1Katsuhisa Nakatsuka, Masanori Atsukawa, Chiaki Kawamoto, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo 113-8603, Japan.
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.