Hepatocyte-specific Allergen Expression by Adeno-associated Virus-mediated Gene Transfer Suppresses Allergic Airway Inflammation

Allergic asthma is a chronic airway inflammatory disease characterized with elevated serum antigen-specific IgE, lung eosinophilia and airway hyperresponsiveness (AHR). Th2 cell-mediated immunity is mainly considered to regulate the pathogenesis of asthma. T regulatory (Treg) cell-maintained tolerance was demonstrated to benefit several T cell-mediated diseases including autoimmune diseases and allergy. Immune tolerance induction by DNA vaccine or allergen-specific immunotherapy might offer an effective treatment for asthma. Some studies proposed that hepatic gene transfer can trigger transgene-specific immune tolerance via generating Foxp3⁺ Treg cells. Thus, we examine whether hepatocyte-specific allergen expression could induce immune tolerance to suppress asthmatic responses in ovalbumin (OVA)-sensitized mice. Before sensitization, mice were pre-treated once with pseudotyped adeno-associated virus (AAV) 2/8 vector carrying membrane-bound OVA (mbOVA) cDNA that is controlled by hepatocyte-specific alpha 1 antitrypsin promoter via intravenous injection. AAV2/8-mbOVA virus significantly suppressed AHR, lung eosinophilia, and Th2-typed cytokines in lungs and from cells of secondary lymphoid organs of OVA-sensitized mice. However, serum levels of OVA-specific IgE were not influenced. Foxp3 expression of CD4⁺CD25⁺ T cells was prominently increased in liver and lung tissues from AAV2/8-mbOVA virus-treated mice. The results suggest that immune tolerance induction by hepatic gene transfer is potentially applied to modulate airway inflammatory responses.