High dose interleukin-12 exacerbatesBordetella pertussisinfection and is associated with suppression of cell-mediated immunity in a murine aerosol challenge model

Abstract

SUMMARYThe 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 m g/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-g (IFN-g ) 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.

Expression of the p60 Autolysin Enhances NK Cell Activation and Is Required forListeria monocytogenesExpansion in IFN-γ-Responsive Mice

“…Likewise, high doses of IL-12 and IFN-␥ suppress cellular immunity through induction of immune inhibitory factors such as inducible NO synthase and IDO (11,12). These latter processes have actually been shown to promote infection by Bordetella pertussis (13), Salmonella typhimurium (7), and Toxoplasma gondii (14), although it is not known whether specific microbial factors contribute to subversion of immune regulatory cytokine responses in vivo.…”

Review:Novel Nonviral Delivery Approaches for Interleukin-12 Protein and Gene Systems: Curbing Toxicity and Enhancing Adjuvant Activity

“…57,58 On the other hand, administration of recombinant IL-12 may have utility in the treatment of diseases associated with pathologic Th2 responses, such as allergic disorders and asthma. [59][60][61][62] …”