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Regulatory T Cell Function Modulated After Successful Direct-Acting Antiviral Treatment for Chronic Hepatitis C Patients

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Abstract

Backgrounds

Regulatory T cells (Tregs) affect the pathogenesis of chronic hepatitis C (CHC) infection.

Aims

This study evaluated the function of Tregs in CHC patients receiving the standard direct-acting antiviral agents (DAA) treatment.

Methods

CHC patients (n = 20) who received DAA treatment, clinical data, and function of Tregs were checked at baseline, Week 4, end of treatment (EOT), and 12 weeks after EOT (SVR 12). Treg-mediated inhibition was measured. The cytokine expression and fold change of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-10, and transforming growth factor (TGF)-β with/without Treg inhibition were also detected.

Results

The cohort included 14 females with a mean age of 59.8 ± 11.5 years. Nineteen had HCV genotype 1. The HCV RNA level was 6.17 ± 0.70 log IU/mL. All patients reached the sustained virologic response. The frequency of CD4+Foxp3+T cells decreased from baseline to EOT and returned at SVR 12. The inhibitory function of Tregs decreased during treatment and then restored (baseline vs. EOT, P = 0.0393; EOT vs. SVR 12, P = 0.0052). The cytokine expression and fold change of IFN-γ and TNF-α were highest at EOT and then decreased at SVR 12. The fold change of IL-10 was lowest at EOT and then increased at SVR 12. The fold change of TGF-β was significantly increased at Week 4 and SVR 12 compared to baseline.

Conclusions

The frequency and inhibitory function of Tregs declined gradually from baseline to EOT and then increased from EOT to SVR 12 in CHC patients receiving DAA therapy. The expression of IFN-γ, TNF-α, IL-10, and TGF-β parallelled Treg function.

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Abbreviations

CHC:

Chronic hepatitis C

DAAs:

Direct-acting antiviral agents

SVR:

Sustained virologic response

Tregs:

Regulatory T cells

nTreg:

Natural Treg

iTreg:

Induced Treg

PEG-IFN:

Pegylated interferon

RBV:

Ribavirin

anti-HCV Ab:

Anti-hepatitis C antibody

EOT:

End of treatment

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

PBMCs:

Peripheral blood mononuclear cells

Foxp3:

Forkhead box P3

CFSE:

Carboxyfluorescein diacetate and succinimidyl ester

TNF:

Tumor necrosis factor

TGF:

Transforming growth factor

MFI:

Mean fluorescence intensity

IFNAR:

IFN-α/β receptor

ARFI:

Acoustic radiation force impulse

FIB-4:

Fibrosis-4 Index

ULN:

Upper limit of normal

References

  1. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333–1342.

    Article  Google Scholar 

  2. Blach S, Zeuzem S, Manns M, et al. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol. 2017;2:161–176.

    Article  Google Scholar 

  3. Maasoumy B, Wedemeyer H. Natural history of acute and chronic hepatitis C. Best Pract Res Clin Gastroenterol. 2012;26:401–412.

    Article  Google Scholar 

  4. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med.. 2001;345:41–52.

    Article  CAS  Google Scholar 

  5. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Recommendations on Treatment of Hepatitis C 2018 J Hepatol. 2018.

  6. Panel AIHG. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015;62:932–954.

    Article  Google Scholar 

  7. Omata M, Kanda T, Wei L, et al. APASL consensus statements and recommendation on treatment of hepatitis C. Hepatol Int. 2016;10:702–726.

    Article  Google Scholar 

  8. Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and kinetics of decrease in liver stiffness after antiviral therapy in patients with chronic hepatitis C: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16:e24.

    Google Scholar 

  9. Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19:222–232.

    Article  CAS  Google Scholar 

  10. Hartling HJ, Ballegaard VC, Nielsen NS, Gaardbo JC, Nielsen SD. Immune regulation in chronic hepatitis C virus infection Scand. Gastroenterol. 2016;51:1387–1397.

    CAS  Google Scholar 

  11. Jung MK, Shin EC. Regulatory T cells in hepatitis B and C virus infections. Immune Netw.. 2016;16:330–336.

    Article  Google Scholar 

  12. Tseng KC, Ho YC, Hsieh YH, et al. Elevated frequency and function of regulatory T cells in patients with active chronic hepatitis C. J Gastroenterol. 2012;47:823–833.

    Article  CAS  Google Scholar 

  13. Tseng KC, Ho YC, Tseng CW, et al. Decrease in regulatory T-cell function in chronic hepatitis C patients receiving pegylated-interferon plus ribavirin. Int J Infect Dis. 2017;58:8–17.

    Article  CAS  Google Scholar 

  14. Langhans B, Nischalke HD, Kramer B, et al. Increased peripheral CD4(+) regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C. J Hepatol. 2017;66:888–896.

    Article  CAS  Google Scholar 

  15. Comarmond C, Garrido M, Pol S, et al. Direct-acting antiviral therapy restores immune tolerance to patients with hepatitis C virus-induced cryoglobulinemia vasculitis. Gastroenterology. 2017;152:e2052.

    Article  CAS  Google Scholar 

  16. Fard SN, Schietroma I, Scheri GC, et al. Direct-acting antiviral therapy enhances total CD4 + and CD8 + T-cells responses, but does not alter T-cells activation among HCV mono-infected, and HCV/HIV-1 co-infected patients. Clin Res Hepatol Gastroenterol. 2017;42:319–329.

    Article  CAS  Google Scholar 

  17. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25 + T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105:2862–2868.

    Article  CAS  Google Scholar 

  18. Cramp ME, Carucci P, Rossol S, et al. Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia. Gut. 1999;44:424–429.

    Article  CAS  Google Scholar 

  19. Sakaguchi S. Naturally arising Foxp3-expressing CD25 + CD4 + regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6:345–352.

    Article  CAS  Google Scholar 

  20. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity. 2006;25:195–201.

    Article  CAS  Google Scholar 

  21. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879–1888.

    Article  CAS  Google Scholar 

  22. Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59:2083–2091.

    Article  CAS  Google Scholar 

  23. Gangaplara A, Martens C, Dahlstrom E, et al. Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment. PLoS Pathog. 2018;14:e1006985.

    Article  CAS  Google Scholar 

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Funding

This study was funded partly by the Dalin Tzuchi General Hospital through Grant Number DTCRD106(2)-E-05 and partly by the Center for Innovative Research on Aging Society (CIRAS) from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project of the Ministry of Education (MOE) in Taiwan.

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Author notes

  1. Shu-Fen Wu and Chih-Wei Tseng have contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences and Institute of Molecular Biology, National Chung Cheng University, Chia-yi, Taiwan

    Shu-Fen Wu & Yun-Che Ho

  2. Center for Innovative Research on Aging Society (CIRAS), National Chung Cheng University, Chia-yi, Taiwan

    Shu-Fen Wu

  3. Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No 2, Ming-Shen Road, Dalin Town, Chia-yi, 622, Taiwan

    Chih-Wei Tseng, Yen-Chun Chen, Ping-Hung Ko, Yi-Ting He & Kuo-Chih Tseng

  4. School of Medicine, Tzuchi University, Hualien, Taiwan

    Chih-Wei Tseng & Kuo-Chih Tseng

Authors
  1. Shu-Fen Wu
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  2. Chih-Wei Tseng
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  3. Yun-Che Ho
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  4. Yen-Chun Chen
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  7. Kuo-Chih Tseng
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Contributions

Tseng KC is the guarantor of the article. Wu SF contributed to substantial contributions to the conception and design, analysis, interpretation of the data, the drafting of the article, critical revision for important intellectual content and final approval of the version to be published; Tseng CW contributed to acquisition of patients and clinical data, analysis, interpretation of the data, critical revision for important intellectual content; Ho YC contributed to experimental procedures, analysis of the data; Chen YC and Ko PH contributed to acquisition of patients and clinical data; He YT contributed to acquisition of patients and clinical data, coordination of study; Tseng KC contributed to substantial contributions to the conception and design, acquisition of patients and clinical data, analysis, or interpretation of the data, the drafting of the article, critical revision for important intellectual content, final approval of the version to be published, agreement to be accountable for all aspects of the work. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Kuo-Chih Tseng.

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Conflict of interest

The authors declared that they have no conflict of interest.

Ethical approval

This study was approved by the Ethics Committee of Dalin TzuChi General Hospital (approval number B10601022).

Informed consent

Written informed consent was obtained from every participant in this study. All experiments were performed in accordance with relevant guidelines and regulations.

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Wu, SF., Tseng, CW., Ho, YC. et al. Regulatory T Cell Function Modulated After Successful Direct-Acting Antiviral Treatment for Chronic Hepatitis C Patients. Dig Dis Sci 65, 1385–1395 (2020). https://doi.org/10.1007/s10620-019-05850-w

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  • DOI: https://doi.org/10.1007/s10620-019-05850-w

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