Down-Regulation of PD-1 Expression on Lymphocytes in Chronic Hepatitis B Patients with Pegylated Interferon α-2b Treatment

Background: Programmed death-1(PD-1) represents a mechanism of T cells dysfunction in hepatitis B virus (HBV) persistence. In periphery blood, PD-1 was up-regulated on virus specific-T cells, leading to the impairment of T cells. Aims: To show the effect of pegylated interferon a-2b treatment on the expression of PD-1 on lymphocytes, the frequency of specific T cells, and the correlation with therapeutic effect. Methods: 21 patients with chronic hepatitis B(CHB) were treated by pegylated IFN a-2b (PegIntron from Schering-Plough, once a week, 0.5 or 1 mg/kg/weight). The periphery bloods were taken at 0 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks. Periphery blood mononuclear cells(PBMC) were isolated from fresh heparinized blood by Ficoll-Hypaque(density:1.077g/L) density gradient centrifugation. Expression of PD-1 and frequency of circulating HBV epitope-specific CD8 T cells were detected by flow cytometry(FCM). Cytokines were detected using Cytometric bead assay(CBA). Results: The expression of PD-1 on lymphocytes was decreased consecutive(P \u3c 0.05), and decreases in responders (P = 0.00) were more than non-responders (P \u3e 0.05). Frequency of circulating HBV core or env-specific CD8 T cells was increased in CHB patients after IFN-a-2b therapy(P \u3c 0.05). Furthermore, the elevation of HBV core specific CD8 T cells at 24 weeks were seen in responders, but not non-responders(P \u3c 0.05). However, there were no differences between responders and non-responders in frequency of HBV env specific CD8 T cells. After IFN-a-2b treatment, Th1-type cytokines(IL-12, TNF-a and IFN-g) increased, but Th2-type cytokines(IL-4, IL-6 and IL-10) decreased. IL-6 was correlated with HBV DNA(r = 0.597, P = 0.04), while IP-10 was correlated with serum ALT(r = 0.545, P = 0.005). PD-1 levels at baseline can predict virologic response (PPV = 73%, NPV = 83%). IP-10 levels at 8 weeks can predict ALT normalization (PPV = 56%, NPV = 92%). Conclusions: Treatment with pegylated IFN a-2b can increase the frequency of circulating HBV epitope-specific CD8 T cells, down-regulate the PD-1 expression on lymphocytes. pegylated IFN a-2b can enhance immune response by regulating Th1/Th2 cytokines. This may be one of the mechanism of T cells dysfunction, and monitor the PD-1/PD-L interaction may partially restore the function of T cells