Chlamydia trachomatis is a major cause of pelvic inflammatory disease which often leads to tubal obstruction and infertility. The most effective means of decreasing the incidence of infertility is to develop a vaccine for the population at risk. In order to develop a successful vaccine, an understanding of the target antigen(s), nature, and mechanism(s) of the protective immune response is required. Both antibody and cell-mediated immune (CMI) mechanisms have been found to play a role in the protective immune response to chlamydiae. While neutralizing antibodies have been described, there is little known about the cellular mechanisms involved in the generation of protective CMI responses. Moreover, the chlamydial epitopes which elicit T cell responses with regard to antibody help and CMI effectors have yet to be defined. In this proposal, a murine model of chlamydial genital infection using the C. trachomatis biovar of mouse pneumonitis (MoPn) will be utilized. This model is unique in that cell- mediated immunity alone is sufficient to resolve of a chlamydial genital infection, although the role of antibody in this model is not clear. thus, CD4 and CD8 T cell clones will be generated and adoptively transferred into genitally-infected nude mice so that their effect on the course of the infection can be determined. The protective capabilities of both CD4 and CD8 clones will be assessed. The relative protective roles of CD4+,Th1 and CD4+,Th2 cells in CMI and antibody responses, respectively, will also be investigated. Two T cell clones (a CD4, Th1 and a CD8) which are able to effect resolution of infection in infected athymic (nude) mice, will be studied to determine the mechanism(s) by which CMI resolves the infection. the local production of gamma interferon and tumor necrosis factor and their relationship to resolution of infection will be investigated by detection of specific cytokine mRNA in genital tract tissues. The frequency of IL-4, gamma interferon, and IL-2 producing T cells in the tissues will also be measured and the relationship to resolution of infection and immunity to reinfection determined. Since one protective clone has been found to be specific for the major outer membrane protein (MOMP) of MoPn, it and other MOMP-specific clones will be used to define protective epitopes on MOMP. This will be done by assessing their reaction against portions of MOMP using recombinant proteins, and eventually against specific peptides. Defined epitopes will be used to immunize mice against genital infection. This proposal will also address the homing and migration patterns of protective T cells with regard to the genital tract, the mucosal-associated and the peripheral immune system. This will be done by following the distribution of MoPn-specific and unrelated T cell clones in the context of primary infection an challenge infection. The role of gamma/delta-bearing T cells will also be explored since they have been proposed to be associated with a first line defense against mucosal infections.
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