Liver-Specific Allergen Gene Transfer by Adeno-Associated Virus Suppresses Allergic Airway Inflammation in Mice
Resource
Hum. Gene Ther., 27(8), 631-642
Journal
Human Gene Therapy
Pages
631-642
Date Issued
2016
Date
2016
Author(s)
Chan, Cheng-Chi
Lai, Chin-Wen
Wu, Chia-Jen
Chen, Li-Chen
Tao, Mi-Hua
Kuo, Ming-Ling
Abstract
Allergic airway inflammation driven by T helper 2 (Th2)-type immunity is characterized by airway hyper-responsiveness, 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 membranebound 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-beta 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.
SDGs
Other Subjects
adenovirus vector; alpha 1 antitrypsin; immunoglobulin E antibody; immunoglobulin G1; immunoglobulin G2a; interleukin 10; ovalbumin; protein antibody; transcription factor FOXP3; transforming growth factor beta; allergen; ovalbumin; allergic airway inflammation; animal cell; animal experiment; animal model; animal tissue; antibody detection; antibody production; antigen expression; antigen specificity; Article; chemotaxis; controlled study; cytokine response; ectopic expression; eosinophil; eosinophilia; female; hypersalivation; immune deficiency; immunological tolerance; leukocyte migration; liver cell; lymphocytic infiltration; mouse; nonhuman; promoter region; protein expression; protein synthesis inhibition; respiratory tract allergy; Th2 cell; transgene; viral gene delivery system; viral tropism; administration and dosage; animal; Bagg albino mouse; Dependoparvovirus; gene therapy; gene vector; genetics; immunology; pneumonia; Respiratory Hypersensitivity; Allergens; Animals; Dependovirus; Female; Genetic Therapy; Genetic Vectors; Mice; Mice, Inbred BALB C; Ovalbumin; Pneumonia; Respiratory Hypersensitivity