Inhibition of antigen-induced eosinophilia and late phase airway hyperresponsiveness by an IL-5 antisense oligonucleotide in mouse models of asthma

Chronic airway eosinophilia is associated with allergic asthma and is media ted in part by secretion of IL-5 from allergen-specific Th2 lymphocytes, IL -5 is a known maturation and antiapoptotic factor for eosinophils and stimu lates release of nascent eosinophils from bone marrow into the peripheral c irculation. An antisense oligonucleotide found to specifically inhibit IL-5 expression in vitro was observed to significantly reduce experimentally in duced eosinophilia in vivo, in both the murine OVA lung challenge and aller gic peritonitis models. Intravenous administration resulted in sequence-dep endent inhibition of eosinophilia coincident with reduction of IL-5 protein levels, supporting an antisense mechanism of action. Potent suppression of lung eosinophilia was observed up to 17 days after cessation of oligonucle otide dosing, indicating achievement of prolonged protection with this stra tegy. Furthermore, sequence-specific, antisense oligonucleotide-mediated in hibition of Ag-mediated late phase airway hyperresponsiveness was also obse rved. These data underscore the potential utility of an antisense approach targeting IL-5 for the treatment of asthma and eosinophilic diseases.