Host defenses at the vaginal mucosa are poorly understood. This includes those against C. albicans, the causative agent of >90 percent of cases of vulvovaginal candidiasis (VVC). Cell-mediated immunity (CMI) is important in host defense against C. albicans infections at several mucosal sites. Our laboratory has employed clinical studies and an estrogen-dependent murine model of vaginal candidiasis to understand the role of CMI as a host defense mechanism against vaginitis. To date, our data suggests that anti-Candida host defense mechanisms at the vaginal mucosa may be distinct from those protecting other mucosal tissues. To this end, studies show that systemic-derived Candida-specific CD4+ Th1-type cells associated with resistance against candidal infections does not provide protection against clinical or experimental vaginitis. Partial protection from experimental infection in the absence of Candida-specific systemic CMI suggested that protective mechanisms were localized to the vaginal mucosa consistent with clinical data. Analysis of local immunity showed that while phenotypically distinct T cells were present in the vagina, they did not significantly change during experimental vaginal infection and there was no evidence for infiltration of systemic T cells into the vaginal mucosa. In addition, polymorphonuclear leukocytes (PMNL) present at times during infection do not influence vaginal C. albicans burden. Together, these data suggest that some level of immunoregulation acts at the vaginal mucosa that limits the function of the local and possibly systemic immune responses. This is supported by the vaginal presence of down-regulatory cytokines. In light of limited activity by conventional immune cells at the vaginal mucosa, we discovered that vaginal epithelial cells have anti-Candida activity in vitro. Based on these findings, we hypothesize that immunoregulatory events at the vaginal mucosa significantly affect local cellular immune mechanisms (innate and/or acquired) important for protection against C. albicans vaginal infection, and that vaginal epithelial cells provide some level of innate resistance against C. albicans. To test this hypothesis, we will (i) further characterize vaginal CMI responses during C. albicans vaginal infection, (ii) elucidate immunoregulatory mechanisms potentially responsible for inefficient anti-Candida responses, and (iii) elucidate properties critical to the mechanism for the epithelial cell-mediated anti-Candida activity. The long term goal is to understand vaginal host defense mechanisms against C. albicans so that immunotherapeutic strategies can be developed to prevent or treat disease.
