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).
