Uveitis is a serious intraocular inflammatory disease. It is strongly associated with many systemic inflammatory disorders. Thus, the study of uveitis will potentially unravel the pathogenesis of other complex immune-mediated diseases. Most forms of uveitis are mediated by T lymphocytes that produce critical cytokines. IL-12 has been strongly implicated in uveitis. Only recently was it realized that many functions attributed to IL-12 are actually due to IL-23. IL-23 plays an important role in the development of pathogenic T cells and elicit IL-17-dependent inflammation. Using a T cell-dependent uveitis model, we demonstrated an enhanced expression of transcripts for IL-23 and its downstream cytokine IL-17 in uveitis. In addition, we have helped develop a novel IL-17 inhibitor. Based on the above findings, we hypothesize that 1) IL-23, the proximal mediator of inflammation, and ThlL-17 cells play an important role in the pathogenesis of T cell-dependent non-infectious uveitis, and 2) neutralization of IL-23 and IL-17 will attenuate ocular inflammation. This project has the following Specific Aims:
Specific Aim I. We will examine expression of IL-23 and IL-17 in different experimental uveitis models. Furthermore, we will identify the cellular sources of IL-23 and IL-17.
Specific Aim II. We propose to visualize IL-17 expression in the eye by generating a transgenic mouse model expressing enhanced green fluorescent protein (EGFP) under the control of mouse IL-17 promoter. Using EGFP as a surrogate marker for uveitis-specific IL-17 induction, we will characterize the kinetics and location of ThlL-17 cells and IL-17 expression.
Specific Aim III. We will test whether neutralizing IL 23 and/or IL-17 will alleviate the uveitis. We propose to compare the efficacies of monoclonal antibodies specifically against IL-23p19, IL-12/IL-23p40, or IL-17, and soluble IL-17 receptor/Fc fusion protein.
Specific Aim I V. We will further define the roles of IL-23 and ThlL-17 cells in uveitis by 1) determining whether adoptive transfer of IL-23-primed ThlL-17 cells augments the inflammation in the uveitis models;and 2) examining if co-transfer of T regulatory cells prevents or inhibits ThlL-17 cell-mediated uveitis. This study will enhance our knowledge of the underlying immunopathological mechanisms of uveitis. By targeting IL-23 or IL-17, we hope to develop a novel therapeutic strategy with more anti-inflammatory efficacy and less suppressive effect on host defense.
