This project addresses the mechanism, regulation and functional significance of immunoglobulin (Ig) uptake buy human vaginal and cervical epithelial cells, and the potential use of this mechanism to enhance the efficacy of topically administered vaginal microbicides containing antibodies for the prevention of STDs.
Specific Aim 1 focuses on the mechanism of IgG and monomeric IgA uptake by vaginal and cervical epithelial cells. Tissue explants and polarized/stratified epithelial cell cultures will be used to determine: 1) whether Ig uptake is directional, 2) the intracellular localization of Ig, 3) Ig retention kinetics, and 4) Ig cervical epithelial cells. Immunohistochemical studies will determine whether Ig receptor expression and uptake of IgG or mIgA in vivo is related to hormonal changes during the menstrual cycle or to inflammatory conditions. Parallel studies will be conducted in vitro at protein and mRNA levels using hormone and cytokine treated epithelial cell lines.
Specific Aim 3 will address the physiological relevance of intracellular Ig. Epithelial cells will be treated with human monoclonal antibodies/plantibodies that have neutralizing activity against pathogens that infect epithelial cells in vitro (HSV-2, chlamydia and HIV-1), or bind to human leukocyte antigens (ICAM1, SPA1); subsequent Ig-treated and untreated cells will be challenged with the respective pathogen(s) in cell- free (HSV-2, chlamydia, HIV-1) or cell-associated (HIV-1) form and inter- and intracellular antibody-mediated protection will be monitored. This project will also provide immortalized cell lines and human genital tract issues for the performance of other studies in the Topic Microbicide Program Project.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045967-03
Application #
6500707
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
Total Cost
$180,480
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
O'Hanlon, Deirdre E; Moench, Thomas R; Cone, Richard A (2013) Vaginal pH and microbicidal lactic acid when lactobacilli dominate the microbiota. PLoS One 8:e80074
O'Hanlon, Deirdre E; Moench, Thomas R; Cone, Richard A (2011) In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect Dis 11:200
O'Hanlon, Deirdre E; Lanier, Blair R; Moench, Thomas R et al. (2010) Cervicovaginal fluid and semen block the microbicidal activity of hydrogen peroxide produced by vaginal lactobacilli. BMC Infect Dis 10:120
Chancey, Caren J; Khanna, Kristen V; Seegers, Jos F M L et al. (2006) Lactobacilli-expressed single-chain variable fragment (scFv) specific for intercellular adhesion molecule 1 (ICAM-1) blocks cell-associated HIV-1 transmission across a cervical epithelial monolayer. J Immunol 176:5627-36
Cone, Richard A; Hoen, Timothy; Wong, Xixi et al. (2006) Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission. BMC Infect Dis 6:90
Tien, Deborah; Schnaare, Roger L; Kang, Feirong et al. (2005) In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials. AIDS Res Hum Retroviruses 21:845-53
Olmsted, Stuart S; Khanna, Kristen V; Ng, Erina M et al. (2005) Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model. BMC Infect Dis 5:79
Spencer, Steven E; Valentin-Bon, Iris E; Whaley, Kevin et al. (2004) Inhibition of Neisseria gonorrhoeae genital tract infection by leading-candidate topical microbicides in a mouse model. J Infect Dis 189:410-9
Moench, Thomas; Mehrazar, Karim; Cone, Richard et al. (2004) Sensitive methods to detect epithelial disruption: tests for microhemorrhage in cervicovaginal lavages. J Acquir Immune Defic Syndr 37 Suppl 3:S194-200
Boskey, Elizabeth R; Moench, Thomas R; Hees, Paul S et al. (2003) A self-sampling method to obtain large volumes of undiluted cervicovaginal secretions. Sex Transm Dis 30:107-9

Showing the most recent 10 out of 16 publications