β‐Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis
β‐Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis
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DOI：
10.1111/j.1365-2249.2009.03971.x
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发表时间：
2009-09
影响因子：
4.6
通讯作者：
Weici Zhang;Y. Moritoki;Koichi Tsuneyama;G‐X. Yang;G‐X. Yang;Yaron Ilan;Zhe‐Xiong Lian;Zhe‐Xiong Lian;M. E. Gershwin
中科院分区：
文献类型：
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作者：
Weici Zhang;Y. Moritoki;Koichi Tsuneyama;G‐X. Yang;G‐X. Yang;Yaron Ilan;Zhe‐Xiong Lian;Zhe‐Xiong Lian;M. E. Gershwin
我们已经证明了在表达限制于T细胞的转化生长因子-β受体（dnTGF-βRII）的显性阴性形式的小鼠中自发发生自身免疫性胆管炎，类似于人类原发性胆汁性肝硬化。自身免疫性胆管炎似乎是由自身反应性CD 8 + T淋巴细胞介导的，这些T淋巴细胞归巢于门脉和胆道系统。由于肝脏病理主要继发于CD 8 + T细胞，因此我们在本文中确定了β-葡萄糖神经酰胺（GC）（一种天然存在的植物鞘糖脂）的给药是否会改变该模型中疾病的自然史。我们选择GC是因为之前的工作已经证明了它能够改变CD 8 + T细胞反应并下调组织炎症。因此，从6周龄开始，用GC或对照处理dnTGF-βRII小鼠18周。重要的是，在接受GC的小鼠中，自身反应性肝脏浸润性CD 8 + T细胞的频率和绝对数量显著降低，同时活化的CD 44 high CD 8 + T细胞群显著降低。此外，GC处理小鼠的门静脉炎症显著减少。有趣的是，抗线粒体抗体、CD 4 + T细胞、CD 19 + B细胞或自然杀伤（NK）T细胞群没有变化，进一步表明GC对肝脏炎症的有益作用特异性靶向肝脏浸润的CD 8 + T细胞。这些数据表明，需要在CD 8 + T介导的炎症模型中进一步研究GC，并指出可能治疗和/或调节自身免疫性疾病的新治疗途径。
We have demonstrated spontaneous development of autoimmune cholangitis, similar to human primary biliary cirrhosis, in mice expressing a dominant negative form of the transforming growth factor‐β receptor (dnTGF‐βRII) restricted to T cells. The autoimmune cholangitis appears to be mediated by autoreactive CD8+ T lymphocytes that home to the portal tracts and biliary system. Because the liver pathology is primarily secondary to CD8+ T cells, we have determined herein whether administration of β‐glucosylceramide (GC), a naturally occurring plant glycosphingolipid, alters the natural history of disease in this model. We chose GC because previous work has demonstrated its ability to alter CD8+ T cell responses and to down‐regulate tissue inflammation. Accordingly, dnTGF‐βRII mice were treated with either GC or control for a period of 18 weeks beginning at 6 weeks of age. Importantly, in mice that received GC, there was a significant decrease in the frequency and absolute number of autoreactive liver‐infiltrating CD8+ T cells, accompanied by a significant decrease in activated CD44high CD8+ T cell populations. Further, there was a significant reduction in portal inflammation in GC‐treated mice. Interestingly, there were no changes in anti‐mitochondrial antibodies, CD4+ T cells, CD19+ B cells or natural killer (NK) T cell populations, indicating further that the beneficial effects of GC on liver inflammation were targeted specifically to liver‐infiltrating CD8+ T cells. These data suggest that further work on GC in models of CD8+ T‐mediated inflammation are needed and point to a new therapeutic venue for potentially treating and/or modulating autoimmune disease.