Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12
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 viru...
| Autores: | , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2009 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/23270 |
| Acceso en línea: | https://hdl.handle.net/10171/23270 |
| Access Level: | acceso abierto |
| Palabra clave: | Gene Therapy/methods Hepatitis B/veterinary Hepatitis B Virus, Woodchuck/immunology Interleukin-12/biosynthesis Interleukin-12/immunology Marmota/virology Hepatología |
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Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12Crettaz, J. (Julien)|||/items/684f8e38-df97-41b5-b96c-cc35728ac1cbOtano, I. (Itziar)|||/items/d3cfe573-3aef-4c87-aa71-d45016c59b03Ochoa, L. (Laura)|||/items/86ab2c6d-1b27-4130-8f8b-89170ec22907Benito-Boíllos, A. (Alberto)|||/items/36f5562b-2392-4f6a-a747-a57b8b201069Pañeda, A. (Astrid)|||/items/54b71a16-7b78-4c64-8961-b514fe1dd58eAurrekoetxea, I. (Igor)|||/items/c109bf8d-7a3b-4b75-9cd6-05bc5e62331fBerraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91Rodriguez-Madoz, J.R. (Juan Roberto)|||/items/9c21019b-aeba-4cdc-b78e-178a176da535Astudillo, A. (Aurora)|||/items/28fc12b7-3005-43d9-858c-4d36c513e2e6Kreppel, F. (Florian)|||/items/732e4916-a8eb-4c4d-bf2d-2e8864b53651Kochanek, S. (Stefan)|||/items/ceca2d35-371f-41d8-8f5e-7d8687ba69b6Ruiz, J. (Juan)|||/items/e71ee758-aef7-4ed6-b282-e483e9d9ba8eMenne, S. (Stephan)|||/items/0d784fc1-9119-4146-9256-8522282567c7Prieto, J. (Jesús)|||/items/0d9c3dec-4a09-400d-8c83-23ece1096c71González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191acGene Therapy/methodsHepatitis B/veterinaryHepatitis B Virus, Woodchuck/immunologyInterleukin-12/biosynthesisInterleukin-12/immunologyMarmota/virologyHepatologíaChronic 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.American Society for MicrobiologyDadun. Depósito Académico Digital Universidad de Navarra20122012-10-0220092009-01-0120092009-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/23270reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/232702026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12 |
| title |
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12 |
| spellingShingle |
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12 Crettaz, J. (Julien)|||/items/684f8e38-df97-41b5-b96c-cc35728ac1cb Gene Therapy/methods Hepatitis B/veterinary Hepatitis B Virus, Woodchuck/immunology Interleukin-12/biosynthesis Interleukin-12/immunology Marmota/virology Hepatología |
| title_short |
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12 |
| title_full |
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12 |
| title_fullStr |
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12 |
| title_full_unstemmed |
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12 |
| title_sort |
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12 |
| dc.creator.none.fl_str_mv |
Crettaz, J. (Julien)|||/items/684f8e38-df97-41b5-b96c-cc35728ac1cb Otano, I. (Itziar)|||/items/d3cfe573-3aef-4c87-aa71-d45016c59b03 Ochoa, L. (Laura)|||/items/86ab2c6d-1b27-4130-8f8b-89170ec22907 Benito-Boíllos, A. (Alberto)|||/items/36f5562b-2392-4f6a-a747-a57b8b201069 Pañeda, A. (Astrid)|||/items/54b71a16-7b78-4c64-8961-b514fe1dd58e Aurrekoetxea, I. (Igor)|||/items/c109bf8d-7a3b-4b75-9cd6-05bc5e62331f Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91 Rodriguez-Madoz, J.R. (Juan Roberto)|||/items/9c21019b-aeba-4cdc-b78e-178a176da535 Astudillo, A. (Aurora)|||/items/28fc12b7-3005-43d9-858c-4d36c513e2e6 Kreppel, F. (Florian)|||/items/732e4916-a8eb-4c4d-bf2d-2e8864b53651 Kochanek, S. (Stefan)|||/items/ceca2d35-371f-41d8-8f5e-7d8687ba69b6 Ruiz, J. (Juan)|||/items/e71ee758-aef7-4ed6-b282-e483e9d9ba8e Menne, S. (Stephan)|||/items/0d784fc1-9119-4146-9256-8522282567c7 Prieto, J. (Jesús)|||/items/0d9c3dec-4a09-400d-8c83-23ece1096c71 González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac |
| author |
Crettaz, J. (Julien)|||/items/684f8e38-df97-41b5-b96c-cc35728ac1cb |
| author_facet |
Crettaz, J. (Julien)|||/items/684f8e38-df97-41b5-b96c-cc35728ac1cb Otano, I. (Itziar)|||/items/d3cfe573-3aef-4c87-aa71-d45016c59b03 Ochoa, L. (Laura)|||/items/86ab2c6d-1b27-4130-8f8b-89170ec22907 Benito-Boíllos, A. (Alberto)|||/items/36f5562b-2392-4f6a-a747-a57b8b201069 Pañeda, A. (Astrid)|||/items/54b71a16-7b78-4c64-8961-b514fe1dd58e Aurrekoetxea, I. (Igor)|||/items/c109bf8d-7a3b-4b75-9cd6-05bc5e62331f Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91 Rodriguez-Madoz, J.R. (Juan Roberto)|||/items/9c21019b-aeba-4cdc-b78e-178a176da535 Astudillo, A. (Aurora)|||/items/28fc12b7-3005-43d9-858c-4d36c513e2e6 Kreppel, F. (Florian)|||/items/732e4916-a8eb-4c4d-bf2d-2e8864b53651 Kochanek, S. (Stefan)|||/items/ceca2d35-371f-41d8-8f5e-7d8687ba69b6 Ruiz, J. (Juan)|||/items/e71ee758-aef7-4ed6-b282-e483e9d9ba8e Menne, S. (Stephan)|||/items/0d784fc1-9119-4146-9256-8522282567c7 Prieto, J. (Jesús)|||/items/0d9c3dec-4a09-400d-8c83-23ece1096c71 González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac |
| author_role |
author |
| author2 |
Otano, I. (Itziar)|||/items/d3cfe573-3aef-4c87-aa71-d45016c59b03 Ochoa, L. (Laura)|||/items/86ab2c6d-1b27-4130-8f8b-89170ec22907 Benito-Boíllos, A. (Alberto)|||/items/36f5562b-2392-4f6a-a747-a57b8b201069 Pañeda, A. (Astrid)|||/items/54b71a16-7b78-4c64-8961-b514fe1dd58e Aurrekoetxea, I. (Igor)|||/items/c109bf8d-7a3b-4b75-9cd6-05bc5e62331f Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91 Rodriguez-Madoz, J.R. (Juan Roberto)|||/items/9c21019b-aeba-4cdc-b78e-178a176da535 Astudillo, A. (Aurora)|||/items/28fc12b7-3005-43d9-858c-4d36c513e2e6 Kreppel, F. (Florian)|||/items/732e4916-a8eb-4c4d-bf2d-2e8864b53651 Kochanek, S. (Stefan)|||/items/ceca2d35-371f-41d8-8f5e-7d8687ba69b6 Ruiz, J. (Juan)|||/items/e71ee758-aef7-4ed6-b282-e483e9d9ba8e Menne, S. (Stephan)|||/items/0d784fc1-9119-4146-9256-8522282567c7 Prieto, J. (Jesús)|||/items/0d9c3dec-4a09-400d-8c83-23ece1096c71 González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac |
| author2_role |
author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Gene Therapy/methods Hepatitis B/veterinary Hepatitis B Virus, Woodchuck/immunology Interleukin-12/biosynthesis Interleukin-12/immunology Marmota/virology Hepatología |
| topic |
Gene Therapy/methods Hepatitis B/veterinary Hepatitis B Virus, Woodchuck/immunology Interleukin-12/biosynthesis Interleukin-12/immunology Marmota/virology Hepatología |
| description |
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. |
| publishDate |
2009 |
| dc.date.none.fl_str_mv |
2009 2009-01-01 2009 2009-01-01 2012 2012-10-02 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/23270 |
| url |
https://hdl.handle.net/10171/23270 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
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open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
American Society for Microbiology |
| publisher.none.fl_str_mv |
American Society for Microbiology |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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1869424168538210304 |
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15,300724 |