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Med Princ Pract 2011;20:345–349

T Helper Type 1/T Helper Type 17-Related Cytokines in Chronic Hepatitis C Patients before and after Interferon and Ribavirin Therapy

Fathy A.a · Ahmed A.S.a · Metwally L.b · Hassan A.c
Departments of aClinical Pathology, bMicrobiology and cTropical Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
email Corresponding Author

 goto top of outline Key Words

  • Cytokine
  • Interferon-γ
  • Interleukin-17
  • Hepatitic C virus
  • Interferon therapy
  • Ribavirin therapy

 goto top of outline Abstract

Objective: This study examined the T helper (Th) 1/Th17-related cytokines, interferon (IFN)-γ and interleukin (IL)-17 in the serum of biopsy-proven chronic hepatitis C patients before and after IFN and ribavirin therapy to address whether or not viral clearance is related to Th1/Th17 cytokines. Subjects and Methods: The serum levels of IFN-γ and IL-17 were assayed by ELISA on 26 patients with chronic hepatitic C virus (HCV) infection before the start and 3 months after treatment with pegylated IFN-α plus ribavarin and compared with sera from 15 normal control subjects. Results: IFN-γ and IL-17 levels are higher in the serum of patients with chronic hepatitis than in normal controls and these elevated levels were not directly correlated (r = –0.01, p = 0.96 for IFN-γ and r = –0.08, p = 0.66 for IL-17) to the viremic state of the HCV infection. In contrast to IL-17, IFN-γ showed significant reduction after 12 weeks of treatment with pegylated IFN plus ribavirin. However, IFN-γ and IL-17 serum levels were not significantly (p = 0.19 and = 0.70, respectively) different among responders and nonresponders for pegylated IFN plus ribavirin therapy. Conclusion: Our findings suggest that the combined treatment with pegylated IFN-α and ribavirin downmodulates the secretion of key cytokine IFN-γ as early as 12 weeks after treatment in infected patients. These findings could encourage new exciting possibilities for immune-based interventions with the aim of restoring functional antiviral T cell responses combined with improved viral clearance.

Copyright © 2011 S. Karger AG, Basel

 goto top of outline References
  1. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL: Two types of murine helper T cell clone. 1. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986;136:2348–2357.
  2. Harrington LE, Mangan PR, Weaver CT: Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 2006;18:349–356.
  3. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R: Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007;8:950–957.
  4. Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK: Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 2001;194:519–527.
  5. Higgins SC, Jarnicki AG, Lavelle EC, Mills KH: TLR4 mediates vaccine-induced protective cellular immunity to Bordetella pertussis: role of IL-17-producing T cells. J Immunol 2006;177:7980–7989.
  6. Maek-A-Nantawat W, Buranapraditkun S, Klaewsongkram J, Ruxrungthum K: Increased interleukin-17 production both in helper T cell subset Th17 and CD4-negative T cells in human immunodeficiency virus infection. Viral Immunol 2007;20:66–75.
  7. Molesworth-Kenyon SJ, Yin R, Oakes JE, Lausch RN: IL-17 receptor signaling influences virus-induced corneal inflammation. J Leukoc Biol 2008;83:401–408.
  8. Hashimoto K, Durbin JE, Zhou W, Collins RD, Ho SB, Kolls JK, Dubin PJ, Sheller JR, Goleniewska K, O’Neal JF, Olson SJ, Mitchell D, Graham BS, Peebles RS Jr: Respiratory syncytial virus infection in the absence of STAT 1 results in airway dysfunction, airway mucus, and augmented IL-17 levels. J Allergy Clin Immunol 2005;116:550–557.
  9. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Filì L, Ferri S, Frosali F, Giudici F, Romagnani P, Parronchi P, Tonelli F, Maggi E, Romagnani S: Phenotypic and functional features of human Th17 cells. J Exp Med 2007;204:1849–1861.
  10. World Health Organization: Global surveillance and control of hepatitis C. Report of a WHO consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 1999;6:35–47.
  11. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H Jr, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM: Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346–355.
  12. Huang SH, Frydas S, Conti P, Kempuraj D, Barbacane RC, Grilli A, Boucher W, Letourneau R, Papadopoulou N, Donelan J, Madhappan B, Theoharides TC, De Lutiis MA, Riccioni G, Sabatino G: Interleukin-17: a revisited study. Int J Immunopathol Pharmacol 2004;17:1–4.
  13. Bowen DG, Walker CM: Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 2005;436:946–952.
  14. Cramp ME, Rossol S, Chokshi S, Carucci P, Williams R, Naoumov N: Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology 2000;118:346–355.
  15. Rowan AG, Fletcher JM, Ryan EJ, Moran B, Hegarty JE, Farrelly CO, Mill KH: Hepatitis C virus-specific Th17 cells are suppressed by virus-induced TGF-β. J Immunol 2008;5:4485–4494.
  16. Ishak KG: Chronic hepatitis: morphology and nomenclature. Mod Pathol 1994;7:690–693.
  17. Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, Huber C: Serum levels of cytokines in chronic liver diseases. Gastroenterology 1992;103:264–274.
  18. MacDonald AJ, Duffy M, Brady MT, McKiernan S, Hall W, Hegarty J, Curry M, Mills KH: CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J Infect Dis 2002;185:720–727.
  19. Neumann-Haefelin C, Blum HE, Chisari FV, Thimme R: T cell response in hepatitis C virus infection. J Clin Virol 2005;32:75–85.
  20. Wherry EJ, Barber DL, Kaech SM, Blattman JN, Ahmed R: Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc Natl Acad Sci USA 2004;101:16004–16009.
  21. Kanda T, Steele R, Ray R, Ray RB: Inhibition of intrahepatic gamma interferon production by hepatitis C virus nonstructural protein 5A in transgenic mice. J Virol 2009;83:8463–8469.
  22. Brady MT, MacDonald AJ, Rowan AG, Mills KH: Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes. Eur J Immunol 2003;33:3448–3457.
  23. Hou W, Kang HS, Kim BS: Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. J Exp Med 2009;2:313–328.

    External Resources

  24. Oyoshi MK, Elkhal A, Kumar L, Scott JE, Koduru S, He R, Leung DY, Howell MD, Oettgen HC, Murphy GF, Geha RS: Vaccinia virus inoculation in sites of allergic skin inflammation elicits a vigorous cutaneous IL-17 response. Proc Natl Acad Sci USA 2009;106:14954–14959.
  25. Inglot M, Gładysz A, Rymer W, Molin I, Zalewska M, Machaj A: Cytokine assessment in untreated hepatitis C virus infected patients and during interferon alpha +ribavirine therapy. Wiad Lek 2008;61:13–18.

    External Resources

  26. Ge J, Wang K, Meng QH, Qi ZX, Meng FL, Fan YC: Implication of Th17 and Th1 cells in patients with chronic active hepatitis B. J Clin Immunol 2010;30:60–67.
  27. R-Viso AT, Duarte MI, Pagliari C, Fernandes ER, Brasil RA, Benard G, Romano CC, Ogusuku S, Cavalheiro NP, Melo CE, Barone AA: Tissue and serum immune response in chronic hepatitis C with mild histological lesions. Mem Inst Oswaldo Cruz 2010;105:25–32.
  28. Wang X, Chen M, Wandinger KP, Williams G, Dhib-Jalbut S: IFN-β-1b inhibits IL-12 production in peripheral blood mononuclear cells in an IL-10-dependent mechanism: relevance to IFN-beta-1b therapeutic effects in multiple sclerosis. J Immunol 2000;165:548–557.
  29. Perrella A, Sbreglia C, Atripaldi L, Esposito C, D’Antonio A, Perrella O: Rapid virological response in peripheral blood mononuclear cells with an increase of hepatitis C virus-specific interferon-gamma production predisposes to sustained virological response in patients with chronic hepatitis C genotype 1 undergoing treatment with pegylated-interferon alpha 2a plus ribavirin. Scand J Gastroenterol 2010;45:250–255.
  30. Jason J, Archibald LK, Nwanyanwu OC, Byrd MG, Kazembe PN, Dobbie H, Jarvis WR: Comparison of serum and cell-specific cytokines in humans. Clin Diagn Lab Immunol 2001;8:1097–1103.
  31. Romagnani S: Human Th17 cells. Arthritis Res Ther 2008;10:206.

 goto top of outline Author Contacts

Amal Sayed Ahmed, MD
Faculty of Medicine, Suez Canal University
41522 Ismailia (Egypt)
Tel. +20 10 170 3125, Fax +20 64 337 8524

 goto top of outline Article Information

Received: May 12, 2010
Accepted: November 9, 2010
Published online: May 11, 2011
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 1, Number of References : 31

 goto top of outline Publication Details

Medical Principles and Practice (International Journal of the Kuwait University Health Sciences Centre)

Vol. 20, No. 4, Year 2011 (Cover Date: May 2011)

Journal Editor: Owunwanne A. (Kuwait), Benov L. (Kuwait)
ISSN: 1011-7571 (Print), eISSN: 1423-0151 (Online)

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