Mechanism of inhibition of lung eosinophilia by CpG DNA

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There is a global increase in the morbidity and mortality from asthma, but a long-term therapy that prevents eosinophilic inflammation in patients with pre-existing asthma has not been described. Asthma is an eosinophil disease of the airways that is promoted by Th2 cytokines, and inhibited by Th1 cytokines such as IFN-gamma. Recent studies suggest the mammalian immune system recognizes unmethylated CpG motifs present in bacteria DNA as a "danger signal". This triggers rapid production of IFN-gamma and Th1-inducing cytokines. These cytokines set up a lung milieu that is optimal for generation of Th1 cells and inhibition of eosinophil recruitment. In this proposal, the rapid and long-term effects of CpG ODN will be evaluated in a mouse model of asthma. The cells internalizing CpG ODN will be identified by confocal microscopy. The ability of these cells to produce IL-12, IL-18 and IFN-gamma will be demonstrated by quantitative RT-PCR and ELISA. The role of p38, JNK and ERK MAP kinases will be characterized by western blotting, immune complex kinase assays, and by using specific pharmacological or antisense oligonucleotide inhibitors of these pathways. The in vivo role of IFN-gamma, IL-12 and IL-18 will be demonstrated by using gene knockout animals, or by using neutralizing antibodies. The research proposal has important implications in the development of novel therapies for asthma, including those that provide long-term protection against eosinophilic inflammation and asthma attacks.