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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Terapia génica y Hepatología > Terapia génica del cáncer > DA - CIMA - Terapia génica y Hepatología - Terapia génica del cáncer - Artículos de revista >

Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12
Authors: Crettaz, J. (Julien)
Otano, I. (Itziar)
Ochoa, L. (Laura)
Benito, A. (Alberto)
Pañeda, A. (Astrid)
Aurrekoetxea, I. (Igor)
Berraondo, P. (Pedro)
Rodriguez-Madoz, J.R. (Juan Roberto)
Astudillo, A. (Aurora)
Kreppel, F. (Florian)
Kochanek, S. (Stefan)
Ruiz, J. (Juan)
Menne, S. (Stephan)
Prieto, J. (Jesús)
Gonzalez-Aseguinolaza, G. (Gloria)
Keywords: Gene Therapy/methods
Hepatitis B/veterinary
Hepatitis B Virus, Woodchuck/immunology
Interleukin-12/biosynthesis
Interleukin-12/immunology
Marmota/virology
Issue Date: 2009
Publisher: American Society for Microbiology
Publisher version: http://jvi.asm.org/content/83/6/2663
ISSN: 1098-5514
Citation: Crettaz J, Otano I, Ochoa-Callejero L, Benito A, Paneda A, Aurrekoetxea I, et al. Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12. J Virol 2009 Mar;83(6):2663-2674.
Abstract
Chronic hepatitis B is a major cause of liver-related death worldwide. Interleukin-12 (IL-12) induction accompanies viral clearance in chronic hepatitis B virus infection. Here, we tested the therapeutic potential of IL-12 gene therapy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), an infection that closely resembles chronic hepatitis B. The woodchucks were treated by intrahepatic injection of a helper-dependent adenoviral vector encoding IL-12 under the control of a liver-specific RU486-responsive promoter. All woodchucks with viral loads below 10(10) viral genomes (vg)/ml showed a marked and sustained reduction of viremia that was accompanied by a reduction in hepatic WHV DNA, a loss of e antigen and surface antigen, and improved liver histology. In contrast, none of the woodchucks with higher viremia levels responded to therapy. The antiviral effect was associated with the induction of T-cell immunity against viral antigens and a reduction of hepatic expression of Foxp3 in the responsive animals. Studies were performed in vitro to elucidate the resistance to therapy in highly viremic woodchucks. These studies showed that lymphocytes from healthy woodchucks or from animals with low viremia levels produced gamma interferon (IFN-gamma) upon IL-12 stimulation, while lymphocytes from woodchucks with high viremia failed to upregulate IFN-gamma in response to IL-12. In conclusion, IL-12-based gene therapy is an efficient approach to treat chronic hepadnavirus infection in woodchucks with viral loads below 10(10) vg/ml. Interestingly, this therapy is able to break immunological tolerance to viral antigens in chronic WHV carriers.
Permanent link: http://hdl.handle.net/10171/23270
Appears in Collections:DA - CUN - Hepatología - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Terapia génica del cáncer - Artículos de revista

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