The objective of this research project is to better define acquired defense mechanisms and their regulation in the human in the human male genital tract (MGT), to provide a foundation for the development of vaccine to prevent sexually transmitted diseases (STDs) in men. Our studies are designed to test the hypothesis that regions in the in the distal MGT (penile, urethra, prostate and seminal vesicle) can effectively mount mucosal antibody-mediated defense, but are normally ineffective sites of T-cell mediated immunity due to the presence of a unique profile of immunoregulatory factors. This could explain the apparent high prevalence and persistence of intracellular pathogens (i.e: chlamydia, HIV-1, HSV-2, HPV, HHV8) in the male genital tract and could confound vaccine strategies to control infections by these pathogens: It is also important to determine to what extent systemic immunological mediators penetrate and function in the distal MGT in normal and infected states. Three aspects of acquired STD immune defense will be addressed.
In Specific Aim 1 we will characterize mediators of cellular immunity in genital tract tissues and secretions of men with and without detectable STD pathogens. T cells and antigen-presenting cells will be quantified by subtype, activation status and origin in MGT tissues and secretions in the normal state, during symptomatic episodes of gonorrhoeae and chlamydia infections and during asymptomatic stages of HPV infections. In addition, we will measure concentrations of chemokines and TH1 vs TH2 cytokines in these samples to obtain information about lymphocyte recruitment and activation under these conditions.
In Specific Aim 2 we will characterize mediators of humoral immunity in MGT tissues and contrast immunoglobulin and STD- antigen-specific antibody subclasses in genital tract secretions in those in peripheral blood and saliva of men infected with symptomatic and symptomatic infections.
In Specific Aim 3 we will characterize expression patters of epithelial cell-derived immunoregulatory factors in the normal and STD-infected MGT and epithelial cell line models of STD infections. We hypothesize that the MGT epithelium normally secretes factors that promote humoral immunity and suppress cellular immunity, but that this tight immunoregulation profile is altered by infections. In addition, we will work with investigators in Projects 2 and 3 to define interactions between classical immunological mediators (immunoglobulins, cytokines, defensins) and mucosins in the male genital tract, and regulation of defensin and mucin gene expression by cytokines. Data from these studies will provide information about the characteristics and duration of local humoral and cellular immune responses in the MGT during infection. Studies on effects on immunoregulatory mechanisms in the MGT will enable better predictions of the competence of immune cells in the MGT under such conditions.
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