Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy.
OBJECTIVE
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 <20,000IU/ml) and spontaneous control over the virus. Subsequently, we assessed HBV-specific T cells in patients with high viral load (HBV DNA >17,182IU/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.
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
Annikki
A
de Niet
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
Femke
F
Stelma
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
Louis
L
Jansen
Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
Marjan J
MJ
Sinnige
Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
Ester B M
EB
Remmerswaal
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands.
R Bart
RB
Takkenberg
Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
Neeltje A
NA
Kootstra
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands. Electronic address: h.w.reesink@amc.nl.
Hendrik W
HW
Reesink
Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands; Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
Rene A W
RA
van Lier
Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
Ester M M
EM
van Leeuwen
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004359:Drug Therapy, Combination; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006801:Humans; D007372:Interferons / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*; D019562:Viral Load
D000998:Antiviral Agents; D016207:Cytokines; D006514:Hepatitis B Surface Antigens; D007372:Interferons
Adaptive immunity; Combination therapy; HBV-specific T cells; HBsAg loss; Hepatitis B