Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy

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• 作者：Annikki de Niet¹ ; ² ; ^&dagger ; ; Femke Stelma¹ ; ² ; ^&dagger ; ; Louis Jansen¹ ; ² ; Marjan J. Sinnige² ; Ester B.M. Remmerswaal² ; R. Bart Takkenberg¹ ; Neeltje A. Kootstra² ; Hendrik W. Reesink¹ ; ² ; ^{h.w.reesink@amc.nl" class="auth_mail" title="E-mail the corresponding author} ; Rene A.W. van Lier² ; ³ ; Ester M.M. van Leeuwen²
• 关键词：HBV ; hepatitis B virus ; HBsAg ; hepatitis B surface antigen ; CHB ; chronic hepatitis B ; HBeAg ; hepatitis B e antigen ; PegIFN ; peginterferon alpha 2a ; NUC ; nucleot(s)ide analogues ; HLA ; human leucocyte antigen ; ALT ; alanine aminotransferase ; LVL ; low viral load ; HVL ; high viral load ; CR ; combined response ; NR ; non-response ; CMV ; cytomegalo virus ; PBA ; phosphate buffer/albumin ; PBS ; phosphate buffered saline ; FACS ; Fluorescence-Activated Cell Sorting ; PMA ; phorbol 12-myristate 13-acetate ; LFU ; long-
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：64
• 期：3
• 页码：539-546
• 全文大小：1168 K

文摘

Chronic hepatitis B virus (HBV) infection is characterized by functional impairment of HBV-specific T cells. Understanding the mechanisms behind T cell dysfunction and restoration is important for the development of optimal treatment strategies.

Methods

In this study we have first analysed the phenotype and function of HBV-specific T cells in patients with low viral load (HBV DNA <20,000 IU/ml) and spontaneous control over the virus. Subsequently, we assessed HBV-specific T cells in patients with high viral load (HBV DNA >17,182 IU/ml) treated with peginterferon/adefovir combination therapy who had various treatment outcomes.

Results

HBV-specific T cells could be detected directly ex vivo in 7/22 patients with low viral load. These showed an early differentiated memory phenotype with reduced ability to produce IL-2 and cytotoxic molecules such as granzyme B and perforin, but with strong proliferative potential.

In a cohort of 28 chronic hepatitis B patients with high viral load treated with peginterferon and adefovir, HBV-specific T cells could not be detected directly ex vivo. However, HBV-specific T cells could be selectively expanded in vitro in patients with therapy-induced HBsAg clearance (HBsAg loss n = 7), but not in patients without HBsAg clearance (n = 21). Further analysis of HBV-specific T cell function with peptide pools showed broad and efficient antiviral responses after therapy.

Conclusions

Our results show that peginterferon based combination therapy can induce HBV-specific T cell restoration. These findings may help to develop novel therapeutic strategies to reconstitute antiviral functions and enhance viral clearance.