title: Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization.
abstract: Our laboratory has suggested that loss of tolerance to pyruvate dehydrogenase (PDC-E2) leads to an anti-mitochondrial antibody response and autoimmune cholangitis, similar to human primary biliary cirrhosis (PBC). We have suggested that this loss of tolerance can be induced either via chemical xenobiotic immunization or exposure to select bacteria. Our work has also highlighted the importance of genetic susceptibility. Using the non-obese diabetic (NOD) congenic strain 1101 (hereafter referred to as NOD.1101 mice), which has chromosome 3 regions from B6 introgressed onto a NOD background, we exposed animals to 2-octynoic acid (2OA) coupled to bovine serum albumin (BSA). 2OA has been demonstrated previously by a quantitative structural activity relationship to react as well as or better than lipoic acid to anti-mitochondrial antibodies. We demonstrate herein that NOD.1101 mice immunized with 2OA-BSA, but not with BSA alone, develop high titre anti-mitochondrial antibodies and histological features, including portal infiltrates enriched in CD8(+) cells and liver granulomas, similar to human PBC. We believe this model will allow the rigorous dissection of early immunogenetic cause of biliary damage.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: P S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Y
authors.initials: Y
authors.lastname: Moritoki
authors.forename: G-X
authors.initials: GX
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Lian
authors.forename: T
authors.initials: T
authors.lastname: Hibi
authors.forename: A A
authors.initials: AA
authors.lastname: Ansari
authors.forename: L S
authors.initials: LS
authors.lastname: Wicker
authors.forename: W M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: R L
authors.initials: RL
authors.lastname: Coppel
authors.forename: I R
authors.initials: IR
authors.lastname: Mackay
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D002761:Cholangitis / Q000276:immunology*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D007114:Immunization; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D016130:Immunophenotyping; D008105:Liver Cirrhosis, Biliary / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008930:Mitochondria, Liver / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015262:Xenobiotics / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015262:Xenobiotics; D012710:Serum Albumin, Bovine; C060855:2-octynoic acid