Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis.
Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis.
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发表时间：
2008
期刊：
影响因子：
13.5
通讯作者：
Y. Chuang;Zhe‐Xiong Lian;Guo‐Xiang-X. Yang;S. Shu;Y. Moritoki;W. Ridgway;A. Ansari;M. Kronenberg;R. Flavell;B. Gao;M. Gershwin
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作者：
Y. Chuang;Zhe‐Xiong Lian;Guo‐Xiang-X. Yang;S. Shu;Y. Moritoki;W. Ridgway;A. Ansari;M. Kronenberg;R. Flavell;B. Gao;M. Gershwin
原发性胆汁性肝硬化（PBC）是一种器官特异性自身免疫性肝病，其特征是存在抗线粒体抗体和肝内小胆管破坏伴门静脉炎症。在以前的研究中，我们报道了PBC患者肝脏中CD 1d表达和CD 1d限制性自然杀伤T（NKT）细胞的频率增加。为了明确CD 1d限制性NKT细胞在PBC发病机制中的特定作用，特别是早期事件，我们在我们的转化生长因子β（TGF-β）受体II显性阴性（dnTGF β RII）PBC小鼠模型中研究了肝脏CD 1d限制性NKT细胞的功能。我们产生了CD 1d（-/-）和CD 1d（+/-）dnTGF β RII小鼠，并进行了肝脏免疫病理学的比较研究。我们在此报告，这些dnTGF β RII小鼠表现出大量增加的过度活跃的CD 1d限制性NKT细胞的肝组织内。与CD 1d（+/-）dnTGF β RII小鼠相比，缺乏CD 1d限制性CD 1d限制性NKT细胞的CD 1d（-/-）dnTGF β RII小鼠表现出显著减少的肝淋巴细胞浸润和轻度胆管炎。有趣的是，在年轻而非老年dnTGF β RII小鼠中，α-半乳糖神经酰胺激活的肝脏CD 1d限制性NKT细胞中干扰素-γ的产生显著增加，表明CD 1d限制性NKT细胞的年龄依赖性作用。结论dnTGF β R Ⅱ小鼠体内CD 1d限制性NKT细胞是肝损伤的重要因素。
UNLABELLED Primary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by the presence of antimitochondrial antibodies and the destruction of small intrahepatic bile ducts with portal inflammation. In previous studies, we reported that both CD1d expression and the frequency of CD1d-restricted natural killer T (NKT) cells were increased in the livers of patients with PBC. To define a specific role of CD1d-restricted NKT cells in the pathogenesis of PBC, particularly early events, we investigated the function of hepatic CD1d-restricted NKT cells in our transforming growth factor beta (TGF-beta) receptor II dominant-negative (dnTGFbetaRII) mouse model of PBC. We generated CD1d(-/-) and CD1d(+/-) dnTGFbetaRII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGFbetaRII mice demonstrate a massive increase of hyperactive CD1d-restricted NKT cells within the hepatic tissues. CD1d(-/-)dnTGFbetaRII mice, which lack CD1d-restricted CD1d-restricted NKT cells, exhibit significantly decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1d(+/-)dnTGFbetaRII mice. Interestingly, there was a significant increase in the production of interferon-gamma in hepatic CD1d-restricted NKT cells activated by alpha-galactosylceramide in young but not older dnTGFbetaRII mice, suggesting an age-dependent role of CD1d-restricted NKT cells. CONCLUSION These data demonstrate that CD1d-restricted NKT cells in dnTGFbetaRII mice are a critical factor in liver injury.