title: Increased pulmonary tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-17A responses compensate for decreased gamma interferon production in anti-IL-12 autovaccine-treated, Mycobacterium bovis BCG-vaccinated mice.
abstract: Interleukin-12 (IL-12) and IL-23 (which share a p40 subunit) are pivotal cytokines in the generation of protective Th1/Th17-type immune responses upon infection with the intracellular pathogen Mycobacterium tuberculosis. The role of IL-12 and IL-23 in protection conferred by the tuberculosis vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) is, however, less well documented. By using an autovaccine approach, i.e., IL-12p70 cross-linked with ovalbumin and PADRE peptide formulated with the GSK proprietary adjuvant system AS02(V), we could specifically neutralize IL-12 while leaving the IL-23 axis intact. Neutralization of IL-12 before M. tuberculosis challenge rendered C57BL/6 mice highly susceptible, resulting in 30-fold-higher CFU in spleen and lungs and accelerated mortality. In contrast, neutralization of IL-12 in BCG-vaccinated mice prior to M. tuberculosis challenge only marginally affected vaccine-mediated protection. Analysis of cytokine production in spleen and lungs 3 weeks post-TB challenge by enzyme-linked immunosorbent assay and functional and flow cytometric assays showed significantly reduced mycobacterium-specific gamma interferon (IFN-γ) responses in M. tuberculosis-infected and BCG-vaccinated mice that had been treated with the autovaccine. Purified protein derivative-induced tumor necrosis factor alpha (TNF-α), IL-6, and IL-17A levels, however, were highest in lungs from BCG-vaccinated/IL-12-neutralized animals, and even unstimulated lung cells from these mice produced significant levels of the three cytokines. Mycobacterium-specific IL-4 and IL-5 production levels were overall very low, but IL-12 neutralization resulted in increased concanavalin A-triggered polyclonal secretion of these Th2-type cytokines. These results suggest that TNF-α, IL-6, and IL-17A may be more important pulmonary effector molecules of BCG-mediated protection than IFN-γ in a context of IL-12 deficiency.
authors.affiliation: WIV-ISP Site Ukkel, 1180 Brussels, Belgium.
authors.forename: Danielle
authors.initials: D
authors.lastname: Freches
authors.forename: Marta
authors.initials: M
authors.lastname: Romano
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: Jacques
authors.initials: J
authors.lastname: Van Snick
authors.forename: Catherine
authors.initials: C
authors.lastname: Uyttenhove
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
mesh_terms: D000818:Animals; D054991:Autovaccines / Q000008:administration & dosage / Q000276:immunology; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000276:immunology*; D020381:Interleukin-17 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D054991:Autovaccines; D001500:BCG Vaccine; D020381:Interleukin-17; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma