T-Cell Mediated Immunity In Chlamydial Genital Infection

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DESCRIPTION (provided by the applicant): Chlamydia trachomatis infection remains a major cause of pelvic inflammatory disease, and often leads to fallopian tube injury and infertility. While effective antibiotics are available, asymptomatic infection may ascend to the upper genital tract (GT) and cause irreversible tissue damage before it is discovered. One strategy for avoiding injury to the upper GT is through preventative vaccination. However, the anti-chlamydial CD4 T helper type 1 (Th1) response that develops to eradicate infection is also thought to damage the upper GT. Preliminary data from our laboratory has found that CD4 cells are primarily recruited to the upper but not the lower GT where infection begins. We have also found that prostaglandin E2 (PGE2) is induced in the upper tract during infection. These date indicate that the upper and lower GT are two immunologically distinct compartments and respond differently during Chlamydia infection. We hypothesize that the recruitment of Th1 CD4 effector cells to the lower GT is insufficient for completely eradicating chlamydiae resulting in upper GT infection. Upper GT infection causes the local production of PGE, a potent inducer of IL- 10, which impedes the antichlamydial Th1 CD4 response, thereby promoting upper GT injury. To test this hypothesis we will 1) Identify chemokines that control the recruitment of Th1 CD4 cells to the upper and lower GT 2) Determine the effect of altered Th1 CD4 cell recruitment on immunity against Chlamydia infection 3) Identify mechanism(s) whereby IL- 10 hampers an anti-chlamydial Th1 CD4 response in the upper GT and 4) Determine if PGE2 influences the anti-chlamydial Th1 CD4 response in the upper GT. To achieve these goals, we will use the mouse model of chlamydial genital infection to manipulate the immune response in BALB/c and various transgenic mouse strains. The results from this proposal will determine if shifting the Th1 CD4 immune response against Chlamydia from the upper to the lower GT can increase protective immunity and reduce tubal pathology. In addition, the role of regulatory factors, such as PGE2/IL-I0 will be characterized. By targeting different immune regulatory mechanisms in this process within the upper and lower GT we hope to enhance protective immunity and reduce upper GT injury. If successful, this approach will aid vaccine development and promote strategies that target immune responses to discrete sites within mucosal surfaces.