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1 Department of Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
2 Department of Pediatrics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
3 Department of Occupational and Environmental Health, University of Iowa College of Public Health, Iowa City, IA, USA
4 Department of Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA; Department of Occupational and Environmental Health, University of Iowa College of Public Health, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: joel-kline{at}uiowa.edu.
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 BAL levels of Th2 cytokines (IL-4, IL-5, IL-13, and IL-10) without changing BAL IFN-
. 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.
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