High-dose IgG therapy mitigates bile duct-targeted inflammation and obstruction in a mouse model of biliary atresia.
High-dose IgG therapy mitigates bile duct-targeted inflammation and obstruction in a mouse model of biliary atresia.
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DOI：
10.1038/pr.2014.46
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发表时间：
2014-07
影响因子：
3.6
通讯作者：
Mack, Cara L.
中科院分区：
文献类型：
--
作者：
Fenner, Erika K.;Boguniewicz, Juri;Tucker, Rebecca M.;Sokol, Ronald J.;Mack, Cara L.
一种提出的胆道闭锁(BA)的病因学是由病毒诱导的、渐进性免疫介导的胆道系统损伤。静脉注射免疫球蛋白(IVIg)已在几种炎症性疾病中显示出临床益处。本研究旨在探讨大剂量免疫球蛋白(Ig G)对恒河猴轮状病毒(RRV)诱导的小鼠BA的治疗作用。新生小鼠感染RRV后，给予高剂量免疫球蛋白或白蛋白对照。分析存活率、组织学、直接胆红素、肝脏免疫细胞亚群和细胞因子的产生情况。RRV感染组的总存活率无差异，但高剂量的免疫球蛋白导致胆红素降低，胆管炎症，肝外胆管通畅率增加。大剂量的免疫球蛋白降低血管细胞黏附分子-1，导致免疫细胞向门静脉的迁移受到限制。高剂量免疫球蛋白显著降低CD_4~+T细胞产生IL-2、干扰素-γ、肿瘤坏死因子-α和CD_8~+T细胞产生干扰素-γ，并使调节性T细胞水平升高。大剂量免疫球蛋白治疗可显著降低Th1细胞介导的炎症反应和胆道梗阻。这项研究为IVIg在婴儿BA中的临床试验提供了支持，以减少进行性肝内胆管损伤。
A proposed etiology of biliary atresia (BA) entails a virus-induced, progressive immune-mediated injury of the biliary system. Intravenous immunoglobulin (IVIg) has demonstrated clinical benefit in several inflammatory diseases. The aim of this study was to determine the therapeutic effects of high dose immunoglobulin (IgG) treatment in the rhesus rotavirus (RRV)-induced mouse model of BA. Newborn mice were infected with RRV and jaundiced mice were given high dose IgG or albumin control. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. There was no difference in overall survival between RRV-infected groups, however high dose IgG resulted in decreased bilirubin, bile duct inflammation, and increased extrahepatic bile duct patency. High dose IgG decreased vascular cell adhesion molecule-1, resulting in limited migration of immune cells to portal tracts. High dose IgG significantly decreased CD4+ T cell production of IL-2, IFN-γ and TNF-α and CD8+ T cell production of IFN-γ, as well as increased levels of regulatory T cells. High dose IgG therapy in murine BA dramatically decreased Th1 cell-mediated inflammation and biliary obstruction. This study lends support for consideration of IVIg clinical trials in infants with BA, to diminish the progressive intrahepatic bile duct injury.
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