title: 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.
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.
authors.affiliation: Liver Unit, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.forename: Miriam
authors.initials: M
authors.lastname: Sklair-Levy
authors.forename: Maya
authors.initials: M
authors.lastname: Margalit
authors.forename: Oren
authors.initials: O
authors.lastname: Shibolet
authors.forename: Moshe
authors.initials: M
authors.lastname: Gomori
authors.forename: Roslana
authors.initials: R
authors.lastname: Alper
authors.forename: Barbara
authors.initials: B
authors.lastname: Thalenfeld
authors.forename: Dean
authors.initials: D
authors.lastname: Engelhardt
authors.forename: Elazar
authors.initials: E
authors.lastname: Rabbani
authors.forename: Yaron
authors.initials: Y
authors.lastname: Ilan
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D016207:Cytokines / Q000097:blood; D005234:Fatty Liver / Q000276:immunology* / Q000473:pathology; D018149:Glucose Intolerance / Q000276:immunology*; D005951:Glucose Tolerance Test; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000097:blood*; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D014280:Triglycerides / Q000097:blood
chemical_list: D000941:Antigens; D016207:Cytokines; D014280:Triglycerides; D016753:Interleukin-10