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The analysis of inflammatory cascade between antigen specific CTLs and liver injury using hepatitis model

利用肝炎模型分析抗原特异性CTL与肝损伤之间的炎症级联反应

基本信息

批准号：
20390203
负责人：
KIMURA Kiminori
金额：
$ 11.48万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390203/
关键词：
肝臓学免疫 B型肝炎ウイルス CTL ケモカイン肝障害接着因子 CD44

项目摘要

There are many uncertain points for regarding with leukocytes movement in the liver, especially interaction between liver sinus endothelial cells (LSECs) and cytotoxic T lymphocytes (CTLs). We examined role of CD44 for these interaction using hepatitis model. CTLs were administered into Hepatitis B virus transgenic mice (HBVTg) mice and HBVTgxCD44 knock out (KO) mice, and alanine aminotransferase activity, number of intrahepatic leukocytes, cytokine and chemokine mRNA level were examined. To determine the number and distribution of CTLs in the liver CFSE-labeled CTLs was administered into HBVTg with or without CD44 mice. sALT activity increased since 12 h though it had declined to 4 h in the CD44KOxHBVTg mice after CTLs injection. Similarly, the levels of Tumor necrosis factor (TNF) a, Interferon (IFN) g, Macrophage inflammatory protein (MIP)-2 mRNAs reduced in 4 h though it had been increased since 12 h in the CD44KOxHBVTg mice. The number of apoptotic hepatocytes increased intentionally at 24 h in the CD44KOxHBVTg livers, and it thought to be due to lower activity of initial nuclear factor kappaB (NF-kB). Although the number of CTLs exhibited lower at 4 h in the CD44KOxHBVTg livers the difference of Intercellular adhesion molecule (ICAM)-1 and CD86 expression on LSECs was not detected. CD44 on LSECs exerts important roles for CTLs migration into the hepatocytes. However, since CD44 deficient state was exacerbate hepatic injury, attention is necessary for hepatitis treatment as CD44 target therapy.

关于白细胞在肝脏中的运动，特别是肝窦内皮细胞与细胞毒性T淋巴细胞之间的相互作用，有许多不确定的地方。我们使用肝炎模型研究了CD44在这些相互作用中的作用。将CTL接种于HBVTg小鼠和HBVTgxCD44基因敲除(KO)小鼠，检测其丙氨酸氨基转移酶活性、肝内白细胞数、细胞因子和趋化因子的mRNA水平。为了确定CTL在肝脏中的数量和分布，将CFSE标记的CTL注射到有或没有CD44的HBVTg小鼠中。CD44KOxHBVTg组小鼠的盐活性在注射CTL后12h开始升高，但已降至4h。CD44KOxHBVTg组小鼠肿瘤坏死因子α、干扰素g、巨噬细胞炎性蛋白-2mRNAs水平在4h内降低，12h后升高。CD44KOxHBVTg组大鼠肝组织中的凋亡肝细胞数在24 h时明显增多，可能是由于初始核因子kappaB活性降低所致。CD44KOxHBVTg肝组织中CTL数量在4h时明显减少，但细胞间黏附分子(ICAM)-1和CD86在LSECs上的表达无明显差异。LSECs表面CD44在CTL向肝细胞迁移过程中发挥重要作用。然而，由于CD44缺乏状态加重了肝脏损伤，因此作为CD44靶向治疗的肝炎治疗是必要的。