CCL5 expression in peripheral blood as a surrogate marker for the stage of fibrosis in patients with chronic hepatitis C

Aims: Recent data suggested that CCL5 (RANTES) may play an important role in liver fibrosis as its expression is upregulated in the liver of patients with cirrhosis. Therefore, we have studied its expression in the peripheral blood of patients with chronic hepatitis C and its modulation by antiviral therapy with IFN-α in vivo.

Materials and methods: A total of 36 Caucasian patients with histologically proven chronic hepatitis C were treated with standard combination therapy consisting of (A: ) pegylated IFN-α2a (Pegasys, 180µg once weekly, n=21) for 12 months (HCV genotype 1, n=19) or 6 months (HCV genotype 3a, n=2) in combination with ribavirin (800–1200mg daily) or (B: ) pegylated IFN-α2b (PEG-Intron, 1,5 mcg/kg/week. s.c, n=15) for 12 months (HCV genotype 1, n=11) or 6 months (HCV genotype 3a, n=4) in combination with ribavirin (800–1200mg daily). RNA was isolated (PAXgene, PreAnalytiX) from peripheral blood which was collected 12h before and 12h after the first injection of IFN-α. In addition, 11 patients with HCV-unrelated liver cirrhosis and 10 healthy individuals were used as controls. The transcriptional profile was analysed using human genomic microarrays (Affymetrix HG U133A) and quantitative real-time RT-PCR. Basal, induced and fold change values were subjected to significance analysis (SAM software) and class prediction analysis (PAM software) to identify genes which are differentially regulated in patients with no or little (group 1; stage 0–1; n=25) or advanced (group 2; stage 2–4; n=11) fibrosis.

Results: Using class prediction analysis, the stage of fibrosis could be predicted by 11 genes with 86% accuracy including CCL5. Patients from group 1 had significantly (P<0.005) higher CCL5 levels compared to healthy controls, patients with HCV-unrelated liver cirrhosis and patients from group 2. In vivo treatment with IFN resulted in a significant downregulation of expression of CCL–5 in group 1 and 2. These results could be verified by quantitative RT-PCR.

Conclusions: CCL5 expression in the peripheral blood is upregulated in earlier stages of HCV infection and returns to normal levels in patients with advanced liver disease or after treatment with IFN-α. Although the differences in hepatic and peripheral expression are not fully understood at this point, CCL5 may play a relevant role in the propagation of liver fibrosis in patients with chronic hepatitis C.

CCL5 - HCV - liver fibrosis