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Immunological parameters controlling chlamydiae

It was known early that both specific humoral and T cell-mediated immune responses are elicited following chlamydial infection [see review: Byrne, 1998], but the contribution of either arm to protective immunity has only recently been clarified. Findings in several laboratories using animal models of experimental ocular, respiratory and genital infections, analysis of specific lymphocyte clones, genetically engineered gene knockout mice, adoptive transfer studies with specific antibodies or T cell subsets, and animal and human strains of Chlamydia, have established that protective anti-chlamydial immunity is mediated primarily by a T cell response, involving the induction and recruitment of CD4+ and CD8+ Th1 cells into the local mucosae [Buzoni-Gatel et al., 1992; Byrne, 1998; Igietseme et al., 1993; Johansson et al., 1997a; Lampe et al., 1998; Perry et al., 1997; Yang & Brunham, 1998]. Thus, the ability of an experimental vaccine regimen to confer short- or long-term protection against genital chlamydial infection in mice correlates with its capacity to induce a high frequency of specific Th1 cells defined by antigen-specific IFN-γ secretion: 

More recent reports have essentially confirmed that T cell response is required for protective chlamydial immunity in humans [Cohen et al., 2000; Johansson et al., 1997a; Stagg, 1998; Yang & Brunham, 1998]. Also, certain accessory cells, such as dendritic cells (DC), function in anti-chlamydial immunity [Stagg et al., 1998]. The importance of DC is likely related to their dynamic presence in mucosal tissues, their motility and ability to transport antigen from the mucosal epithelium to the draining mucosal inductive sites [Neutra et al., 1996], and their efficient processing and presentation of antigens [Ojcius et al., 1998; Su et al., 1998]. Moreover, as antigen-presenting cells (APCs), DC have a proclivity for preferential activation of Th1 responses, due in part to their potent co-stimulatory ability associated with an elevated density expression of co-stimulators such as IL-1, IL-12, ICAM-1, LFA-3, CD40 and B7 molecules [Jenkins et al., 1993] In addition, specific humoral immune responses, including secretory and systemic antibodies, appear to play an ancillary role in protective immunity, facilitating memory response and augmenting the primary T cell-mediated immunity (CMI) during a reinfection [Morrison et al., 2000; Morrison & Morrison, 2001]. Analysis of Fc-receptor deficient knock out (FcRKO) mice indicated that a major role of antibodies in chlamydial immunity is to facilitate antigen uptake, processing and presentation by FcR-positive APCs for enhanced Th1 activation [Moore et al., 2002]. Subsequently, Moore et al., 2003 reported that FcR(-/-) mice lacking receptor for immunoglobulin Fc fragment had a delayed and reduced frequency of Chlamydia-specific Th1 cells, compared to FcR(+/+) mice. In vitro, antichlamydial antibodies increased the rate of Th1 activation by FcR(+/+) but not FcR(-/-) antigen-presenting cells. FcR(-/-) dendritic cells and the T cell-associated IgG2A and IgA mediated enhanced Th1 activation by antibodies. Immunization with chlamydia-antibody complexes induced elevated and protective Th1 response. Protection against genital infection correlated better with the induction of the Th1-associated IgG2a than with secretory IgA [Igietsmeme et al., 1998]. These results support the hypothesis that humoral and cell mediated immunity cooperate to clear chlamydial infection.

Thus, current findings support the operational paradigm that a potentially efficacious chlamydial vaccine should elicit high levels of both mucosal and systemic Th1 responses as well as a humoral response that rapidly augments Th1 activation following a reinfection.

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