Experimental Ocular Inflammation

100多万美国人受到葡萄膜炎(眼部炎症)的影响，每年约有45000例新诊断病例。此外，在美国，大约10%的失明病例是由葡萄膜炎并发症引起的，包括角膜疤痕、白内障、青光眼、黄斑水肿等。我们小组对分析各种类型的眼部炎症的机制很感兴趣。因此，我们开发了模拟人类眼部炎症性疾病的动物模型。其中，内毒素诱导性葡萄膜炎(EIU)是急性前部葡萄膜炎(AAU)的模型，实验性黑色素蛋白诱导性葡萄膜炎(EMIU)是自身免疫性葡萄膜炎的模型，实验性弓形虫病是感染性获得性弓形体视网膜脉络膜炎的模型，过敏性结膜炎是季节性变态反应性结膜炎(SAC)的模型。我们分析了Fas介导的细胞凋亡(程序性细胞死亡)在我们的小鼠眼部弓形虫病模型中的作用，在该模型中，小鼠体内注射了缓殖子。这种模型与人类获得性疾病很接近，弓形虫感染通常通过进食开始。在我们的模型中，LPR和GLD小鼠(缺乏Fas介导的细胞凋亡的两个组成部分)在细胞凋亡或寄生虫病方面与野生型对照组相比没有显著差异。额外的数据表明，LPR和GLD小鼠比野生型对照小鼠显著更早地表达干扰素-伽玛mRNA。此外，眼部一氧化氮的产生也显著增加。我们的数据表明，在没有Fas介导的细胞凋亡的情况下，小鼠仍然可以通过增加干扰素-γ和NO的产生来控制弓形虫感染。 在2001财年，我们进一步分析了含有未甲基化CpG寡核苷酸基序的DNA(CpG-ODN)在过敏性结膜炎中的治疗作用。这种DNA显然介导了干扰素和IL-12的诱导。我们发现CpG-ODN粘膜给药抑制豚草小鼠模型中的过敏性结膜炎。我们的数据表明，CpG-ODN既抑制了即刻超敏反应，也抑制了晚期细胞浸润。此外，豚草特异的Th1反应被启动，抗豚草IgE的产生被抑制。我们证明了CpG-ODN在疾病已经确定后局部应用时具有保护作用。这对过敏性结膜炎患者的治疗有重要意义，因为它可以防止过敏性疾病的复发。

More than 1 million Americans are affected by uveitis (ocular inflammation) and approximately 45,000 new cases are diagnosed each year. Additionally, in the USA, approximately 10% of all blindness cases are due to uveitis complications including corneal scarring, cataract, glaucoma, macular edema, etc? Our group is interested in analyzing the mechanisms involved in various types of ocular inflammation. Therefore, we developed animal models mimicking human ocular inflammatory diseases. Among these, endotoxin-induced uveitis (EIU) is a model for acute anterior uveitis (AAU), experimental melanin protein-induced uveitis (EMIU) is a model for autoimmune uveitis, experimental toxoplasmosis is a model for infectious acquired toxoplasmic retinochoroiditis and allergic conjunctivitis is a model for seasonal allergic conjunctivitis (SAC), a type I hypersensitivity disorder. We analyzed the role of Fas-mediated apoptosis (programmed cell death) in our murine ocular toxoplasmosis model in which mice are injected intraperitoneally with bradyzoites. This model is close to the human acquired disease where Toxoplasma gondii (T. gondii) infection usually starts through eating. In our model, lpr and gld mice (deficient in the 2 components of Fas mediated apoptosis) do not show significant differences in apoptosis or parasitic disease compared to wild-type controls. Additional data indicate that lpr and gld mice express IFN-gammma mRNA significantly earlier than wild-type controls. Additionally, ocular NO production is significantly increased. Our data indicate that in the absence of Fas-mediated apoptosis, mice can still control T. gondii infection by increasing IFN-gamma and NO production. In FY2001, we further analyzed the therapeutic role of DNA containing unmethylated CpG oligodinucleotide motifs (CpG-ODN) in allergic conjunctivitis. Such DNA are apparently mediating the induction of Interferons and IL-12. We showed that mucosal administration of CpG-ODN inhibits allergic conjunctivitis in a ragweed murine model. Our data indicate that CpG-ODN inhibits both the immediate hypersensitivity response and the late phase cellular infiltration. Additionally, a ragweed specific Th1 response is initiated and the production of anti-ragweed IgE is suppressed. We demonstrated that CpG-ODN have a protective effect when applied topically after the disease has already been established. This has important implications in the treatment of patients with allergic conjunctivitis as it can prevent the recurring of the allergic disease.