Murine models of acute atopic
asthma may be inadequate to study the effects of recurrent exposure to inhaled
allergens, such as the epithelial changes seen in asthmatic patients. We developed a murine model in which chronic airway
inflammation is maintained by repeated
allergen [
ovalbumin (OVA)] inhalation; using this model, we examined the response to
mucosal administration of CpG
DNA (
oligonucleotides) and specific
antigen immunotherapy. Mice repeatedly exposed to OVA developed significantly greater
airway hyperresponsiveness and goblet cell
hyperplasia, but not airway
eosinophilia, compared with those exposed only twice. CpG-based
immunotherapy significantly reversed both acute and chronic markers of
inflammation as well as
airway hyperresponsiveness. We further examined the effect of mucosal
immunotherapy on the response to a second, unrelated
antigen. Mice sensitized to both OVA and schistosome eggs, challenged with inhaled OVA, and then treated with OVA-directed
immunotherapy demonstrated significant reduction of
airway hyperresponsiveness and a moderate reduction in
eosinophilia, after inhalation challenge with schistosome egg
antigens. In this model,
immunotherapy treatment reduced bronchoalveolar lavage (BAL) levels of Th2
cytokines (IL-4, IL-5, IL-13, and IL-10) without changing BAL IFN-gamma.
Antigen recall responses of splenocytes from these mice demonstrated an
antigen-specific (OVA) enhanced release of
IL-10 from splenocytes of treated mice. These results suggest that CpG
DNA may provide the basis for a novel form of
immunotherapy of allergic
asthma. Both
antigen-specific and, to a lesser extent,
antigen-nonspecific responses to
mucosal administration of CpG
DNA are seen.