Adeno-Associated Virus-Mediated Interleukin-12 Gene Expression Alleviates Lung Inflammation and Type 2 T-Helper-Responses in Ovalbumin-Sensitized Asthmatic Mice.

Abstract

High levels of allergen exposure increase the prevalence of asthma in developed countries. The asthmatic type 2 T-helper (Th2) response is characterized with high eosinophil infiltration, elevated Th2 cytokines, and immunoglobulin (Ig) E secretion resulting in local or systemic inflammation. However, the treatment with palliative Th2 inhibitor drugs cannot completely control asthma and that is why the development of novel approaches is still important. Based on type 1 T-helper (Th1) and Th2 immune homeostasis, the enhanced Th1 immune response has high potential to alleviate Th2 immune response. Thus, we aimed to overexpress single chain IL-12 (scIL-12) through recombinant adeno-associated virus (rAAV) vector (as rAAV-IL-12) and test the efficacy in an ovalbumin (OVA)-induced asthmatic murine model. We firstly demonstrated the bioactivity of exogenous scIL-12. The expression of exogenous scIL-12 was also detected in the lungs of rAAV-IL-12 transduced mice. The data demonstrated that overexpression of exogenous scIL-12 significantly suppressed total number of cells and eosinophil infiltration, as well as the mucus secretion in rAAV-IL-12-treated mice. The decreased OVA-specific IgE in bronchoalveolar lavage fluid and gene expression of Th2-cytokines or C-C motif ligand (CCL) 11 (also eotaxin-1) in lung were observed. In addition, the production of cytokines in the supernatants of OVA-stimulated splenocytes were suppressed with rAAV-IL-12 treatment. Thus, scIL-12 expression by rAAV vector was able to modulate Th2 activity and has the potential to be developed as a feasible strategy in modulating allergic diseases.