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The immunopathogenesis and the regulation of hepatic lesions in murine model of primary biliary cirrhosis.

原发性胆汁性肝硬化小鼠模型的免疫发病机制及肝脏病变的调控。

基本信息

批准号：
08457160
负责人：
TANAKA Naomi
金额：
$ 4.48万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457160/
关键词：
primary biliary cirrhosis graft versus host reaction helper T cell subset cytokine interleukin-l0 Interferon-gamma adhesion molecule VLA-4 Th2

项目摘要

We have previously reported that CD4^+ T cells induced primary biliary cirrhosis (PBC) Iike hepatic lesions in mice with graft-versus-host reaction (GVHR) due to major histocompatibility complex (MHC) class [[disparity. In this srudy, to ciarify the relationship between the cytokine profile produced by CD4^+ T cells and the formation of hepatic lesions. we sorted CD4^+ T cells from the liver using flowcytometer and examined their cytokine mRNA expressions at various time points after GVHR induction. Furthermore, we examined wheather Th1/Th2 balance might change during the suppression of lesions by antibodies against adhesion molecules. l) Histologically, the infiltration of CD4^+ T cells around the bile ducts was observed from day 5, and the lesions deteriorated gradually untii day 14. On day 14, CD8^-, B220^+ and Mac-l^+ cells, as well as CD4^+ T cells around the bile ducts were seen. In the liver infiltrating CD4^- T cells. the expression level of Th1 cytokine IFN-gamma mRNA was obse … More rved to increae at an early phase day 3, whereas that of Th2 cytokine IL-l0 mRNA was elevated at a later phase day 14. Serum levels of AMA on day 14 were significantly higher than that on day 5.2) H.E.staining showed the grade of portal cellular infiltration both in groups administered anti-VLA-4 antibodies and anti-VCAM-1 antibodies and only anti-VLA-4 antibodies were significantly suppressed compared to the control adminstered normal rat lgG.The induction of GVHR and the elevation of AMA were not alterd in these groups by administering monoclonal antibodies. The expressions of IL-2, IFNgamma, IL-4 and IL-l0 mRNA were not changed in these groups. Immunohistochemically, CD4, CD8, B220 or Mac-1 positive cells were detected in these groups. The elevation of IFN-gamma mRNA expression in the early phase before the appearance of NSDC lesions suggest that Th1 cells may be related to the pathogenesis of PBC in this model. Delayd expression of IL-l0 mRNA may reflect the suppression of cytokine production by Th1 cells in the liver. Moreover, the portal cellular infiltration in PBC animal model Is reduced by the administration of antibodies against VLA-4. However, cytokine profile of liver infiltrating Thyl.2^+CD4^+ lymphocytes and the composition of infiltrating cells were not changed. These results suggest that the administration of antibodies against adhision molecule may suppress PBC Iike lesions without Th1/Th2 balance. Less

我们之前报道过，CD4^+ T细胞在移植物抗宿主反应（GVHR）小鼠中诱导原发性胆汁性肝硬化（PBC）样肝脏病变，原因是主要组织相容性复合体（MHC）类别差异。本研究旨在阐明CD4^+ T细胞产生的细胞因子谱与肝脏病变形成的关系。我们用流式细胞仪对肝细胞CD4^+ T细胞进行分类，检测GVHR诱导后不同时间点细胞因子mRNA的表达。此外，我们还检测了抗粘附分子抗体抑制病变过程中Th1/Th2平衡是否会发生变化。l)组织学上，从第5天开始观察到胆管周围CD4^+ T细胞浸润，病变逐渐恶化至第14天。第14天，胆管周围可见CD8^-、B220^+、Mac-l^+细胞及CD4^+ T细胞。在肝脏浸润CD4^- T细胞。Th1细胞因子ifn - γ mRNA的表达量在早期第3天显著升高，而Th2细胞因子il - 10 mRNA的表达量在晚期第14天显著升高。第14天血清AMA水平显著高于第5.2天)h.e.e染色显示抗vcam -1抗体组和抗vcam -4抗体组门静脉细胞浸润程度均显著低于正常大鼠lgG对照组，且只有抗vcam -4抗体组门静脉细胞浸润程度明显低于正常大鼠lgG对照组。在这些组中，单克隆抗体对GVHR的诱导和AMA的升高没有改变。各组IL-2、IFNgamma、IL-4、il - 10mrna表达无明显变化。免疫组化检测各组细胞CD4、CD8、B220、Mac-1阳性。在NSDC病变出现之前的早期阶段ifn - γ mRNA表达的升高提示Th1细胞可能与该模型中PBC的发病机制有关。il - 10mrna的延迟表达可能反映了肝脏中Th1细胞抑制细胞因子的产生。此外，在PBC动物模型中，给药抗vla4抗体可减少门静脉细胞的浸润。浸润thyl2 ^+CD4^+淋巴细胞的细胞因子谱及浸润细胞的组成无明显变化。这些结果表明，抗adadision分子的抗体可以抑制无Th1/Th2平衡的PBC样病变。少