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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022082-11
Application #
6124186
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Quackenbush, Robert L
Project Start
1985-09-01
Project End
2003-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
11
Fiscal Year
2000
Total Cost
$331,135
Indirect Cost
Name
University of Washington
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lichtenwalner, Anne B; Patton, Dorothy L; Van Voorhis, Wesley C et al. (2004) Heat shock protein 60 is the major antigen which stimulates delayed-type hypersensitivity reaction in the macaque model of Chlamydia trachomatis salpingitis. Infect Immun 72:1159-61
Van Voorhis, W C; Barrett, L K; Sweeney, Y T et al. (1997) Repeated Chlamydia trachomatis infection of Macaca nemestrina fallopian tubes produces a Th1-like cytokine response associated with fibrosis and scarring. Infect Immun 65:2175-82
Van Voorhis, W C; Barrett, L K; Sweeney, Y T et al. (1996) Analysis of lymphocyte phenotype and cytokine activity in the inflammatory infiltrates of the upper genital tract of female macaques infected with Chlamydia trachomatis. J Infect Dis 174:647-50
Cappuccio, A L; Patton, D L; Kuo, C C et al. (1994) Detection of Chlamydia trachomatis deoxyribonucleic acid in monkey models (Macaca nemestrina) of salpingitis by in situ hybridization: implications for pathogenesis. Am J Obstet Gynecol 171:102-10
Patton, D L; Sweeney, Y T; Kuo, C C (1994) Oral contraceptives do not alter the course of experimentally induced chlamydial salpingitis in monkeys. Sex Transm Dis 21:89-92
Patton, D L; Sweeney, Y T; Kuo, C C (1994) Demonstration of delayed hypersensitivity in Chlamydia trachomatis salpingitis in monkeys: a pathogenic mechanism of tubal damage. J Infect Dis 169:680-3
Patton, D L; Cosgrove, Y T; Kuo, C C et al. (1993) Effects of quinolone analog CI-960 in a monkey model of Chlamydia trachomatis salpingitis. Antimicrob Agents Chemother 37:8-13
Patton, D L; Kuo, C C; Brenner, R M (1989) Chlamydia trachomatis oculogenital infection in the subcutaneous autotransplant model of conjunctiva, salpinx and endometrium. Br J Exp Pathol 70:357-67
Patton, D L; Kuo, C C (1989) Histopathology of Chlamydia trachomatis salpingitis after primary and repeated reinfections in the monkey subcutaneous pocket model. J Reprod Fertil 85:647-56
Patton, D L; Kuo, C C; Wang, S P et al. (1987) Chlamydial infection of subcutaneous fimbrial transplants in cynomolgus and rhesus monkeys. J Infect Dis 155:229-35