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Divergent Effects of Biolistic Gene Transfer in a Mouse Model of Allergic Airway Inflammation

¹ Department of Dermatology, Clinical Research Unit Allergology; ² I. Medical Clinic, Asthma Core Facility SFB 548; and ³ III. Medical Clinic, University of Mainz, Mainz, Germany

Correspondence and requests for reprints should be addressed to Stephan Sudowe, Ph.D., Clinical Research Unit Allergology, Department of Dermatology, Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, D-55131 Mainz, Germany. E-mail: sudowe{at}mail.uni-mainz.de

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 β-galactosidase (βGal) as model allergen under control of the DC-targeting fascin promoter and the ubiquitously active cytomegalovirus promoter, respectively. Mice were challenged intranasally with βGal-protein with or without intermediate sensitization with βGal adsorbed to aluminiumhydroxide. Subsequently, local cytokine production and recruitment of IFN-–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 βGal-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 βGal-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.

Key Words: bronchial asthma • immunologic model • DNA vaccines • gene gun technique • Th1/Tc1 cells

CLINICAL RELEVANCE The therapeutic approach to initiate strong systemic type 1 immune responses, with the intention to counteract the activation of allergen-specific Th2 cells in the lung, might entail detrimental consequences for inflammatory reactions in the airways.