title: Divergent effects of biolistic gene transfer in a mouse model of allergic airway inflammation.
abstract: Particle-mediated epidermal delivery (PMED) of allergen genes efficiently prevents systemic sensitization and suppresses specific immunoglobulin E synthesis. We investigated in a mouse model of allergic airway disease the effect of PMED on the elicitation of local inflammatory reactions in the lung. BALB/c mice were biolistically transfected with plasmids encoding beta-galactosidase (betaGal) as model allergen under control of the DC-targeting fascin promoter and the ubiquitously active cytomegalovirus promoter, respectively. Mice were challenged intranasally with betaGal-protein with or without intermediate sensitization with betaGal adsorbed to aluminiumhydroxide. Subsequently, local cytokine production and recruitment of IFN-gamma-producing CD8(+) effector T cells into the airways were determined, and inflammatory parameters such as cellular infiltration in the bronchoalveolar lavage (BAL) and airway hyperresponsiveness (AHR) were measured. PMED of betaGal-encoding plasmids before sensitization significantly reduced frequencies of eosinophils in the BAL and shifted the local T helper (Th) cell response from a distinct Th2 response toward a Th1-biased response. However, AHR triggered by allergen challenge via the airways was not alleviated in vaccinated mice. Most important, we show that PMED using betaGal-encoding DNA without subsequent sensitization recruited Tc1 cells into the lung and caused a Th1-prone local immune response after subsequent intranasal provocation, accompanied by neutrophilic infiltration into the airways and elicitation of AHR. We conclude that robust Th1/Tc1 immune responses, although highly effective in the counter-regulation of local Th2-mediated pathology, might as well trigger local inflammatory reactions in the lung and provoke the induction of AHR in the mouse model of allergic airway disease.
authors.affiliation: Clinical Research Unit Allergology, Department of Dermatology, Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, D-55131 Mainz, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Zindler
authors.forename: Nadine
authors.initials: N
authors.lastname: Gehrke
authors.forename: Cornelia
authors.initials: C
authors.lastname: Luft
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reuter
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.forename: Susetta
authors.initials: S
authors.lastname: Finotto
authors.forename: Angelika B
authors.initials: AB
authors.lastname: Reske-Kunz
authors.forename: Stephan
authors.initials: S
authors.lastname: Sudowe
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004817:Epidermis / Q000276:immunology / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins / Q000235:genetics; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D008840:Microfilament Proteins; C020324:fascin; D007073:Immunoglobulin E; D007371:Interferon-gamma; D001616:beta-Galactosidase