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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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.