< > Home : FAQ : Professional : Chlamydiales : Immunobiology : Infections : Diagnosis & Treatment : Links : Contact Us

The basis of protective immunity against chlamydial infection. 

Attempts until recently to base chlamydial vaccines on MOMP have not been notably successful. The problems among others are: 1) the most relevant epitopes probably have a complex and critical topography difficult to mimic with synthetic or genetically engineered antigens and 2) for mucosal infections it is difficult to sustain an adequate immune response in the absence of replicating agent. Recognition of the importance of cell mediated immune responses was therefore timely. 

Firstly, in both the guinea pig and mice [Igietseme et al., 1993; Rank et al., 1989; Rank 1999; Ramsey & Rank, 1991], it was shown that animals susceptible to chlamydial genital tract infection could be made resistant by the transfer of chlamydia-reactive, generally interferon gamma producing cell clones. 

Secondly, in a milestone study of experimental chlamydial infection in gene knock-out mice, Morrison and colleagues clearly demonstrated that MHC Class II restricted T-cell responses were necessary for the development of protective immunity whereas MHC Class I deficient mice resolved genital tract infection normally [Morrison et al., 1995]. 

Thirdly, a number of workers have shown that the CD4+ Thelper 1 response with its key effector gamma interferon is critical for the adaptive immune response to chlamydial genital tract infection, at least in knockout mice. Thus Lycke and colleagues, in a mouse vaginal infection model of acquired immunity to a human isolate of C. trachomatis serovar D, showed that gene knock-out mice lacking functional B cells, CD8⁺ T cells or the key T-helper 2 cytokine, IL-4, were similar to wild type mice in their ability to resist and contain the infection. In contrast, mice lacking CD4⁺ T cells or lacking the ability to respond to ifng had prolonged and more severe infection with a greater likelihood of upper genital tract involvement [Johansson 1997a, 1997b]. The mouse pneumonitis agent Chlamydia muridarum is less sensitive to ifng -mediated clearance than are human isolates of C. trachomatis [Perry et al., 1999], suggesting that caution is needed when extrapolating experiments with C. muridarum to human C. trachomatis. 

IL-12 is required to generate ifng-producing T-helper-1 responses following chlamydial antigen processing by dendritic cells and its effect is antagonised by IL-10.   IL-12 is protective in mice and apparently more important than IL-18 [Lu et al., 2001]. However mice eventually resolve infection via IL-12 and ifng - independent mechanisms [Geng et al., 2000; del Rio et al., 2001]. 

The enhanced immunogenicity of live versus UV-inactivated whole organism vaccines has been attributed to the greater ability of viable organisms to produce IL-12 and GMCSF [Su et al., 1998; see: antigen processing]. Ideally a vaccine should generate neutralising antibody and T-helper 1 responses. However, if infection can become established, T-helper 1 responses might exacerbate immunopathological damage, as reported for C. abortus infection in mice [del Rio et al., 2001]. The role of a vaccine must be to either prevent infection becoming established in the first place or, failing that,  to ensure that adequate curative immunity is generated.

NEXT: New approaches to vaccine development.

References.

Del Rio, L., Buendia, A. J., Sanchez, J., Gallego, M. C., Caro, M. R., Ortega, N., Seva, J., Pallares, F. J., Cuello, F. & Salinas, J. (2001). Endogenous interleukin-12 is not required for resolution of Chlamydophila abortus (Chlamydia psittaci serotype 1) infection in mice. Infection and Immunity 69, 4808 - 4815. Full article     

Geng, Y., Berencsi, K., Gyulai, Z., Valyi-Nagy, T., Gonczol, E. & Trinchieri, G. (2000). Roles of interleukin-12 and gamma interferon in murine Chlamydia pneumoniae infection. Infection and Immunity 68, 2245 - 2253. Full article  

Igietseme, J. U., Perry, L.L., Ananaba, G. A., Uriri, I. M., Ojior, O. O., Kumar, S. N, & Caldwell, H. D. (1998). Chlamydial infection in inducible nitric oxide synthase knockout mice. Infection and Immunity 66, 1282 - 1286. Full article     [ifn gamma mediated clearance is not primarily due to iNOS & NO]

Igietseme, J. U., Ramsey, K. H., Magee, D. M., Williams, D. M., Kincy, T. J. & Rank, R. G. (1993). Resolution of murine chlamydial genital infection by the adoptive transfer of a biovar-specific, Th1 lymphocyte clone. Regulatory Immunology 5, 317 - 324.

Johansson, M., Schon, K., Ward, M. E & Lycke, N. (1997). Genital tract infection with Chlamydia trachomatis fails to induce protective immunity in gamma interferon receptor deficient mice despite a strong local immunoglobulin A response. Infection and Immunity  65, 1032 - 1044. Full article    [Established the importance of CD4+ Th1 response for the adaptive immune response to genital chlamydial infection with a human strain of C. trachomatis]

Johansson, M., Schon, K., Ward, M. & Lycke N. (1997b). Front line: Studies in knockout mice reveal that anti-chlamydial protection requires TH1 cells producing IFN-gamma: is this true for humans? Scandinavian Journal of Immunology 46, 546 - 552. [An interesting summary of work by one group using a human C. trachomatis isolate and a wide range of knockout mice to determine the key factors for the protective adaptive immune response].

Lu, H., Yang, X., Takeda, K., Zhang, D., Fan, Y., Luo, M., Shen, C., Wang, S., Akira, S. & Brunham, R. C. (2001). Chlamydia trachomatis mouse pneumonitis lung infection in IL-18 and IL-12 knockout mice: IL-12 is dominant over IL-18 for protective immunity. Molecular Medicine 6, 604 - 612.

Morrison, R. P., Feilzer, K. & Tumas, D. B. (1995). Gene knockout mice establish a primary protective role for major histocompatibility complex class II-restricted responses in Chlamydia trachomatis genital tract infection. Infection and Immunity 63, 4661 - 4668. Full article  [Milestone paper which established the key importance of class II restricted responses in cell mediated immunity to chlamydial infection].

Perry, L. L., Su, H., Feilzer, K., Messer, R., Hughes, S., Whitmire, W. & Caldwell, H. D. (1999). Differential sensitivity of distinct Chlamydia trachomatis isolates to IFN-gamma-mediated inhibition. Journal of Immunology 162, 3541 - 3548. Full article      

Ramsey, K. H. & Rank, R. G. (1991). Resolution of chlamydial genital infection with antigen-specific T-lymphocyte lines. Infection and Immunity 59, 925 - 931.

Rank, R. G., Soderberg, L. S., Sanders, M. M. & Batteiger, B. E. (1989). Role of cell-mediated immunity in the resolution of secondary chlamydial genital infection in guinea pigs infected with the agent of guinea pig inclusion conjunctivitis. Infection and Immunity 57, 706 - 710.

Rank, R. G. (1999). Models of immunity. In: Chlamydia: Intracellular Biology, Pathogenesis and Immunity (Stephens RS, ed.). pp 239 - 295. American Society of Microbiology Press, Washington DC ISBN 1-55581-155-8 [Comprehensive review in a valuable book]

Su, H., Messer, R., Whitmire, W., Fischer, E., Portis, J. C. & Caldwell, H. D. (1998). Vaccination against chlamydial genital tract infection after immunization with dendritic cells pulsed ex vivo with nonviable Chlamydiae. Journal of Experimental Medicine 188, 809 - 818. Full article

NEXT: New approaches to vaccine development.