Regulation of allergic mucosal sensitization by interleukin-12 gene transfer to the airway.
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.
Stämpfli
M R
MR
Department of Pathology and Molecular Medicine and Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
Scott Neigh
G
G
Wiley
R E
RE
Cwiartka
M
M
Ritz
S A
SA
Hitt
M M
MM
Xing
Z
Z
Jordana
M
M
D000256:Adenoviridae / Q000235:genetics; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001980:Bronchi / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018014:Gene Transfer Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000494:pharmacology
D000336:Aerosols; D016207:Cytokines; D018664:Interleukin-12; D007073:Immunoglobulin E; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010047:Ovalbumin