Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-α and ribavirin therapy for chronic hepatitis C patients
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Abstract
Background
For the treatment of chronic hepatitis C, a combination of pegylated interferon-α (PEG-IFNα) and ribavirin has been widely used as a standard of care. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. Our aim was to elucidate whether or not the frequency or function of blood cells is related to the outcome of the therapy.
Methods
Sixty-seven chronic hepatitis C patients with high viral load of HCV genotype 1 infection who underwent 48 weeks of PEG-IFNα2b and ribavirin therapy were examined. During the treatment, frequencies of myeloid or plasmacytoid dendritic cells, Th1, Th2 cells, NK cells, and regulatory T cells were phenotypically determined.
Results
Among the patients enrolled, 29 showed a sustained virological response (SVR), 18 a transient response (TR) and 17 no response (NR). The clinical and immunological markers were compared between the SVR and non-SVR patients, including TR and NR. Based on clinical, histological, immunological parameters, and cumulative dosage of PEG-IFNα2b and ribavirin, multivariate analyses revealed that higher platelet counts and higher regulatory T cell frequency at week 12 are indicative of SVR. Even in patients who attained complete early virological response at week 12, multivariate analyses disclosed that higher platelet counts and higher plasmacytoid dendritic cell frequency are indicative of SVR.
Conclusions
In PEG-IFNα and ribavirin combination therapy for chronic hepatitis C patients, the increments of regulatory T cells and plasmacytoid dendritic cell frequency are independently related to favorable virological response to the therapy.
Keywords
Early virological response Plasmacytoid dendritic cells Regulatory T cellsNotes
Acknowledgments
This study was funded in part by Grant-in-Aid Ministry of Health, Labor and Welfare of Japan and Ministry of Education, Science and Culture of Japan (ID: 22590729 and 22590730).
Conflict of interest
The authors declare that they have no conflict of interest.
References
- 1.Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010;42(Suppl 3):S206–14.Google Scholar
- 2.Kanwal F, Hoang T, Kramer JR, Asch SM, Goetz MB, Zeringue A, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology. 2010:140:1182–8.e1.Google Scholar
- 3.Poynard T, Colombo M, Bruix J, Schiff E, Terg R, Flamm S, et al. Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy. Gastroenterology. 2009;136:1618–28.e2.Google Scholar
- 4.Jacobson IM. Treatment options for patients with chronic hepatitis C not responding to initial antiviral therapy. Clin Gastroenterol Hepatol. 2009;7:921–30.PubMedCrossRefGoogle Scholar
- 5.Hayashi N, Takehara T. Antiviral therapy for chronic hepatitis C: past, present, and future. J Gastroenterol. 2006;41:17–27.PubMedCrossRefGoogle Scholar
- 6.Poynard T. Treatment of hepatitis C virus: the first decade. Semin Liver Dis. 2004;24(Suppl 2):19–24.PubMedCrossRefGoogle Scholar
- 7.Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645–52.PubMedCrossRefGoogle Scholar
- 8.Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Goncales FL Jr, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol. 2005;43:425–33.PubMedCrossRefGoogle Scholar
- 9.Berg T, von Wagner M, Nasser S, Sarrazin C, Heintges T, Gerlach T, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology. 2006;130:1086–97.PubMedCrossRefGoogle Scholar
- 10.Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest. 2009;119:1745–54.PubMedCrossRefGoogle Scholar
- 11.Kanto T, Hayashi N. Immunopathogenesis of hepatitis C virus infection: multifaceted strategies subverting innate and adaptive immunity. Intern Med. 2006;45:183–91.PubMedCrossRefGoogle Scholar
- 12.Kamal SM, Fehr J, Roesler B, Peters T, Rasenack JW. Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C. Gastroenterology. 2002;123:1070–83.PubMedCrossRefGoogle Scholar
- 13.Pachiadakis I, Chokshi S, Cooksley H, Farmakiotis D, Sarrazin C, Zeuzem S, et al. Early viraemia clearance during antiviral therapy of chronic hepatitis C improves dendritic cell functions. Clin Immunol. 2009;131:415–25.PubMedCrossRefGoogle Scholar
- 14.Itose I, Kanto T, Inoue M, Miyazaki M, Miyatake H, Sakakibara M, et al. Involvement of dendritic cell frequency and function in virological relapse in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients. J Med Virol. 2007;79:511–21.PubMedCrossRefGoogle Scholar
- 15.Pawlotsky JM, Bouvier-Alias M, Hezode C, Darthuy F, Remire J, Dhumeaux D. Standardization of hepatitis C virus RNA quantification. Hepatology. 2000;32:654–9.PubMedCrossRefGoogle Scholar
- 16.Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19:1513–20.PubMedCrossRefGoogle Scholar
- 17.Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335–74.PubMedCrossRefGoogle Scholar
- 18.Oze T, Hiramatsu N, Yakushijin T, Kurokawa M, Igura T, Mochizuki K, et al. Pegylated interferon alpha-2b (Peg-IFN alpha-2b) affects early virologic response dose-dependently in patients with chronic hepatitis C genotype 1 during treatment with Peg-IFN alpha-2b plus ribavirin. J Viral Hepat. 2009;16:578–85.PubMedCrossRefGoogle Scholar
- 19.Hiramatsu N, Oze T, Yakushijin T, Inoue Y, Igura T, Mochizuki K, et al. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin. J Viral Hepat. 2009;16:586–94.PubMedCrossRefGoogle Scholar
- 20.Itose I, Kanto T, Kakita N, Takebe S, Inoue M, Higashitani K, et al. Enhanced ability of regulatory T cells in chronic hepatitis C patients with persistently normal alanine aminotransferase levels than those with active hepatitis. J Viral Hepat. 2009;16:844–52.PubMedCrossRefGoogle Scholar
- 21.Kanto T, Hayashi N, Takehara T, Tatsumi T, Kuzushita N, Ito A, et al. Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J Immunol. 1999;162:5584–91.PubMedGoogle Scholar
- 22.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;38:1437–48.PubMedGoogle Scholar
- 23.Soldevila B, Alonso N, Martinez-Arconada MJ, Morillas RM, Planas R, Sanmarti AM, et al. A prospective study of T- and B-lymphocyte subpopulations, CD81 expression levels on B cells and regulatory CD4(+) CD25(+) CD127(low/−) FoxP3(+) T cells in patients with chronic HCV infection during pegylated interferon-alpha2a plus ribavirin treatment. J Viral Hepat. 2011;18:384–92.Google Scholar
- 24.Akiyama M, Ichikawa T, Miyaaki H, Motoyoshi Y, Takeshita S, Ozawa E, et al. Relationship between regulatory T cells and the combination of pegylated interferon and ribavirin for the treatment of chronic hepatitis type C. Intervirology. 2010;53:154–60.Google Scholar
- 25.Burton JR Jr, Klarquist J, Im K, Smyk-Pearson S, Golden-Mason L, Castelblanco N, et al. Prospective analysis of effector and regulatory CD4+ T cells in chronic HCV patients undergoing combination antiviral therapy. J Hepatol. 2008;49:329–38.PubMedCrossRefGoogle Scholar
- 26.Franceschini D, Paroli M, Francavilla V, Videtta M, Morrone S, Labbadia G, et al. PD-L1 negatively regulates CD4+CD25+Foxp3+Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest. 2009;119:551–64.PubMedCrossRefGoogle Scholar
- 27.Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–11.PubMedCrossRefGoogle Scholar
- 28.Oze T, Hiramatsu N, Yakushijin T, Mochizuki K, Oshita M, Hagiwara H, et al. Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy. J Hepatol. 2011;54:604–11.Google Scholar
- 29.McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061–9.PubMedCrossRefGoogle Scholar
- 30.Gilliet M, Cao W, Liu YJ. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol. 2008;8:594–606.PubMedCrossRefGoogle Scholar
- 31.Ito T, Amakawa R, Inaba M, Ikehara S, Inaba K, Fukuhara S. Differential regulation of human blood dendritic cell subsets by IFNs. J Immunol. 2001;166:2961–9.PubMedGoogle Scholar
- 32.Sarasin-Filipowicz M, Oakeley EJ, Duong FH, Christen V, Terracciano L, Filipowicz W, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A. 2008;105:7034–9.PubMedCrossRefGoogle Scholar
- 33.Mengshol JA, Golden-Mason L, Castelblanco N, Im KA, Dillon SM, Wilson CC, et al. Impaired plasmacytoid dendritic cell maturation and differential chemotaxis in chronic hepatitis C virus: associations with antiviral treatment outcomes. Gut. 2009;58:964–73.PubMedCrossRefGoogle Scholar
- 34.Cicinnati VR, Kang J, Sotiropoulos GC, Hilgard P, Frilling A, Broelsch CE, et al. Altered chemotactic response of myeloid and plasmacytoid dendritic cells from patients with chronic hepatitis C: role of alpha interferon. J Gen Virol. 2008;89:1243–53.PubMedCrossRefGoogle Scholar
- 35.Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, et al. Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol. 2007;46:403–10.PubMedCrossRefGoogle Scholar
- 36.Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.PubMedCrossRefGoogle Scholar