title: Liver-Specific Allergen Gene Transfer by Adeno-Associated Virus Suppresses Allergic Airway Inflammation in Mice.
abstract: Allergic airway inflammation driven by T helper 2 (Th2)-type immunity is characterized by airway hyperresponsiveness, eosinophilic infiltration, and elevated IgE production. Various novel strategies for managing asthma have been explored, such as DNA vaccines, T-cell peptides, and allergen-specific immunotherapy. A principal goal of most immunotherapeutic approaches is active and long-term allergen-specific tolerance. Liver-specific gene transfer using adeno-associated virus (AAV) has been shown to favorably induce tolerogenic responses to therapeutic products in various experimental models. AAV8 has strong liver tropism and induces immune tolerance in mice. The present study aimed to determine whether hepatocyte-specific allergen expression by pseudotyped AAV2/8 alleviates asthmatic symptoms in ovalbumin (OVA)-sensitized mice. Mice were intravenously injected with AAV2/8 vector carrying membrane-bound OVA transgene under transcriptional control of a hepatocyte-specific alpha 1 antitrypsin promoter (AAV2/8-OVA) and then sensitized with OVA. AAV2/8-OVA specifically transduced the OVA transgene in the liver. Airway hyperresponsiveness, eosinophilia, mucus hypersecretion, and Th2 cytokines were significantly suppressed in both the lungs and secondary lymphoid organs of asthmatic mice infected with AAV2/8-OVA. Significant reduction of OVA-specific antibodies was detected in the bronchoalveolar lavage fluid from AAV2/8-OVA-treated mice. Moreover, AAV2/8-OVA treatment prominently promoted the expression of Foxp3, IL-10, and TGF-β in the liver. Enhanced Foxp3 expression was also detected in the lungs of asthmatic mice after AAV2/8-OVA treatment. Taken together, these results suggest that the induction of immune tolerance by hepatic AAV gene transfer may be beneficial for modulating allergic asthma.
authors.affiliation: 1 Graduate Institute of Biomedical Sciences, Chang Gung University , Taoyuan, Taiwan .
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chan
authors.affiliation: 2 Institute of Biomedical Sciences , Academia Sinica, Taipei, Taiwan .|3 Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University , Taoyuan, Taiwan .
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Lai
authors.affiliation: 2 Institute of Biomedical Sciences , Academia Sinica, Taipei, Taiwan .
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: 4 Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital , Taoyuan, Taiwan .
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Chen
authors.affiliation: 2 Institute of Biomedical Sciences , Academia Sinica, Taipei, Taiwan .
authors.forename: Mi-Hua
authors.initials: MH
authors.lastname: Tao
authors.affiliation: 1 Graduate Institute of Biomedical Sciences, Chang Gung University , Taoyuan, Taiwan .|4 Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital , Taoyuan, Taiwan .|5 Department of Microbiology and Immunology, College of Medicine, Chang Gung University , Taoyuan, Taiwan .|6 Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University , Taoyuan, Taiwan .
authors.forename: Ming-Ling
authors.initials: ML
authors.lastname: Kuo
mesh_terms: D000485:Allergens / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000235:genetics* / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000628:therapy*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000628:therapy*
chemical_list: D000485:Allergens; D010047:Ovalbumin