Z Gastroenterol 2013; 51 - P_5_44
DOI: 10.1055/s-0032-1332158

Comprehensive analysis of NK cell phenotype and function during the initial phase of antiviral therapy: distinct roles of Ribavirin and Interferon alpha

AA Markova 1, B Bremer 1, U Mihm 2, V Schlaphoff 1, E Herrmann 2, K Stegmann 1, J Jaroszewicz 3, S Lunemann 1, J Grabowski 1, T Berg 4, S Zeuzem 2, MP Manns 1, M Cornberg 1, H Wedemeyer 1
  • 1Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hanover, Germany
  • 2JW Goethe University Hospital, Department of Medicine 1, Frankfurt a. M., Frankfurt/Main, Germany
  • 3Medical University of Bialystok, Department of Infectious Diseases and Hepatology, Bialystok, Poland
  • 4University of Leipzig, Department of Internal Medicine, Division of Gastroenterology and Rheumatology, Leipzig, Germany

Background: Ribavirin (RBV) remains part of several interferon-free treatment strategies even though the mechanisms of action of RBV are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNα) has recently been shown to alter phenotype and function of NK cells which correlates with control of HCV infection. However, the effects of ribavirin alone or in combination with IFNα on peripheral NK cells are unknown. The aim of this study was to investigate NK cells during RBV monotherapy, PEG-IFNα monotherapy or combination treatment.

Methods: Extensive ex-vivo phenotyping of NK cells during treatment was performed in 30 individuals with chronic hepatitis C infection at 10 time-points (including day 2 of treatment). Patients were treated for 6 weeks with RBV monotherapy (n=11, group A), placebo (Group B, n=13) or PEG-IFNα-2a alone (group C n=6) followed by standard PEG-IFNα-2a/Ribavirin combination therapy. Additionally functionality of NK cells during therapy was assessed by degranulation (CD107 expression) and cytokine production. PBMC of healthy controls were stimulated with RBV and PEG-IFNα and co-cultured with K562 or Huh7 cells.

Results: Ribavirin monotherapy had no obvious effects on expression levels of CD56, CD57, NKG2A, NKG2C, NKG2D, CD81, NKp30 or NKp46. In contrast, PEG-IFNα-2a therapy was associated with a relative increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype. NK cells functionality was also enhanced by treatment with PEG-IFNα. In vitro, PEG-IFNα but not RBV stimulation of NK cells increased degranulation as well as IFN-γ and TNF expression after co-culture with target cells, which was not altered by additional RBV co-stimulation.

Conclusions: Antiviral activities of RBV alone or in combination with PEG-IFNα cannot be linked to obvious phenotypical or functional changes of NK cells. PEG-IFNα activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.