lipid-a and Syphilis

Immune regulation during syphilitic infection is extremely complex. This paper presents findings on the early events of T-cell activation following testicular infection in rabbits. Treponema pallidum was preincubated for 24 h with nonadherent spleen cells. After being washed to remove the organisms, these spleen cells were either stimulated with concanavalin A (ConA) to induce interleukin-2 (IL-2), or added to adherent cells that were then stimulated with lipopolysaccharide to induce IL-1. Preincubation with the treponemes up-regulated nonadherent cell functions. These sensitized cells increased their IL-2 production and augmented macrophage IL-1 synthesis. In sharp contrast, if this preincubation step was omitted, down-regulation was apparent. When T. pallidum was directly incubated with nonadherent cells in the presence of ConA, reduced levels of IL-2 were detected. Nonadherent cells from infected rabbits secreted soluble suppressive factors after 48 h of in vitro incubation; these factors inhibited ConA-induced IL-2 generation as well as ConA-induced lymphocyte proliferation. At least some of this suppressive activity was attributed to transforming growth factor. In addition, when T lymphocytes were depleted, less suppression was detected. Treponemes also inhibited ConA-induced T-cell proliferation, and monophosphoryl lipid A reversed this inhibitory effect. Since monophosphoryl lipid A neutralizes T-suppressor activity, these findings further suggest a role for T-suppressor activity during syphilitic infection. Finally, T. pallidum directly stimulated IL-2 synthesis when coincubated with phorbol myristate acetate. This agent reverses the prostaglandin E2 blockage of T-helper cell protein kinase C, a necessary second messenger signal for IL-2 synthesis. In summary, T-cell functions are extremely complex and represent a composite of both stimulation and down-regulation, which occur concurrently but to different degrees.

Topics: Animals; Concanavalin A; Indomethacin; Interleukin-2; Lipid A; Lymphocyte Activation; Rabbits; Spleen; Syphilis; T-Lymphocytes; Tetradecanoylphorbol Acetate; Time Factors; Transforming Growth Factors; Treponema pallidum

Many unsuccessful attempts have been made to develop effective vaccines against experimental syphilitic infection. The focus of this report was to evaluate newer approaches to up-regulate immune responses following immunization with Treponema pallidum. Rabbits were injected once on day 0 with heat-inactivated treponemes suspended in the Ribi adjuvant system containing monophosphoryl lipid A (MPL) and trehalose dimycolate; animals were challenged dermally on day 29 with viable organisms. Various up-regulating agents were then tested using this general immunization protocol. When rabbits were pretreated on day -2 with cyclophosphamide (CYC), no protection was apparent. CYC pretreatment exhibited some protection when combined with a daily course of indomethacin on days 29 to 36. When rabbits were injected on day 0, then given a boost of MPL alone on day +2 plus indomethacin on days 29 to 36, minor protection was again apparent. Excellent protection was achieved when the vaccine protocol involved a combination of CYC pretreatment on day -2, an MPL boost on day +2, and indomethacin on days 29 to 36. Ninety-two percent of the subsequent lesions were atypical as indicated by their flat appearance, small size, lack of ulceration, and rapid healing. Importantly, this vaccine regimen also decreased dissemination of T. pallidum to distant tissues. These results suggest a new perspective in understanding immune responses in syphilis. We propose that vaccination, like infection, generates immune down-regulation that counter-balances immune stimulation. THus, effective vaccines will depend on removal and/or neutralization of treponemal components that down-regulate immune reactivity.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Bacterial; Bacterial Vaccines; Cyclophosphamide; Indomethacin; Lipid A; Male; Rabbits; Spleen; Syphilis; Treponema pallidum; Up-Regulation; Vaccines, Inactivated