The macaque pocket model has been used to detect cytokine production, T -cell subsets and resulting inflammation and pathology following acute and chronic chlamydial infection. The responses of macaque salpingeal tissues support earlier observation that chlamydial salpingitis is an immunopathogenic response, and that potential interventions should include specific immune modulators. They propose to test the roles of these cellular responses to chlamydiae. Due to the nature of the chlamydial infection, the host response must be to clear the organism without destroying uninfected host cells, and without inciting fibrosis and scarring. Cytokines are produced which may promote clearance of chlamydial (IFN-g, IL-2, IL-6), which may decrease clearance (IL-10) or which may cause fibrosis and scarring (TGF-b). The functional role of these cytokines will further elucidate the immunopathological mechanisms leading to chlamydial salpingitis. Utilizing cytokines that have clinical relevance are likely to lead to development of additional preventive measures or treatment in chlamydial genital tract infections.
The Specific Aims will extend these studies to further elucidate the immunomodulatory roles of cHSP60and of cytokines in chlamydial salpingitis, providing new information which will further direct research in the usefulness of anti-cytokine therapy. 1. Test the immunomodulatory role of IFN-g in chlamydial PID. The chlamydiacidal activity of IFN-g in primate tissue in vitro or in vivo has not been tested. Direct or indirect modulation of IFN-g may provide a method for intervention in women at risk for pelvic inflammatory disease. 2. Test the immunomodulatory role of IL-10, a cytokine which down-regulates inflammatory responses, in chlamydial PID. Investigating the role of IL-10 will provide a means of evaluating the importance of the pattern of cytokine production in chlamydial immunopathology. 3. Test the immunomodulatory role of IL-6, which promotes proliferation of lymphocytes and recruitment of macrophages, in chlamydial PID. 4. Directly test the role of the fibrogenic cytokine TGF-b as a cause of immunomodulation, and of the tubal scarring associated with PID. Establishing the role of TGF-b will determine the feasibility of anti- TGF-b therapy in chlamydial salpingitis. 5. Test the role of major chlamydial antigens as the cause of immunopathology in C. trachomatis- induced PID. If one chlamydial antigen is the major cause of the DTH response in PID, diagnostic or immunomodulatory efforts can be directed towards that antigen.
