Amelioration of non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice by oral immune regulation towards liver-extracted proteins is associated with elevated intrahepatic NKT lymphocytes and serum IL-10 levels
Amelioration of non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice by oral immune regulation towards liver-extracted proteins is associated with elevated intrahepatic NKT lymphocytes and serum IL-10 levels
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DOI：
10.1002/path.1869
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发表时间：
2006-01-01
影响因子：
7.3
通讯作者：
Ilan, Y
中科院分区：
文献类型：
--
作者：
Elinav, E;Pappo, O;Ilan, Y
非酒精性脂肪性肝炎（NASH）是西方世界隐源性肝硬化的常见原因。在NASH动物模型中，瘦素缺陷型ob/ob小鼠肝脏NKT和外周CD 4淋巴细胞的数量和功能发生改变。口服免疫调节是改变对口服施用的抗原的免疫应答的方法。为了确定口服免疫调节对肝脏提取的蛋白质对ob/ob小鼠代谢紊乱的影响，口服给予野生型或ob/ob小鼠的肝脏提取物或牛血清白蛋白1个月。通过磁共振成像（MRI）和组织学脂肪性肝炎分级量表测量治疗对肝脏脂肪含量的影响。通过口服葡萄糖耐量试验（GTT）测量葡萄糖耐量。流式细胞术分析T淋巴细胞亚群。通过口服肝脏提取的蛋白质诱导免疫调节导致用野生型或ob/ob肝脏提取物喂养1个月的ob/ob小鼠的肝脏脂肪含量显著降低18%。治疗组小鼠的MRI信号强度指数分别降至0.48和0.51，而饲喂BSA的对照组为0.62（分别为p = 0.037和p = 0.019），而两个治疗组的组织学脂肪性肝炎评分均降至2.0，而饲喂BSA的对照组为2.4（p = 0.05）。在治疗的ob/ob小鼠中观察到GTT的显著改善。这些变化伴随着喂食从野生型和ob/ob小鼠提取的蛋白质的小鼠中肝内NKT淋巴细胞群体的显著增加（分别为46.96%和56.72%，而喂食BSA的对照组为26.21%; p < 0.05）和血清IL-10水平的显著升高。对瘦素缺乏小鼠肝脏提取蛋白的口服免疫调节导致肝脏脂肪含量显着降低，并改善葡萄糖耐量。这种效应与肝内NKT淋巴细胞群和血清IL-10水平的显著增加相关，表明Th 1向Th 2免疫转移。针对疾病相关抗原的免疫调节有望成为NASH治疗的新模式。版权所有（c）2005英国和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Non-alcoholic steatohepatitis (NASH) is a common cause of cryptogenic cirrhosis in the Western world. In an animal model of NASH, leptin-deficient ob/ob mice present with alterations in number and function of hepatic NKT and peripheral CD4 lymphocytes. Oral immune regulation is a method to alter the immune response towards orally administered antigens. To determine the effect of oral immune regulation towards liver-extracted proteins on the metabolic disorders in ob/ob mice, ob/ob mice and their lean littermates were orally administered liver extracts from wild-type or ob/ob mice or bovine serum albumin for I month. The effect of treatment on hepatic fat content was measured by magnetic resonance imaging (MRI) and using a histological steatohepatitis grading scale. Glucose tolerance was measured by an oral glucose tolerance test (GTT). T lymphocyte subpopulations were assessed by flow cytometry analysis. Induction of immune regulation by oral presentation of liver-extracted proteins resulted in a significant 18% reduction of the hepatic fat content in ob/ob mice fed with either wild-type or ob/ob liver extracts for 1 month. The MRI signal intensity index in treated mice decreased to 0.48 and 0.51, respectively, compared with 0.62 in BSA-fed controls (p = 0.037 and p = 0.019, respectively), while the histological steatohepatitis score decreased in both treated groups to 2.0, compared with 2.4 in BSA-fed controls (p = 0.05). A significant improvement in GTT was noted in treated ob/ob mice. These changes were accompanied by a marked increase in the intrahepatic NKT lymphocyte population in mice fed with proteins extracted from both wild-type and ob/ob mice (46.96% and 56.72%, respectively, compared with 26.21% in BSA-fed controls; p < 0.05) and a significant elevation in serum IL-10 levels. Oral immune regulation towards liver extracted proteins in leptin-deficient mice resulted in a marked reduction in hepatic fat content and improved glucose tolerance. This effect was associated with a significant increase in the intrahepatic NKT lymphocyte population and serum IL-10 levels, suggesting a Th1 to Th2 immune shift. Immune regulation towards disease-associated antigens holds promise as a new mode of therapy for NASH. Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.