studies

1010A AASLD ABSTRACTS HEPATOLOGY, October, 2015
lates BNC entry into hepatoma cells. As a result from confocal
microscopy observation, endocytosis of NTCP seemed to be
up-regulated in HB611 cells in terms of core fucosylation. Conclusions:
Core-fucosylation and sialylation have pivotal roles in
HBV infection into hepatoma cells. Especially, downregulation
of core-fucosylation with Fut8 knockdown or treatment with
core-fucose specific lectin might be a novel target for HBV
therapy.
Disclosures:
Hayato Hikita - Grant/Research Support: Bristol-Myers Squibb
Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD
K.K., Bristol-Meyer Squibb, Mitsubishi Tanabe Pharma Corparation, Toray Industories
Inc. ; Speaking and Teaching: MSD K.K., Bristol-Meyer Squibb, Janssen
Pharmaceutical Companies
The following authors have nothing to disclose: Eiji Miyoshi, Shinji Takamatsu,
Mayuka Shimomura, Yoshihiro Kamada, Haruka Maeda, Tomoaki Subajima,
Iijima Mayumi, Yuta Okamato, Ryo Misaki, Kazuhito Fujiyama, Keiji Ueda,
Shunichi Kuroda
1643
Indoleamine-2, 3-dioxygenase as the intrinsic anti-HBV
effector that leads to durable immune responses in
patients with acute hepatitis B: A comparative analysis
with the sequence in hepatic flare
Sachiyo Yoshio 1 , Masaya Sugiyama 1 , Hirotaka Shoji 1 , Yohei
Mano 1 , Yoshihiko Aoki 1 , Toru Okamoto 2 , Yoshiharu Matsuura 2 ,
Masashi Mizokami 1 , Tatsuya Kanto 1 ; 1 The Research Center for
hepatitis and immunology, National Center for global health and
medicine, Chiba, Japan; 2 Molecular Virology, Research Institute
for Microbial Diseases, Osaka University, Suita, Japan
BACKGROUD&AIMS: Primary HBV infection to immune competent
adults is mostly a self-limited disease, resulting in the HBV
clearance. However, HBV is hard-to-eradicate once it attains
persistent infection. The factors that distinguish these conditions
should be crucial for the control of HBV. Indoleamine-2, 3-dioxygenase
(IDO) is induced in hepatocytes by IFN-γ and catalyzes
tryptophan to form kynurenine. IDO exerts dual function
in infectious diseases; acting as a suppressor of intracellular
pathogens and as an immune regulator. We aimed to explore
the factors, including IDO, capable of suppressing HBV, by
comprehensive immunological analysis between patients with
acute hepatitis with HBV clearance and those at hepatic flare
with persistent infection. METHODS: We enrolled HBV-positive
patients with acute hepatitis (AH, N=26), chronic hepatitis
(CH, 12), hepatic flare (HF, 14) and healthy volunteers (HV,
10) in this study. We longitudinally compared serum levels of
40 cytokines and chemokine by a multiplexed assay. Systemic
IDO activity was determined by the ratio of kynurenine to tryptophan
measured by HPLC. In order to examine the mechanism
of IDO induction and its impact on HBV replication, we set up
the co-culture consisting of HBV transfected Huh7 (HBV+Huh7),
freshly-isolated human NK cells and plasmacytoid dendritic
cells (pDCs). The IDO-knock out (IDO-KO) Huh7 was established
by CRISPR-Cas9 system. RESULTS: The AH group showed
a robust increase of IDO activity prior to the peak of ALT elevation,
the levels of which were higher than those in the CH,
HF or HV group. The IDO activity subsided overtime in accordance
with the decline of ALT and HBVDNA. In the AH group,
the levels of CXCL9, CXCL10 and CXCL11 were increased in
the acute phase, followed by the sustained increase of IFN-γ,
TNF-α, CCL19 and CCL22 until the disappearance of HBsAg.
In contrast, such sequential transition of the immune factors,
beginning from the robust IDO activation, was not observed
in the HF group. In the co-culture, the coexistence of NK and
pDCs synergistically increased the production of IFN-γ and
IFN-α thereby enhancing IDO activity in HBV+Huh7, resulting
in HBV suppression. In IDO-KO HBV+Huh7, the suppressive
effect of NK and pDCs on HBV replication was abrogated
(P