title: High dose interleukin-12 exacerbates Bordetella pertussis infection and is associated with suppression of cell-mediated immunity in a murine aerosol challenge model.
abstract: The in-vivo clearance of Bordetella pertussis infections in murine models in naive mice and animals vaccinated with whole-cell vaccine is considered to be via a Th-1-dependent mechanism in which interleukin-12 (IL)-12 may play a prominent role. It has also been demonstrated clearly that the treatment of animals with macrophage-derived IL-12 administered with an acellular vaccine can increase the efficacy of this vaccine preparation to levels seen with the whole-cell vaccine. However, the effects of exogenously added IL-12 on immune responses in non-vaccinated B. pertussis-challenged mice remain unclear, with two studies giving contradictory findings. In this study we have treated mice with escalating doses of mIL-12 (0.1-10 microg/mouse) prior to challenge with B. pertussis (using an aerosol challenge model of infection). The ability of mice to clear infection was assessed in IL-12 treated and in phosphate buffered saline (PBS) control animals at days 6 and 13 post-challenge. Lymphoid cells were isolated from spleen and cell-mediated immune responses assessed at days 1, 6 and 13 post-challenge. In addition, the direct effects of high-dose IL-12 on challenged mice was assessed by checking natural killer (NK) activity from isolated lung and spleen lymphoid cells as well as interferon-gamma (IFN-gamma) generation from isolated cells and serum at day 1 post-challenge. The results from this study show that bacterial colonization of the lungs is actually enhanced following treatment with high-dose IL-12. This is associated with impaired cellular immune responses. The mechanisms associated with the immunosuppressive effects of IL-12 are discussed.
authors.affiliation: Divisions of Immunobiology and Bacteriology, NIBSC, S. Mimms, UK.
authors.forename: C R D
authors.initials: CR
authors.lastname: Carter
authors.forename: B M
authors.initials: BM
authors.lastname: Dagg
authors.forename: K M
authors.initials: KM
authors.lastname: Whitmore
authors.forename: J R
authors.initials: JR
authors.lastname: Keeble
authors.forename: C
authors.initials: C
authors.lastname: Asokanathan
authors.forename: D
authors.initials: D
authors.lastname: Xing
authors.forename: K B
authors.initials: KB
authors.lastname: Walker
mesh_terms: D000336:Aerosols; D000818:Animals; D002478:Cells, Cultured; D003208:Concanavalin A / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000276:immunology; D013154:Spleen / Q000166:cytology; D014917:Whooping Cough / Q000276:immunology*
chemical_list: D000336:Aerosols; D003208:Concanavalin A; D018664:Interleukin-12; D007371:Interferon-gamma; D019331:NG-Nitroarginine Methyl Ester