IMMUNITY TO OCULAR INFECTIONS

本项目的长期目标是了解 T细胞对细菌抗原的反应和随后的 激活巨噬细胞作为炎症介质， 室。 我们的提案探讨了这一目标的新模式， 晶状体相关性葡萄膜炎，称为细菌诱导的晶状体相关性葡萄膜炎 (BLU)在我们的实验室里开发的。 在该模型中，刺激物（毒性） 将一定剂量的细菌抗原注入前房（AC）， 同时损伤透镜囊的免疫小鼠。 的 产生的炎症反应类似于超声速发过敏反应 眼内炎，晶状体相关性葡萄膜炎（L-aU）的经典形式。 我们 假设是，该模型模拟了 与发生在美国的晶状体相关性葡萄膜炎病例相关， 设置一个低度细菌感染的眼睛， 痤疮丙酸杆菌。 AC注射细菌粗抗原 模拟细菌感染的产物（即，细菌抗原和 毒素），从而简化了模型，从诱导的 活细菌 虽然这个提议是基于对一种新的动物模型的分析， 对于晶状体相关性葡萄膜炎， 这项研究将对理解 眼内炎症的一般机制。 在第一个目标中，A 将对这一模式进行更好的定性。 在第二 T细胞作为重要的免疫效应细胞的作用， 评估。 T细胞扩增级联反应的概念， 该模型中的贡献元素将适用于许多形式 免疫原性炎症 此外，这些研究将 最终与新出现的人类疾病有关（例如，T细胞的作用 对细菌热休克蛋白或超抗原的反应）。 在 第三个目的，我们的研究也将阐明激活的作用， 巨噬细胞及其炎症产物在眼部炎症中的作用。 如果 活化的巨噬细胞是关键的炎症效应子 细胞类型在这个模型中，正如假设的那样，它将使我们能够提出一个 与其他形式的L-aU（包括自身免疫）的常见致病联系 以及与麻醉相关的假性眼内炎。 一些衍生的概念 该项目将提出具体建议， 白内障手术在活动性葡萄膜炎眼睛中的表现与 透镜。 此外，这些研究将提供一些见解， 对研究激活的 巨噬细胞在其他眼部炎症模型中。 最后在 第四个目标，自衍生蛋白质增强组织 炎症通过与免疫和 将探索炎性细胞。 如果正确的话，这个概念是 与晶状体相关的炎症之外的相关性，因为这种相互作用 可能是由于对非晶状体组织的损伤（即，其他实质 细胞类型）。

The long term goal of this project is to understand the relationship between T cell response to bacterial antigens and the subsequent activation of macrophages as mediators of inflammation in the anterior chamber. Our proposal explores this goal in terms of a new model for lens-associated uveitis, called bacteria-induced lens-associated uveitis (BLU), developed in our laboratory. In this model, irritant (toxic) doses of bacterial antigens are injected into the anterior chamber (AC) of immunized mice with simultaneous injury to the lens capsule. The resultant inflammatory reaction resembles Phacoanaphylactic Endophthalmitis, the classic form of lens-associated uveitis (L-aU). Our hypothesis is that this model mimics the pathophysiologic events that are relevant to those human cases of lens-associated uveitis occuring in the setting of a lowgrade bacterial infection of the eye with Propionibacterium acnes. The AC injections of crude bacterial antigens mimics the products of bacterial infection (i.e., bacterial antigens and toxins) thereby simplifying the model from that induced by inoculating live bacteria. Although this proposal is based upon the analysis of a new animal model for lens-associated uveitis, the concepts derived from the proposed research will have much broader implications for understanding the mechanisms of intraocular inflammation in general. In the first aim, a better characterization of this model will be undertaken. In the second aim, the role of T cells as important immune effector cells will be evaluated. The concepts of a T cell amplification cascade as a contributing elements in this model will have applicability to many forms of immunogenic inflammation. Additionally, theses studies will eventually related to new emerging human diseases (e.g., role of T cell responses to bacterial heat shock proteins or superantigens). In the third aim, our studies will also illuminate the role of activated macrophages and their inflammatory products in ocular inflammation. If activated macrophages turn out to be the crucial inflammatory effector cell type in this model, as hypothesized, it will allow us to propose a common pathogenic link with other forms of L-aU, including autoimmunity and surgical-related pseudoendophthamitis. Some of the concepts derived from this project will suggest specific recommendations relevant to the performance of cataract surgery in eyes with active uveitis unrelated to the lens. Furthermore, these studies will provide insights that might be useful for additional studies investigating the role of activated macrophages in other models of ocular inflammation. Finally, in the fourth aim, the ability of self-derived proteins to enhance tissue inflammation via non-antigen specific interactions with immune and inflammatory cells will be explored. If correct, this concept is relevant beyond lens-associated inflammation, since such interactions could results from injury to non-lens tissue (i.e., other parenchymal cell types).