CD56^bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

Abstract

Summary HBV surface antigen ( HB sAg) reduction is well observed in chronic hepatitis B ( CHB ) patients treated with pegylated interferon alpha‐2a (Peg IFN α). However, the mechanism of HB sAg suppression has not been fully elucidated. Twenty‐seven of 55 entecavir‐treated CHB e antigen positive patients were switched to Peg IFN α treatment (Group A) whereas 28 patients continued entecavir treatment (Group B). The percentage or absolute number of CD 56 bright / CD 56 dim NK cells, expression of receptors and cytokines were evaluated by flow cytometry for 48 weeks and correlated with treatment efficacy. In vitro, purified NK cells were co‐cultured with Hep AD 38 cells for measurement of HB sAg, apoptosis and covalently closed circular DNA (ccc DNA ). In association with a reduction of HB sAg, the percentage and absolute number of CD 56 bright NK cells was significantly elevated in patients in group A, especially in Virologic Responders ( VR s, HB sAg decreased). Furthermore, the percentage of NK p30 + , NK p46 + , TRAIL + , TNF ‐α + and IFN γ + CD 56 bright NK cells were significantly expanded in Group A, which were positively correlated with the decline of HB sAg at week 48. In vitro, peripheral NK cells from Group A induced a decline of HB sAg in comparison with NK cells from Group B which was significantly inhibited by anti‐ TRAIL , anti‐ TNF ‐α and anti‐ IFN γ antibodies. Furthermore, apoptosis of Hep AD 38 cells and levels of ccc DNA , were significantly reduced by TRAIL + and TNF ‐α + / IFN γ + NK cells from Group A, respectively. A functional restoration of CD 56 bright NK cells in entecavir‐treated patients who were switched to Peg IFN α contributes to HB sAg and ccc DNA clearance through TRAIL ‐induced cytolysis and TNF ‐α/ IFN γ‐mediated noncytolytic pathways.