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Vol. 53, No. 3, 2010
Issue release date: April 2010
Section title: Original Paper
Intervirology 2010;53:154–160
(DOI:10.1159/000274976)

Relationship between Regulatory T Cells and the Combination of Pegylated Interferon and Ribavirin for the Treatment of Chronic Hepatitis Type C

Akiyama M. · Ichikawa T. · Miyaaki H. · Motoyoshi Y. · Takeshita S. · Ozawa E. · Miuma S. · Shibata H. · Taura N. · Nakao K.
Department of Gastroenterology and Hepatology, Graduate School of Biochemical Science, Nagasaki University, Nagasaki, Japan
email Corresponding Author

Abstract

Background/Aim: The frequency of regulatory T cells (Tregs) may be related to persistent hepatitis C virus (HCV) infection. We studied the alteration of the Treg ratio in peripheral blood mononuclear cells (PBMCs) from chronic hepatitis C patients during combination therapy compared with the Treg ratio in liver-infiltrating lymphocytes (LILs) before therapy. Method: The study group consisted of 20 patients who were treatment-naive and had high virus titers of HCV genotype 1. Blood samples were collected prior to treatment and at several time points during treatment. All patients received a liver biopsy prior to treatment. Forkhead box P3 (Foxp3)+, CD3+, CD4+ and CD8+ cells in PBMCs and LILs were stained by specific antibodies. Results: Ten patients had a sustained virological response (SVR), and 10 patients were non-responders. The SVR group had a significant increase in the Foxp3+/CD4+ ratio in PBMCs at 8 and 12 weeks as well as a significant decrease in the Foxp3+/CD4+ ratio and increase in the CD8+/Foxp3+ ratio in LILs. Conclusion: The evaluation of Tregs, a potentially significant factor for persistent HCV infection, in LILs prior to treatment and in PBMCs during treatment could predict the result of combination therapy.

© 2010 S. Karger AG, Basel


  

Key Words

  • Chronic hepatitis C
  • Hepatitis C virus
  • Interferon
  • Ribavirin
  • Regulatory T cells

References

  1. Rakela J, Vargas HE: Hepatitis C: magnitude of the problem. Liver Transpl 2002;8:3–6.

    External Resources

  2. Strader DB, Wright T, Thomas DL, Seeff LB: Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147–1171.
  3. Hoofnagle JH: Hepatitis C: the clinical spectrum of disease. Hepatology 1997;26:15–20.

    External Resources

  4. Gremion C, Cerny A: Hepatitis C virus and the immune system: a concise review. Rev Med Virol 2005;15:235–268.
  5. Timm J, Roggendorf M: Sequence diversity of hepatitis C virus: implications for immune control and therapy. World J Gastroenterol 2007;13:4808–4817.
  6. Lohr HF, Gerken G, Roth M, Weyer S, Schlaak JF, Meyer zum Buschenfelde KH: The cellular immune responses induced in the follow-up of interferon-α-treated patients with chronic hepatitis C may determine the therapy outcome. J Hepatol 1998;29:524–532.
  7. Cerny A, Chisari FV: Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology 1999;30:595–601.
  8. Rehermann B, Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005;5:215–229.
  9. Lauer GM, Barnes E, Lucas M, Timm J, Ouchi K, Kim AY, Day CL, Robbins GK, Casson DR, Reiser M, Dusheiko G, Allen TM, Chung RT, Walker BD, Klenerman, P: High-resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology 2004;127:924–936.
  10. Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH: Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T-helper cells. J Exp Med 2002;196:255–260.
  11. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD, Isaacs JD, Lechler RI: Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood 2001;98:2736–2744.
  12. O’Garra A, Vieira P: Regulatory T cells and mechanisms of immune system control. Nat Med 2004;10:801–805.
  13. Sugimoto K, Ikeda F, Stadanlick J, Nunes FA, Alter HJ, Chang KM: Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 2003;38:1437–1448.
  14. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, Nelson DR: An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection. Hepatology 2004;40:1062–1071.
  15. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, Blum HE, von Weizsacker F, Thimme R: T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol 2005;79:7860–7867.
  16. Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, Alexander GJ: Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005;79:7852–7859.
  17. Miyaaki H, Zhou H, Ichikawa T, Nakao K, Shibata H, Takeshita S, Akiyama M, Ozawa E, Miuma S, Eguchi K: Study of liver-targeted regulatory T cells in hepatitis B and C virus in chronically infected patients. Liver Int 2009;29:702–707.
  18. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, Janssen HL: Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 2005;41:771–778.
  19. Longhi MS, Ma Y, Mitry RR, Bogdanos DP, Heneghan M, Cheeseman P, Mieli-Vergani G, Vergani D: Effect of CD4+CD25+ regulatory T cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun 2005;25:63–71.
  20. Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, Chuang YH, Nakamura T, Saito S, Shimoda S, Tanaka A, Bowlus CL, Takano Y, Ansari AA, Coppel RL, Gershwin ME: Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006;43:729–737.
  21. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–965.
  22. Almasio PL, Cottone C, D’Angelo F: Pegylated interferon therapy in chronic hepatitis C: lights and shadows of an innovative treatment. Dig Liver Dis 2007;39(suppl 1):88–95.

    External Resources

  23. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS: Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 1998;282:103–107.
  24. Pilli M, Zerbini A, Penna A, Orlandini A, Lukasiewicz E, Pawlotsky JM, Zeuzem S, Schalm SW, von Wagner M, Germanidis G, Lurie Y, Esteban JI, Haagmans BL, Hezode C, Lagging M, Negro F, Homburger Y, Neumann AU, Ferrari C, Missale G: HCV-specific T-cell response in relation to viral kinetics and treatment outcome (DITTO-HCV Project). Gastroenterology 2007;133:1132–1143.
  25. Herrmann E, Lee JH, Marinos G, Modi M, Zeuzem S: Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology 2003;37:1351–1358.
  26. Layden-Almer JE, Cotler SJ, Layden TJ: Viral kinetics in the treatment of chronic hepatitis C. J Viral Hepat 2006;13:499–504.
  27. Dahari H, Ribeiro RM, Perelson AS: Triphasic decline of hepatitis C virus RNA during antiviral therapy. Hepatology 2007;46:16–21.
  28. Ebinuma H, Nakamoto N, Li Y, Price DA, Gostick E, Levine BL, Tobias J, Kwok WW, Chang KM: Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J Virol 2008;82:5043–5053.
  29. Ward SM, Fox BC, Brown PJ, Worthington J, Fox SB, Chapman RW, Fleming KA, Banham AH, Klenerman P: Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J Hepatol 2007;47:316–324.
  30. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G: Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J Exp Med 2001;193:1303–1310.
  31. Levings MK, Sangregorio R, Roncarolo MG: Human CD25+CD4+ T-regulatory cells suppress naive and memory T-cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193:1295–1302.
  32. Taura N, Ichikawa T, Hamasaki K, Nakao K, Nishimura D, Goto T, Fukuta M, Kawashimo H, Fujimoto M, Kusumoto K, Motoyoshi Y, Shibata H, Abiru N, Yamasaki H, Eguchi K: Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. Am J Gastroenterol 2006;101:2752–2759.
  33. Payan C, Pivert A, Morand P, Fafi-Kremer S, Carrat F, Pol S, Cacoub P, Perronne C, Lunel F: Rapid and early virological response to chronic hepatitis C treatment with IFNα2b or PEG-IFNα2b plus ribavirin in HIV/HCV co-infected patients. Gut 2007;56:1111–1116.
  34. Manigold T, Shin EC, Mizukoshi E, Mihalik K, Murthy KK, Rice CM, Piccirillo CA, Rehermann B: Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 2006;107:4424–4432.
  35. Stoop JN, van der Molen RG, Kuipers EJ, Kusters JG, Janssen HL: Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B. Virology 2007;361:141–148.
  36. Landau DA, Rosenzwajg M, Saadoun D, Trebeden-Negre H, Klatzmann D, Cacoub P: Correlation of clinical and virologic responses to antiviral treatment and regulatory T-cell evolution in patients with hepatitis C virus-induced mixed cryoglobulinemia vasculitis. Arthritis Rheum 2008;58:2897–2907.

  

Author Contacts

Motohisa Akiyama
First Department of Internal Medicine, Unit of Translational Medicine
Graduate School of Biochemical Science, Nagasaki University
1-7-1 Sakamoto, Nagasaki 852-8501 (Japan)
Tel. +81 95 819 7260, Fax +81 95 849 7270, E-Mail moakiyama-gi@umin.ac.jp

  

Article Information

Received: March 3, 2009
Accepted after revision: November 2, 2009
Published online: January 13, 2010
Number of Print Pages : 7
Number of Figures : 5, Number of Tables : 1, Number of References : 36

  

Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 53, No. 3, Year 2010 (Cover Date: April 2010)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


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References

  1. Rakela J, Vargas HE: Hepatitis C: magnitude of the problem. Liver Transpl 2002;8:3–6.

    External Resources

  2. Strader DB, Wright T, Thomas DL, Seeff LB: Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147–1171.
  3. Hoofnagle JH: Hepatitis C: the clinical spectrum of disease. Hepatology 1997;26:15–20.

    External Resources

  4. Gremion C, Cerny A: Hepatitis C virus and the immune system: a concise review. Rev Med Virol 2005;15:235–268.
  5. Timm J, Roggendorf M: Sequence diversity of hepatitis C virus: implications for immune control and therapy. World J Gastroenterol 2007;13:4808–4817.
  6. Lohr HF, Gerken G, Roth M, Weyer S, Schlaak JF, Meyer zum Buschenfelde KH: The cellular immune responses induced in the follow-up of interferon-α-treated patients with chronic hepatitis C may determine the therapy outcome. J Hepatol 1998;29:524–532.
  7. Cerny A, Chisari FV: Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology 1999;30:595–601.
  8. Rehermann B, Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005;5:215–229.
  9. Lauer GM, Barnes E, Lucas M, Timm J, Ouchi K, Kim AY, Day CL, Robbins GK, Casson DR, Reiser M, Dusheiko G, Allen TM, Chung RT, Walker BD, Klenerman, P: High-resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology 2004;127:924–936.
  10. Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH: Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T-helper cells. J Exp Med 2002;196:255–260.
  11. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD, Isaacs JD, Lechler RI: Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood 2001;98:2736–2744.
  12. O’Garra A, Vieira P: Regulatory T cells and mechanisms of immune system control. Nat Med 2004;10:801–805.
  13. Sugimoto K, Ikeda F, Stadanlick J, Nunes FA, Alter HJ, Chang KM: Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 2003;38:1437–1448.
  14. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C, Nelson DR: An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection. Hepatology 2004;40:1062–1071.
  15. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, Blum HE, von Weizsacker F, Thimme R: T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol 2005;79:7860–7867.
  16. Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, Alexander GJ: Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005;79:7852–7859.
  17. Miyaaki H, Zhou H, Ichikawa T, Nakao K, Shibata H, Takeshita S, Akiyama M, Ozawa E, Miuma S, Eguchi K: Study of liver-targeted regulatory T cells in hepatitis B and C virus in chronically infected patients. Liver Int 2009;29:702–707.
  18. Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, Janssen HL: Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 2005;41:771–778.
  19. Longhi MS, Ma Y, Mitry RR, Bogdanos DP, Heneghan M, Cheeseman P, Mieli-Vergani G, Vergani D: Effect of CD4+CD25+ regulatory T cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun 2005;25:63–71.
  20. Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, Chuang YH, Nakamura T, Saito S, Shimoda S, Tanaka A, Bowlus CL, Takano Y, Ansari AA, Coppel RL, Gershwin ME: Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006;43:729–737.
  21. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958–965.
  22. Almasio PL, Cottone C, D’Angelo F: Pegylated interferon therapy in chronic hepatitis C: lights and shadows of an innovative treatment. Dig Liver Dis 2007;39(suppl 1):88–95.

    External Resources

  23. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS: Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 1998;282:103–107.
  24. Pilli M, Zerbini A, Penna A, Orlandini A, Lukasiewicz E, Pawlotsky JM, Zeuzem S, Schalm SW, von Wagner M, Germanidis G, Lurie Y, Esteban JI, Haagmans BL, Hezode C, Lagging M, Negro F, Homburger Y, Neumann AU, Ferrari C, Missale G: HCV-specific T-cell response in relation to viral kinetics and treatment outcome (DITTO-HCV Project). Gastroenterology 2007;133:1132–1143.
  25. Herrmann E, Lee JH, Marinos G, Modi M, Zeuzem S: Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology 2003;37:1351–1358.
  26. Layden-Almer JE, Cotler SJ, Layden TJ: Viral kinetics in the treatment of chronic hepatitis C. J Viral Hepat 2006;13:499–504.
  27. Dahari H, Ribeiro RM, Perelson AS: Triphasic decline of hepatitis C virus RNA during antiviral therapy. Hepatology 2007;46:16–21.
  28. Ebinuma H, Nakamoto N, Li Y, Price DA, Gostick E, Levine BL, Tobias J, Kwok WW, Chang KM: Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J Virol 2008;82:5043–5053.
  29. Ward SM, Fox BC, Brown PJ, Worthington J, Fox SB, Chapman RW, Fleming KA, Banham AH, Klenerman P: Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J Hepatol 2007;47:316–324.
  30. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G: Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J Exp Med 2001;193:1303–1310.
  31. Levings MK, Sangregorio R, Roncarolo MG: Human CD25+CD4+ T-regulatory cells suppress naive and memory T-cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193:1295–1302.
  32. Taura N, Ichikawa T, Hamasaki K, Nakao K, Nishimura D, Goto T, Fukuta M, Kawashimo H, Fujimoto M, Kusumoto K, Motoyoshi Y, Shibata H, Abiru N, Yamasaki H, Eguchi K: Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. Am J Gastroenterol 2006;101:2752–2759.
  33. Payan C, Pivert A, Morand P, Fafi-Kremer S, Carrat F, Pol S, Cacoub P, Perronne C, Lunel F: Rapid and early virological response to chronic hepatitis C treatment with IFNα2b or PEG-IFNα2b plus ribavirin in HIV/HCV co-infected patients. Gut 2007;56:1111–1116.
  34. Manigold T, Shin EC, Mizukoshi E, Mihalik K, Murthy KK, Rice CM, Piccirillo CA, Rehermann B: Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 2006;107:4424–4432.
  35. Stoop JN, van der Molen RG, Kuipers EJ, Kusters JG, Janssen HL: Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B. Virology 2007;361:141–148.
  36. Landau DA, Rosenzwajg M, Saadoun D, Trebeden-Negre H, Klatzmann D, Cacoub P: Correlation of clinical and virologic responses to antiviral treatment and regulatory T-cell evolution in patients with hepatitis C virus-induced mixed cryoglobulinemia vasculitis. Arthritis Rheum 2008;58:2897–2907.