Immunostimulatory DNA mediates inhibition of eosinophilic inflammation andairway hyperreactivity independent of natural killer cells in vivo

Background: Immunostimulatory DNA sequences (ISS) inhibit eosinophilic infl ammation and airway hyperreactivity in mouse models of asthma. In vitro ISS activate natural killer (NK) cells to secrete IFN-gamma, and this cytokine is hypothesized to contribute to the antiallergic effect of ISS in vivo. O bjective: We investigated whether ISS activation of NK cells is important i n mediating the reduction in airway hyperreactivity and the antieosinophili c effect of ISS in vivo. Methods: We assessed whether ISS modulated the development of eosinophilic airway inflammation and airway hyperreactivity to methacholine in ovalbumin (OVA)-sensitized and OVA allergen-challenged mice pretreated with an antib ody to deplete NK cells. Results: Mice sensitized and challenged with OVA had significant bronchoalv eolar lavage and lung eosinophilia, as well as airway hyperresponsiveness. ISS induced significant inhibition of bronchoalveolar lavage and lung eosin ophilia, as well as airway hyperresponsiveness, in OVA-sensitized mice pret reated before OVA challenge with an NK cell-depleting antibody (NK-mice), a s well as in mice pretreated with a control non-NK cell-depleting antibody (NK+ mice). The NK cell-depleting antibody inhibited ISS-induced IFN-gamma production by spleen cells. Conclusion: These studies demonstrate that depletion of NK cells has no sig nificant effect on ISS-mediated inhibition of airway eosinophilia and airwa y hyperresponsiveness in vivo, suggesting that non-NK cells and cytokines o ther than IFN-gamma derived from NK cells mediate the majority of the ISS-i nhibitory effect on eosinophilic inflammation and airway hyperresponsivenes s in vivo.