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Am. J. Respir. Cell Mol. Biol., Volume 21, Number 3, September, 1999 317-326

Regulation of Allergic Mucosal Sensitization by Interleukin-12 Gene Transfer to the Airway

Martin R. Stämpfli, G. Scott Neigh, Ryan E. Wiley, Monika Cwiartka, Stacey A. Ritz, Mary M. Hitt, Zhou Xing, and Manel Jordana

Department of Pathology and Molecular Medicine and Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada

Expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in the airway allows allergic sensitization to ovalbumin (OVA) in an experimental protocol that others have shown to induce inhalation tolerance. The ensuing response is characterized by T helper (Th)2 cytokines, marked eosinophilia in the bronchoalveolar lavage fluid (BALF) and the tissue, and goblet-cell hyperplasia. These findings, which underscore the importance of the airway microenvironment in the development of immune responses to airborne antigens, prompted us to investigate whether a Type 1 polarized cytokine milieu in the airway would modulate the allergic sensitization. To this end, we concurrently expressed GM-CSF and interleukin (IL)-12 in the airway, using an adenovirus-mediated gene transfer approach. Coexpression of IL-12 did not prevent the development of an antigen-specific immune inflammatory response, but altered its phenotype. Whereas a similar total cell number was observed in the BALF, airway eosinophilia was abrogated. Histologic evaluation of the tissue corroborated the findings in the BALF and demonstrated that IL-12 coexpression prevented goblet-cell hyperplasia. Expression of IL-12 decreased IL-4 and IL-5 content in the BALF by about 80 and 95%, respectively, and IL-5 in the serum by approximately 80%. In contrast, interferon (IFN)-gamma was increased in both BALF and serum. Similarly, we observed a Th2/Th1 shift in OVA-specific cytokine production in vitro. Recall challenge with OVA in vivo after resolution of the initial inflammatory response demonstrated that the effect of IL-12 was persistent. IL-12-mediated inhibition of airway eosinophilia was mainly IFN-gamma -independent, whereas inhibition of OVA-specific IgE synthesis was IFN-gamma -dependent. Our data underscore the importance of the airway microenvironment in the elicitation of immune responses to environmental antigens.




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