Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice

We have used a mouse model of allergen-induced airway hyperresponsiveness t o demonstrate that immunostimulatory DNA sequences (ISS) containing a CPG D NA motif significantly inhibit airway eosinophilia and reduce responsivenes s to inhaled methacholine. ISS not only inhibited eosinophilia of the airwa y (by 93%) and lung parenchyma (91%), but also significantly inhibited bloo d eosinophilia (86%), suggesting that ISS was exerting a significant effect on the bone marrow production of eosinophils, The inhibition of the bone m arrow production of eosinophils by 58% was associated with a significant in hibition of T cell-derived cytokine generation (IL-5, granulocyte-macrophag e CSF, and IL-3), ISS exerted this inhibitory effect on T cell cytokine pro duction indirectly by stimulating monocytes/macrophages and NK cells to gen erate IL-12 and IFNs, The onset of the ISS effect on reducing the number of tissue eosinophils was both immediate (within I day of administration) and sustained (lasted 6 days), and was not due to ISS directly inducing eosino phil apoptosis. ISS was effective in inhibiting eosinophilic airway inflamm ation when administered either systemically (i.p.), or mucosally (i.e., int ranasally or intratracheally). Interestingly, a single dose of ISS inhibite d airway eosinophilia as effectively as daily injections of corticosteroids for 7 days. Moreover, while both ISS and corticosteroids inhibited IL-5 ge neration, only ISS was able to induce allergen-specific IFN-gamma productio n and redirect the immune system toward a Th1 response. Thus, systemic or m ucosal administration of ISS before allergen exposure could provide a novel form of active immunotherapy in allergic diseases.