Skip to main content
SpringerLink
Log in

Relationship Between Response to Interferon-α and Function of Peripheral Blood Mononuclear Cells in Chronic Hepatitis C Patients

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The factors responsible for the low response of chronic hepatitis C patients to interferon-α treatment are not fully understood, although it is known that interferon requires an efficient host immune response to achieve viral clearance. This study was designed to test the hypothesis that hepatitis C virus infection is associated with functional impairment of peripheral blood mononuclear cells, which influence the response to interferon. The proliferative and apoptotic responses of peripheral blood mononuclear cells and purified T cells stimulated with polyclonal mitogenic signals were assessed in 35 chronic hepatitis C patients and 30 healthy controls. Patients were divided into responders and nonresponders according to their sustained response to a course of alpha-interferon-α (3 MU three times weekly for 12 months). The proliferative response to polyclonal mitogens (PHA, TPA) was significantly decreased in nonresponders compared to responders and controls. The defective response was partially normalized by the exogenous addition of interleukin-2 or interleukin-4, and cannot be ascribed to increased apoptosis. Interestingly, the proliferative response of enriched T cells to the same signals was normal. In conclusion, the clinical response to interferon-α defines two different patterns of proliferation by mononuclear cells in chronic hepatitis C patients. This suggests that an alteration of the immune system in these patients may underlie their inadequate response to antiviral therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MM, Cort S, Albrecht JK: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 339:1485–1492, 1998

    Google Scholar 

  2. Lu M, Wiese M, Funsch B, Roggendorf M: Different susceptibilities of genetic variants of hepatitis C virus (HCV) to interferon (IFN). Arch Virol 142:588, 1997

    Google Scholar 

  3. Davis GL, Lau JY: Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 26(suppl 1):122–127, 1997

    Google Scholar 

  4. Furusyo N, Hayashi J, Ohmiya M, Sawayama Y, Kawakami Y, Ariyama I, Kinukawa N, Kashiwagi S: Differences between interferon-alpha and-beta treatment for patients with chronic hepatitis C virus infection. Dig Dis Sci 44:608–617, 1999

    Google Scholar 

  5. Herbert T: New insights into the mechanisms of interferon alfa: An immunoregulatory and anti-inflammatory cytokine. Gastroenterology 112:1017–1021, 1997

    Google Scholar 

  6. Hanley JP, Haydon GH: The biology of interferon-alpha and the clinical significance of anti-interferon antibodies. Leuk Lymphoma 29:257–268, 1998

    Google Scholar 

  7. Jung MC, Diepolder HM, Pape GR: T cell recognition of hepatitis B and C viral antigens. Eur J Clin Invest 24:641–650, 1994

    Google Scholar 

  8. Lohr H, Fleischer B, Michel G, Rossol S, Hess G, Meyer zum Buschenfelde KH, Manns M: Hepatitis C virus antibody secretion in vitro by peripheral blood lymphocytes. J Hepatol 14:112–117, 1992

    Google Scholar 

  9. Shirai M, Okada H, Nishioka M, Akatsufa T, Wychowski C, Houghten R, Pendleton CD, Feinstone SM, Berzofsky JA: An epitope in hepatitis C virus core region recognized by cytotoxic T cells in mice and humans. J Virol 68:3334–3342, 1994

    Google Scholar 

  10. Alter HJ: To C or not to C: These are the questions. Blood 85:1681–1695, 1995

    Google Scholar 

  11. Cacciarelli TV, Martinez OM, Gish RG, Villanueva JC, Krahs SM: Immunoregulatory cytokines in chronic hepatitis C virus infection: Pre-and posttreatment with interferon alpha. Hepatology 24:6–9, 1996

    Google Scholar 

  12. Kishihara Y, Hayashi J, Yoshimura E, et al: IL-1? and TNF-? produced by peripheral blood mononuclear cells before and during interferon therapy in patients with chronic hepatitis C. Dig Dis Sci 41:315–321, 1996

    Google Scholar 

  13. Bouffard P, Hayashi PH, Acevedo R, et al: Hepatitis C virus is detected in a monocyte/macrophage subpopulation of peripheral blood mononuclear cells of infected patients. J Infect Dis 166:1276–1280, 1992

    Google Scholar 

  14. Shapiro S, Gershtein V, Elias N, et al: mRNA cytokine profile in peripheral blood cells from chronic hepatitis C virus (HCV)-infected patients: Effects of interferon-alpha (IFN-alpha) treatment. Clin Exp Immunol 114:55–60, 1998

    Google Scholar 

  15. Martin J, Quiroga JA, Navas S, Pardo M, Carreno V: Modulation by biologic response modifiers of hepatitis C virus antigen-independent cytokine secretion in blood mononuclear cells Cytokine 11:267–273, 1999

    Google Scholar 

  16. Scheuer P: Clasification of chronic viral hepatitis: A need for reassessment. J Hepatol 13:372–374, 1991

    Google Scholar 

  17. Roman L-I, Manzano L, De-La-Hera A, Abreu L, Rossi I, Alvarez-Mon M.: Expanded CD4+CD45RO+ phenotype and defective proliferative response in T lymphocytes from patients with Crohn's disease. Gastroenterology 110:1008–1019, 1996

    Google Scholar 

  18. Nicoletti Y, Migliorati G, Pagliacci MC, Grignani F, Riccardi C: A rapid and single method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139:271–279, 1991

    Google Scholar 

  19. Quinti I, Hassan NF, El Salman D, Shazaby M, El Zimatty D, Monier MK, Arthur RR: Hepatitis C virus-specific B cell activation: IgG and IgM detection in acute and chronic hepatitis C. J.Hepatol. 23:640–647, 1995

    Google Scholar 

  20. Rice CM, Walker CM: Hepatitis C virus-specific T lymphocyte responses. Curr Opin Immunol 7:532–538, 1995

    Google Scholar 

  21. Koziel MJ: Immunology of viral hepatitis. Am J Med 100:98–109, 1996

    Google Scholar 

  22. Cerny A, Chisari FV: Pathogenesis of chronic hepatitis C: Immunological features of hepatitis injury and viral persistence. Hepatology 30:595–601, 1999

    Google Scholar 

  23. Molto L, Alvarez-Mon M, Carballido J, Manzano L, Guillen C, Prieto A, Olivier C, Rodriguez-Zapata M: Intracavitary prophylactic treatment with interferon alpha 2b of patients with superficial bladder cancer is associated with a systemic T cell activation. Br J Cancer 70:1247–1251, 1994

    Google Scholar 

  24. Molto L, Carballido J, Manzano L, Martinez-Martin B, Esquivel F, Chafer J, Olivier C, Alvarez-Mon M: Immunological changes in peripheral blood mononuclear cells of patients with metastatic renal cell carcinoma after low doses of subcutaneous immunotherapy with IFN-alpha-2b and IL-2. J Immunother 22:260–267, 1999

    Google Scholar 

  25. Reyes E, Carballido J, Manzano L, Molto L, Olivier C, Alvarez-Mon M: The association between CD2+ peripheral blood lymphocyte subsets and the relapse of bladder cancer in prophylactically BCG-treated patients. Br J Cancer 79:1162–1167, 1999

    Google Scholar 

  26. Adinolfi LE, Andreana A, Utili R, Zampino R, Ragone E, Ruggiero G: HCV RNA levels in serum, liver, and peripheral blood mononuclear cells of chronic hepatitis C patients and their relationship to liver injury. Am J Gastroenterol 93:2162–2166, 1998

    Google Scholar 

  27. Pozzato G, Morreti M, Crovatto M, Modolo ML, Gennari D, Saurini G: Lymphocyte subsets in HCV-positive chronic liver disease. Immunol Today 15, 1994

  28. Wejstal R, Norkrans G, Lenkei R, Weiland O, Schuarcz R, Fryden A: Peripheral blood lymphocyte subsets in patients with chronic hepatitis C-effects of interferon treatment. Liver 12:161–167, 1992

    Google Scholar 

  29. Schupper H, Hayashi P, Scheffel J, Aceituno S, Paglieroni T, Holland PV, Zeldis JB: Peripheral-blood mononuclear cell responses to recombinant hepatitis C virus antigens in patients with chronic hepatitis C. Hepatology 18:1055–1060, 1993

    Google Scholar 

  30. Garcia-Suarez J, Prieto A, Manzano L, Reyes E, Molto L, Alvarez-Mon M: T lymphocytes from autoimmune thrombocytopenic purpura show a defective activation and proliferation after cytoplasmic membrane and intracytoplasmic mitogenic signals. Am J Hematol 44:1–8, 1993

    Google Scholar 

  31. Paul WE, Seder RA: Limphocyte response and cytokines. Cell 76:241–251, 1994

    Google Scholar 

  32. Hernandez-Fuentes MP, Reyes E, Prieto A, Zea A, Villa L, Sanchez-Atric A, Esquivel F, Alvarez-Mon M.: Defective proliferative response of T lymphocytes from patients with inactive systemic lupus erythematosus. J Rheumatol 26:1518–1526, 1999

    Google Scholar 

  33. Mor F, Cohen IR: IL-2 rescues antigen-specific T cells from radiation or dexamethasone-induced apoptosis. Correlation with induction of Bcl-2-. J Immunol 156:515–522, 1996

    Google Scholar 

  34. Molto L, Carballido J, Manzano L, Reyes E, Olivier C, Alvarez-Mon M.: Prophylactic intracavitary treatment with interferon alpha increases interferon gamma production by peripheral blood mononuclear cells in patients with superficial transitional cell carcinoma of the bladder. Br J Cancer 75:1849–1853, 1997

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Hospital Principe de Asturias, Madrid, Spain

    Fátima Esquivel, Agustín Albillos, Flavio Carrión, Alfredo Prieto, Eduardo Reyes & Belén Martínez-Martín

  2. Gastroenterology Service, Hospital Ramón y Cajal, Madrid, Spain

    Agustín Albillos

  3. Gastroenterology Service, Clínica Puerta de Hierro, University of Alcalá, Madrid, Spain

    José Luis Calleja & Guillermo Cacho

  4. Department of Medicine, Hospital Principe de Asturias, Madrid, Spain. Immune System Diseases and Oncology Service, Hospital Principe de Asturias, Madrid, Spain

    Melchor Alvarez-Mon

Authors
  1. Fátima Esquivel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Agustín Albillos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Flavio Carrión
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alfredo Prieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eduardo Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Belén Martínez-Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. José Luis Calleja
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guillermo Cacho
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Melchor Alvarez-Mon
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Esquivel, F., Albillos, A., Carrión, F. et al. Relationship Between Response to Interferon-α and Function of Peripheral Blood Mononuclear Cells in Chronic Hepatitis C Patients. Dig Dis Sci 47, 2154–2162 (2002). https://doi.org/10.1023/A:1020162605925

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020162605925

Search

Navigation