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Article first published online: 2 JUL 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 2, pages 474–483, August 2012
How to Cite
Otano, I., Suarez, L., Dotor, J., Gonzalez-Aparicio, M., Crettaz, J., Olagüe, C., Vales, A., Riezu, J. I., Larrea, E., Borras, F., Benito, A., Hernandez-Alcoceba, R., Menne, S., Prieto, J. and González-Aseguinolaza, G. (2012), Modulation of regulatory T-cell activity in combination with interleukin-12 increases hepatic tolerogenicity in woodchucks with chronic hepatitis B. Hepatology, 56: 474–483. doi: 10.1002/hep.25667
Potential conflict of interest: Dr. Dotor is an employee of Digna Biotech.
Supported by grants UTE project CIMA, Fundación Barrié de la Maza y Condesa de Fenosa, CIBERehd Instituto de Salud Carlos III, SAF 2006-03623 and SAF2009-08524 (Ministerio Educación y Ciencia/Ministerio de Ciencia e Innovación) to G.G-A. Itziar Otano received a grant from Ministerio de Ciencia e Innovación. Julien Crettaz received a grant from Gobierno de Navarra.
- Issue published online: 25 JUL 2012
- Article first published online: 2 JUL 2012
- Accepted manuscript online: 15 FEB 2012 04:11AM EST
- Manuscript Accepted: 9 FEB 2012
- Manuscript Received: 1 OCT 2011
Regulatory T cells (Treg) play a critical role in the modulation of immune responses to viral antigens in chronic viral hepatitis. Woodchucks (Marmota monax) infected with the woodchuck hepatitis virus (WHV) represent the best animal model for chronic hepatitis B virus (HBV) infection. Examination of intrahepatic and peripheral Treg in uninfected and WHV chronically infected woodchucks showed a significant increase of intrahepatic Treg numbers in chronically infected animals, whereas no differences were found in peripheral blood. In agreement with these data, higher expression levels of Forkhead box P3 (Foxp3), interleukin (IL)-10, transforming growth factor beta (TGF-β) were detected in the liver of chronic WHV carriers in comparison to uninfected animals. Furthermore, treatment of WHV-infected animals with an adenovirus encoding IL-12 failed to reduce viral load, a finding that was associated with lymphocyte unresponsiveness to IL-12 stimulation in vitro. We observed that TGF-β and Treg play a major role in the lack of lymphocyte response to IL-12 stimulation, as TGF-β inhibition and Treg depletion allowed recovery of T-cell responsiveness to this cytokine. Based on these results, woodchucks were treated with IL-12 in combination with a TGF-β inhibitory peptide or Treg depletion. However, no antiviral effect was achieved and, instead, an enhancement of the intrahepatic tolerogenic environment was observed. Conclusion: Our data show that TGF-β inhibition or Treg depletion had no added benefit over IL-12 therapy in chronic WHV infection. IL-12 immunostimulation induces a strong immunosuppressive reaction in the liver of chronic WHV carriers that counteracts the antiviral effect of the treatment. (HEPATOLOGY 2012)