Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-γ in experimental biliary atresia
Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-γ in experimental biliary atresia
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DOI：
10.1172/jci200421153
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发表时间：
2004-08-01
影响因子：
15.9
通讯作者：
Bezerra, JA
中科院分区：
文献类型：
--
作者：
Shivakumar, P;Campbell, KM;Bezerra, JA
胆道闭锁儿童胆管梗阻的病因和发病机制尚不清楚。我们之前曾报道过，尽管存在表型异质性，但患者肝脏的基因组特征显示出促炎表型。在这里，我们使用轮状病毒诱导的胆道闭锁小鼠模型提出了这样的假设：IFN-γ的产生是疾病的关键致病机制。我们发现新生小鼠轮状病毒感染对胆管细胞具有独特的趋向性，通过产生IFN-γ的CD4+和CD8+淋巴细胞引发肝胆炎症。这种炎症是组织特异性的，会导致进行性黄疸、生长障碍，并且由于肝外胆管阻塞导致死亡率超过 90%。在该模型中，IFN-γ的遗传缺失并没有改变黄疸的发生，但它显着抑制了T淋巴细胞的组织特异性靶向，并完全阻止了肝外胆管的炎症和纤维化阻塞。结果，黄疸消退，长期生存率提高到 80% 以上。值得注意的是，重组IFN-γ的施用导致轮状病毒感染IFN-γ缺陷小鼠后胆管阻塞复发。因此，IFN-γ驱动的胆管阻塞是疾病的关键致病机制，并且可能构成阻止胆道闭锁患者疾病进展的治疗靶点。
The etiology and pathogenesis of bile duct obstruction in children with biliary atresia are largely unknown. We have previously reported that, despite phenotypic heterogeneity, genomic signatures of livers from patients display a proinflammatory phenotype. Here, we address the hypothesis that production of IFN-gamma is a key pathogenic mechanism of disease using a mouse model of rotavirus-induced biliary atresia. We found that rotavirus infection of neonatal mice has a unique tropism to bile duct cells, and it triggers a hepatobiliary inflammation by IFN-gamma-producing CD4(+) and CD8(+) lymphocytes. The inflammation is tissue specific, resulting in progressive jaundice, growth failure, and greater than 90% mortality due to obstruction of extrahepatic bile ducts. In this model, the genetic loss of IFN-gamma did not alter the onset of jaundice, but it remarkably suppressed the tissue-specific targeting of T lymphocytes and completely prevented the inflammatory and fibrosing obstruction of extrahepatic bile ducts. As a consequence, jaundice resolved, and long-term survival improved to greater than 80%. Notably, administration of recombinant IFN-gamma led to recurrence of bile duct obstruction following rotavirus infection of IFN-gamma-deficient mice. Thus, IFN-gamma-driven obstruction of bile ducts is a key pathogenic mechanism of disease and may constitute a therapeutic target to block disease progression in patients with biliary atresia.