附分子的单抗 显著抑制了疾病的传播，表明阻断 这些细胞黏附分子可能是一种有效的治疗方法。 适用于自身免疫性葡萄膜炎患者。 在过去的一年里，我们调查了两种药物的效果， 三氯二氧乙烯-0-0‘-碲酸铵(AS101)和镓 葡萄膜炎动物模型中的硝酸盐(GN)AS101是一种强大的 免疫调节剂，可增加细胞因子的产生，包括肿瘤 肿瘤坏死因子-α(TNF-α)和白介素12(IL-12)。我们展示了 AS101显著抑制内毒素诱导的大鼠急性胰腺炎的发生 葡萄膜炎(EIU)对Lewis大鼠的影响，减少炎症的数量 渗入眼部的细胞和细胞内蛋白质的浓度 房水体液。这些结果与我们以前的发现是一致的 房内注射IL-12抑制内毒素诱导的眼部炎症。 我们还测试了GN对两种实验性自身免疫性葡萄膜炎的影响。 (EAU)和EIU。GN显著抑制EAU、A T细胞介导的葡萄膜炎动物模型。相反，GN加剧了 内毒素引起的眼炎性疾病。因为增加了 细胞间黏附分子-1的表达在肿瘤的发病机制中起重要作用 对于EIU，我们检测了GN对脾ICAM-1表达的影响 细胞。GN治疗与小但可重复性的 脾细胞表面ICAM-1的表达增加 经过生理盐水处理的动物。因此，虽然GN抑制T细胞 介导性炎症性疾病，这种化合物有可能 加剧T细胞非依赖性炎症过程，可能是通过 细胞黏附分子表达上调。 最后，我们的实验室对T细胞、细胞因子和 细胞黏附分子在过敏性眼病发病机制中的作用 它每年影响着美国数百万人。我们有 开发了一种新的实验模型来研究这种疾病。动物 用豚草免疫的人会用局部的豚草来挑战。临床 局部使用豚草后20分钟内出现结膜炎症状 给药和炎性细胞，包括淋巴细胞和 嗜酸性粒细胞，在6小时内开始渗入眼睛。我们现在计划 使用这种新的模型来测试新的治疗方法，如阻断 细胞黏附分子与口服耐受性。

The goal of this project is 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 in the development of uveitis and ocular allergy. Over the past year, we showed that lymphocyte activation is critical for the adoptive transfer of cellular immunity and inflammatory eye disease in a transgenic animal model of autoimmune uveitis. Importantly, fluorescein activated cell sorter (FACS) analysis showed that this activation appeared to involve the upregulated expression of cell adhesion molecules, including very late antigen-4 (VLA-4), intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated molecule-1 (LFA-1). Furthermore, administration of monoclonal antibodies against these adhesion molecules significantly inhibited the transfer of disease, suggesting that blocking these cell adhesion molecules may be an effective therapeutic approach for patients with autoimmune uveitis. Over the past year, we have investigated the effect of two drugs, ammonium trichloro (dioxyethelene-0-0') tellurate (AS101) and gallium nitrate (GN) in animal models of uveitis. AS101 is a potent immunomodulator that augments cytokine production, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-12 (IL-12). We showed that AS101 significantly inhibits the development of endotoxin-induced uveitis (EIU) in Lewis rats, decreasing both the number of inflammatory cells infiltrating the eye and the concentration of protein in the aqueous humor. These results are consistent with our previous findings that intracameral IL-12 inhibits endotoxin-induced ocular inflammation. We also tested the effect of GN on both experimental autoimmune uveitis (EAU) and EIU. GN significantly inhibited the development of EAU, a T-cell mediated animal model of uveitis. In contrast, GN exacerbated ocular inflammatory disease elicited by endotoxin. Because increased expression of ICAM-1 has been shown to be important in the pathogenesis of EIU, we examined the effect of GN on ICAM-1 expression on spleen cells. GN treatment was associated with a small but reproducible increase in the expression of ICAM-1 on spleen cells when compared with saline-treated animals. Therefore, although GN suppresses T-cell mediated inflammatory diseases, this compound has the potential to exacerbate T-cell independent inflammatory processes, possibly by upregulated expression of cell adhesion molecules. Finally, our lab is interested in the role of T-cells, cytokines, and cell adhesion molecules in the pathogenesis of allergic ocular disease, which affects millions of people in the United States each year. We have developed a new experimental model to study this disorder. Animals immunized with ragweed are challenged with topical ragweed. Clinical signs of conjunctivitis occur within 20 minutes of topical ragweed administration, and inflammatory cells, including lymphocytes and eosinophils, start infiltrating the eye within 6 hours. We now plan to use this new model to test novel therapeutic approaches such as blocking cell adhesion molecules and oral tolerance.