AASLD2020[852]肝内肝炎乙肝表面的抑制 抗原（HBsAg）预防干扰素

StephenW

852
SUPPRESSION OF INTRAHEPATIC HEPATITIS B SURFACE
ANTIGEN (HBsAg) PREVENTS INTERFERON MEDIATED LIVER
INJURY
Yasuhito Tanaka1,2, Ian Baudi2, Masanori Isogawa2 and
Keigo Kawashima2, (1)Department of Gastroenterology and
Hepatology, Kumamoto University, (2)Department of Virology
& Liver Unit, Nagoya City University Graduate School of
Medical Sciences
Background: Acute, potentially fatal, hepatitis often precedes
virologic responses to IFN⍺ treatment in some chronic HBV
patients. The molecular determinants for such liver flares are
unclear We previously reported that IFNs induce liver injury in
HBV transgenic mice that overproduce HBsAg (lineage 107-
5D) The aim of the current study was to examine the impact of
differential HBs expression on IFN-mediated liver injury in HBV
mouse models Methods: Two different HBV transgenic mice
were used Lineage 107-5D transgenic mice express HBsAg
in the liver under mouse albumin promoter Lineage 1 3 32
transgenic mice replicate HBV in the liver from a terminally
redundant 1 3-fold HBV DNA genome Groups of transgenic
mice were intravenously injected with a synthetic type I IFN
inducer, poly I:C (10 μg/mouse) The role of HBs transcripts
(HBs mRNA) in IFN-mediated liver damage was examined by
treating lineage 107-5D mice with siRNA targeting HBs mRNA
(siHBs) or control siRNA (siCTRL) one week before IFN⍺
administration (5 million U/kg) To determine the importance
of HBsAg retention in IFN-mediated liver damage, lineage
107-5D mice were first adoptively transferred with HBsAgspecific
CD8+ T cells to eliminate hepatocytes that had
already accumulated HBsAg Seven days later, the mice were
treated with siHBs or siCTRL, and then administered with
IFN⍺ Results: Non-treated lineage 107-5D mice retained
100-fold more HBsAg in the liver than lineage 1 3 32 mice
(852±358 vs 10±4 IU/mg, p=0 015), although serum HBsAg
levels of lineage 107-5D were much lower than lineage
1 3 32 (serum HBsAg: 11±3 vs 395±64 IU/ml, p=0 001)
After poly I:C treatment, lineage 107-5D mice showed severe
liver damage (4194±750 U/L), while no sALT elevation was
observed in lineage 1 3 32 (40±6 U/L), suggesting that IFN
mediated liver injury is directly correlated with intrahepatic
HBsAg levels Treatment with siHBs effectively reduced
HBs mRNA levels, approximately 10-fold, in lineage 107-
5D mice within one week but had no impact on intrahepatic
HBsAg levels Consequently, siHBs treatment alone failed to
prevent liver injury after IFN⍺ -treatment On the other hand, if
HBsAg accumulating hepatocytes were eliminated by HBsAgspecific
CD8+ T cells before siRNA treatment, IFN mediated
liver injury was significantly reduced in siHBs treated mice
compared to siCTRL groups (sALT 425±103 vs 4227±2533,
p=0 027) Conclusion: HBsAg level in the liver determines
the magnitude of IFN⍺ mediated liver injury.

StephenW

852
肝内肝炎乙肝表面的抑制
抗原（HBsAg）预防干扰素介导的肝
受伤
田中靖人1,2，伊恩·巴迪（Ian Baudi）2，井川正则（2）和
川岛圭吾2，（1）消化内科
熊本大学肝病学，（2）病毒学系
名古屋市立大学大学院生命・肝脏科
医学科学
背景：急性，可能致命的肝炎通常先于
某些慢性HBV对IFN治疗的病毒学应答
耐心。此类肝耀斑的分子决定因素为
不清楚我们以前曾报道过IFN诱导肝损伤
产生HBsAg的HBV转基因小鼠（谱系107-
5D）当前研究的目的是检验
HBs表达对IFN介导的HBV肝损伤的影响
小鼠模型方法：两只不同的HBV转基因小鼠
使用沿袭107-5D表达HBsAg的转基因小鼠
在小鼠白蛋白启动子下的肝细胞系1 3 32
转基因小鼠从末端复制肝中的HBV
冗余1 3倍HBV DNA基因组
给小鼠静脉注射合成的I型干扰素
诱导剂，poly I：C（10μg/小鼠）HBs转录本的作用
（HBs mRNA）在IFN介导的肝损伤中的检测
用靶向HBs mRNA的siRNA治疗谱系107-5D小鼠
（siHBs）或对照siRNA（siCTRL）在IFN⍺前一周
管理（500万U / kg）确定重要性
介导的肝损伤，谱系中HBsAg保留的变化
首先将HBsAg特异性过继转移至107-5D小鼠
CD8 + T细胞可消除具有以下功能的肝细胞
已经积累了HBsAg七天后，小鼠
用siHBs或siCTRL治疗，然后与
IFN⍺结果：保留未经治疗的谱系107-5D小鼠
肝脏HBsAg比谱系1 3 32小鼠多100倍
（852±358 vs 10±4 IU / mg，p = 0 015），尽管血清HBsAg
107-5D血统水平远低于血统
1 3 32（血清HBsAg：11±3 vs 395±64 IU / ml，p = 0 001）
经过poly I：C处理后，谱系107-5D小鼠表现出严重的
肝损害（4194±750 U / L），而sALT无升高
在谱系1 3 32（40±6 U / L）中观察到，提示IFN
介导的肝损伤与肝内直接相关
HBsAg水平有效降低siHBs治疗
血统107-中的HBs mRNA水平约为10倍
5D小鼠在一周之内但对肝内无影响
因此，仅siHBs治疗无法达到
预防IFN⍺治疗后的肝损伤
HBsAg特异性消除了积累HBsAg的肝细胞
干扰素介导的siRNA治疗前的CD8 + T细胞
siHBs治疗的小鼠肝损伤明显减少
与siCTRL组相比（sALT 425±103 vs 4227±2533，
p = 0 027）结论：肝脏中的HBsAg水平决定了
IFN⍺介导的肝损伤的程度。