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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Nov 8, 2015; 7(25): 2590-2596
Published online Nov 8, 2015. doi: 10.4254/wjh.v7.i25.2590
Ribavirin contributes to eradicate hepatitis C virus through polarization of T helper 1/2 cell balance into T helper 1 dominance
Katsuhisa Nakatsuka, Masanori Atsukawa, Masumi Shimizu, Hidemi Takahashi, Chiaki Kawamoto
Katsuhisa Nakatsuka, Masanori Atsukawa, Chiaki Kawamoto, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo 113-8603, Japan
Masumi Shimizu, Hidemi Takahashi, Microbiology and Immunology, Nippon Medical School, Tokyo 113-8603, Japan
Author contributions: All authors contributed to this work.
Conflict-of-interest statement: Authors declare no conflict of interest for this review article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Katsuhisa Nakatsuka, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
Telephone: +81-44-7335181 Fax: +81-44-3968087
Received: April 27, 2015
Peer-review started: May 1, 2015
First decision: August 4, 2015
Revised: August 22, 2015
Accepted: October 12, 2015
Article in press: October 13, 2015
Published online: November 8, 2015

The mechanism of action of ribavirin (RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus (HCV) infection are reviewed. RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper (Th) 1/2 cell balance to Th1 dominance. Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells, which contributes to differentiating naïve Th cells into Th2 cells while reducing their interleukin-10 production. The effects on T-regulatory (Treg) cells were also investigated, and RBV inhibited the differentiation of naïve Th cells into adaptive Treg cells by down-modulating forkhead box-P3. These findings indicate that RBV mainly down-regulates the activity of Th2 cells, resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes. Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications, regimens with RBV will be still be used because of their ability to facilitate the cellular immune response, which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.

Keywords: Ribavirin, Forkhead box-P3, T helper 1/2 cell balance, T-regulatory lymphocytes, Inducible co-stimulator, Interleukin-10, Hepatitis C virus infection

Core tip: Ribavirin has the potential to regulate the T-helper (Th) 1/2 cell balance into Th1 dominance by modulating the co-stimulatory signaling between antigen-presenting cells and naïve Th cells as well as the inhibitory activity of T-regulatory cells. These are considered useful in treating hepatitis C virus infection, especially to inhibit hepatocellular carcinoma development.