SUMMARYWe evaluated the use of recombinant human interleukin-6 (rhIL-6) and a monoclonal antibody speci®c for interferon-c (IFN-c) as co-adjuvants in a subunit vaccine against tuberculosis consisting of the culture ®ltrate proteins of Mycobacterium tuberculosis (ST-CF) emulsi®ed in the adjuvant dimethyl-dioctadecylammonium bromide (DDA). Both the addition of rhIL-6 and the neutralization of IFN-c resulted in an increased T helper type 1 (Th1) response characterized by enhanced IFN-c production and cell proliferation. Nevertheless, this did not result in the enhancement of protection against either an intravenous or an aerosol M. tuberculosis challenge. Our data stress the need to identify further correlates of protection in addition to IFN-c production to screen vaccines against tuberculosis infection.
We examined the role of cytokines in the development of gamma interferon (IFN-γ)-secreting protective T cells following immunization with a culture filtrate subunit vaccine againstMycobacterium tuberculosis containing the adjuvant dimethyldioctadecylammonium bromide (DDA). Depletion of either interleukin-6 (IL-6) or IL-12 with specific neutralizing antibodies during vaccination reduced the priming of T cells for antigen-specific proliferation and IFN-γ secretion. Such reduction was also observed in IL-6 gene-disrupted mice as compared to wild-type animals. IL-6 was found to play a role in the initial differentiation of Th1 cells but not in their expansion. The defect found after IL-6 depletion or in IL-6-knockout mice was compensated by the inclusion of recombinant mouse IL-12 in the vaccine. The induction of protective immunity against an intravenous or an aerosol challenge with live, virulentM. tuberculosis was markedly reduced by neutralizing either IL-6 or IL-12 during immunization with the vaccine. Likewise, the effects of IL-6 neutralization were partially reversed by including IL-12 in the vaccine. Our data point to an important role of IL-6 and IL-12 in the generation of cell-mediated immunity to tuberculosis.
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