Type I interferon receptor and response to interferon therapy in chronic hepatitis C patients: a prospective study D. Fujiwara, 1 K. Hino, 1 Y. Yamaguchi, 1 Y. Kubo, 2 S. Yamashita, 3 K. Uchida, 4 T. Konishi, 5 H. Nakamura, 6 M. Korenaga, 1 M. Okuda 1 and K. Okita 1 1 Department of Gastroenterology and Hepatology, School of Medicine, Yamaguchi University, Yamaguchi; 2 Department of Gastroenterology, Kokura Memorial Hospital, Fukuoka; 3 Department of Gastroenterology, Shimonoseki Kohsei Hospital, Yamaguchi; 4 Department of Medicine, Yamaguchi Rohsai Hospital, Yamaguci; 5 Department of Medicine, Shuhtoh General hospital, Yamaguchi; and 6 Department of Medicine, Hagi Civil Hospital, Yamaguchi, Japan Received February 2003; accepted for publication July 2003 SUMMARY. The type I interferon (IFN) receptor consists of at least two subunits, IFNAR1 and IFNAR2. We previously found a correlation between IFNAR1 and IFNAR2 expres- sion in liver, and a correlation in IFNAR2 expression, but not in IFNAR1, between liver and peripheral blood mono- nuclear cells (PBMCs). The aim of this study was to pro- spectively assess whether IFNAR2 expression levels in PBMCs as well as in liver act as markers for predicting response to IFN therapy in chronic hepatitis C patients. Fifty- two Japanese patients with chronic hepatitis C, were enrolled. IFNAR2 mRNA was quantified using competitive polymerase chain reaction, in liver and PBMC specimens, and of the 52 patients assigned to receive a 6-month course of interferon-a therapy, 36 patients who received more than 300 million units of interferon were analysed. IFNAR2 mRNA expression levels were significantly higher in liver than in PBMCs in all 36 patients (P ¼ 0.016). Seventeen sustained virologic responders showed lower pretreatment hepatitis C virus (HCV)-RNA levels (P ¼ 0.017) in serum and higher pretreatment levels of IFNAR2 mRNA in liver (P ¼ 0.007), but not in PBMCs, compared with nonsus- tained virologic responders. In multivariate analysis, these factors were independently associated with a sustained vir- ologic response (i.e. HCV-RNA level: odds ratio 0.23, 95% CI 0.038–0.864; and IFNAR2 in liver: odds ratio 1.116, 95% CI 1.015–1.227). Hence, IFNAR2 expression levels in liver, but not in PBMCs, is predictive of response to IFN treatment in chronic hepatitis C patients. Keywords: IFNAR1, IFNAR2, liver tissue, peripheral blood mononuclear cells, PBMCs. INTRODUCTION To date, interferon (IFN) with or without ribavirin is the only therapy known to eradicate 1 the hepatitis C virus (HCV) and induce long-term normalization of aminotransferase levels in patients with chronic hepatitis C. However, this occurs in <50% of the treated patients. Therefore, the identification of prognostic factors predictive of response to IFN therapy is important and several factors have been reported [1–5]. As IFN elicits antiviral activity by binding to receptors on the cell surface [6,7], expression of the type I IFN receptor in liver tissue is likely to be involved in the pathogenesis of viral hepatitis and response to IFN therapy. In fact, recent studies have demonstrated a significant correlation between hepatic expression of the type I IFN receptor and response to IFN therapy in chronic hepatitis C patients [8–12]. A prospective study, however, has not been conducted. The type I IFN receptor consists of at least two subunits; the IFNAR1 (IFNa receptor) and the IFNAR2 (IFNa/b receptor) [13,14], both of which have been cloned and are directly involved in signal transduction [13,15,16]. We have previously quantified mRNA levels of both subunits, using a competitive polymerase chain reaction (PCR) assay, in liver and peripheral blood mononuclear cells (PBMCs) from chronic hepatitis C patients [17]. We have demonstrated that levels of IFNAR1 expression are strongly correlated with IFNAR2 levels in liver, and further that IFNAR2 expression, but not IFNAR1 expression, in liver is related to that in Abbreviations: IFN, interferon; IFNAR1, interferon receptor subunit 1; IFNAR2, interferon receptor subunit 2; PBMC, peripheral blood mononuclear cells. Correspondence: Keisuke Hino, Department of Laboratory Sciences, Faculty of Health Sciences, Yamaguchi University School of Medi- cine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan. E-mail: k.hino@yamaguchi-u.ac.jp Journal of Viral Hepatitis, 2004, 11, 136–140 Ó 2004 Blackwell Publishing Ltd