Role of regulatory T cells in natural immunity and sustained pharmacological control of chronic hepatitis B infection

Abstract

Background/Aim: The effectiveness of hepatitis B virus therapy is reflected not only by the reduction of viral load but also recovery of viral-specific T-cell immunity. Regulatory T cells (Treg) can suppress the functions of CD4 and CD8 effector cells. The aim of the current study is to investigate the role of Treg in nucleoside/ nucleotide analogue (Nucs)-induced and spontaneous sustained Background/Aim: The effectiveness of hepatitis B virus therapy is reflected not only by the reduction of viral load but also recovery of viral-specific T-cell immunity. Regulatory T cells (Treg) can suppress the functions of CD4 and CD8 effector cells. The aim of the current study is to investigate the role of Treg in nucleoside/ nucleotide analogue (Nucs)-induced and spontaneous sustained remission after HBeAg-seroconversion. Methods: We studied 30 hepatitis B e antigen (HBeAg)-positive patients treated with either adefovir dipivoxil (ADV) monotherapy [n 16] or ADV in combination with emtricitabine [n 14] for 96 weeks followed by ADV monotherapy. Nucs was discontinued 6-months after HBeAgseroconversion and patients followed-up for post-treatment relapse (HBV DNA 10,000 copies/ml with ALT 2 times upper limit of normal). Nine historical control patients with spontaneous HBeAg-seroconversion were recruited for comparison. Serial HBV DNA, Treg (defined as CD4 CD25 CD45RO CTLA-4 ) cell frequency by FACS, FoxP3 mRNA expression level by realtime PCR and intracellular cytokine staining for virus-specific CD8 T-cells by FACS were evaluated every 4-8 weekly. Results: At the time of analysis, 10 of 30 patients (33.3%) had HBeAgseroconversion. All these 10 patients had normal serum ALT and HBV DNA 300 copies/ml at the end-of-treatment (ET). After follow-up of mean 16.1 months, 4 of the 10 patients (40.0%) with Nucs-induced HBeAg-seroconversion had sustained response (SR)and 6 patients (60.0%) had post-treatment relapse. A decline in Treg (mean /- SEM 1.89 /- 0.47 vs. 4.35 /- 1.02 respectively, p 0.01) and FoxP3 (mean /- SEM 14.62 /- 7.48 vs. 48.89 /-24.51 respectively, p 0.002) was detected 8-weeks before HBeAgseroconversion in patients with spontaneous HBeAg-seroconversion when compared with baseline. This decrease in Treg and FoxP3 was sustained until 24 weeks after spontaneous HBeAgseroconversion. No change in Treg was detected in Nucs-induced HBeAg-seroconversion. The 4 patients with SR showed a significantly lower percentage of Treg at ET (mean /- SEM 1.50 /-0.63) when compared with the 6 patients with post-treatment relapse (mean /- SEM 4.41 /- 1.34, p 0.03). Post-treatment relapse was preceded by an increase in Treg and FoxP3. Downregulation of Treg was associated with an increase in virus-specific CD8 T-cells. However, no serum ALT flare was detected during T cell recovery. Conclusion: Downregulation of Treg is associated with spontaneous HBeAg seroconversion and sustained post-treatment remission without cytolytic mediated liver damage. A lower Treg at ET contribute to SR upon withdrawal of nucs after HBeAg-seroconversion.