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Review
. 2015 Nov 8;7(25):2590-6.
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  1 , Masanori Atsukawa  1 , Masumi Shimizu  1 , Hidemi Takahashi  1 , Chiaki Kawamoto  1
Affiliations
Review

Ribavirin contributes to eradicate hepatitis C virus through polarization of T helper 1/2 cell balance into T helper 1 dominance

Katsuhisa Nakatsuka et al. World J Hepatol. .

Abstract

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

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Figures

Figure 1
Figure 1
Schema of the potential mechanism of action of ribavirin on T-regulatory cells in the T helper 1/2-regulatory cascade. RBV interferes with FOXP3 expression in naïve Th cells, making them unable to differentiate into adaptive Treg cells. RBV also disrupts the inhibitory activities of adaptive Treg and Treg 1 cells by suppressing their IL-10 production. In addition, RBV down-modulates ICOS, expressed on naïve Th cells after stimulation, to inhibit the differentiation of naïve Th cells in to Th2 cells. The combination of these affects may contribute to maintain Th1 activity against exogenous antigens, which would contribute to the elimination of HCV-infected cells via the activation of specific CTLs. RBV: Ribavirin; ICOS: Inducible co-stimulator; IL: Interleukin; HCV: Hepatitis C virus; CTL: Cytotoxic T cell; FOXP3: Forkhead box-P3; Treg: T-regulatory; Th: T helper; TGF: Tumor growth factor; MHC: Major histocompatibility complex; TCR: T cell receptor; GITR: Glucocorticoid-induced tumour-necrosis-factor-receptor-related protein; APC: Antigen presenting cells.
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