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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

2005; Volume: 208; Issue: 1 Linguagem: Inglês

10.1002/path.1869

1096-9896

Eran Elinav, Orit Pappo, Miriam Sklair‐Levy, Maya Margalit, Oren Shibolet, Moshe Gomori, R. Alper, Barbara Thalenfeld, Dean Engelhardt, Elazar Rabbani, Yaron Ilan,

Regulation of Appetite and Obesity

Abstract 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 1 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 © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.