Background: Oligodeoxynucleotides (ODNs) containing the dinucleotide CpG in a specific sequence context (CpG-ODNs) have the ability to prevent the development of eosinophilic airway inflammation and bronchial hyperreactivity in a murine model of asthma. We have previously demonstrated that CpG-ODNs stimulate expression of the T_H1-inducing cytokines IFN-γ and IL-12 in a murine model of asthma and that this stimulation is associated with the protection against asthmatic inflammation. Objective: The purpose of this study was to examine whether the protection conferred by CpG-ODNs in a schistosome egg-egg antigen murine model of asthma is dependent on the induction of IFN-γ, IL-12, or both. Methods: C57BL/6 mice were sensitized to schistosome eggs in the presence or absence of CpG-ODNs or control ODNs and then stimulated with soluble egg antigen in the airway. The protection offered by CpG-ODNs in these mice was compared with the protection induced by CpG-ODNs in IL-12 and IFN-γ knockout mice and in mice treated with anticytokine blocking antibodies. Double-knockout mice (IL-12/IFN-γ) were also generated and used in these studies. Determinations included airway eosinophilic inflammation and bronchial hyperreactivity to inhaled methacholine. Results: We found that CpG-ODNs confer protection against both airway eosinophilia and bronchial hyperreactivity in the absence of IFN-γ or IL-12 or in the presence of both cytokines together. However, in the absence of either IL-12 or IFN-γ, mice require 10 times as much CpG-ODNs to be protected against the induction of airway eosinophilia. The T_H2 cytokines IL-4 and IL-5 were reduced in all of the CpG-treated mice, although less in the absence of IL-12 and IFN-γ. Conclusion: These data indicate that CpG-ODNs prevent the generation of T_H2-like immune responses by multiple mechanisms, which involve, but do not require, IL-12 and IFN-γ. A direct suppressive effect of CpG-ODNs on T_H2 responses is suggested by their reduction in IFN-γ and IL-12 knockout mice. (J Allergy Clin Immunol 1999;1258-64.)