Adeno-associated virus-mediated CCL11 shRNA reduced lung inflammatory responses in a mite allergen-sensitized mouse model (107.13)

Abstract Asthma is considered as a chronic pulmonary inflammatory disease, characterized by eosinophilia. Lung epithelium cells secrete CCL11, the major chemokine for the recruitment of eosinophils. Hybrid adeno-associated virus serotype 2/9 might achieve long-term gene delivery specifically to lung epithelium cells. Thus, this study tested whether hybrid AAV2/9 virus carrying shRNA specific for CCL11, sh47 and sh137, could reduce eosinophilia in a mite allergen-sensitized mouse model. Both sh47 and sh137 viruses significantly reduced CCL11 level in CCL11-transformed NIH 3T3 cells, compared with others. Both viruses were delivered into Dp2 (group 2 allergen of Dermatophagoides pteronyssinus) sensitized mice before first challenge. The results showed that sh47 virus significantly reduced airway resistance, airway hyperresponsiveness, CCL11 levels and eosinophilia in the lungs of Dp2-sensitized mice. Th2 cytokines were also significantly reduced in the bronchoalveolar lavage fluid and Dp2-stimulated mediastinal lymphocytes of sh47 virus-treated mice. However, serum levels of Dp2-specific IgG1 and IgE as well as Th2 cytokine levels in Dp2-stimulated splenocytes culture supernatants were at the comparable levels to the untreated group. The results suggest that sh47 virus relieved local instead of systemic inflammatory responses. Therefore, the hybrid AAV2/9 viral vector, which is preferable to target lung epithelia cells, might be applied as a novel therapeutic approach for asthma.