Novel Model of Antigen-Specific Induction of Bile Duct Injury

James Buxbaum, Peiqing Qian, Ciera Khuu, Benjamin L. Shneider, David I. Daikh, M. Eric Gershwin, Paul M. Allen, Marion G. Peters

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10 Scopus citations

Abstract

Background & Aims: Biliary-directed inflammation is an important cause of acute and chronic liver disease. We developed and characterized a transgenic mouse model of immune-mediated hepatobiliary injury. Methods: Ovalbumin (OVA)-BIL mice were developed using 3.0 kilobase of the rat apical sodium-dependent bile acid transporter promoter to drive aberrant expression of a membrane form of ovalbumin (OVA) on biliary epithelium. Liver inflammation resulted from adoptive transfer of OVA-specific T cells. Liver immune cells were characterized to determine the mechanism of the response by assessing activation, proliferation, and intracellular cytokine expression. Results: OVA-BIL transgenic mice were tolerant to OVA, without evidence of liver disease. Adoptive transfer of OVA-specific CD4+ and CD8+ T cells into naïve OVA-BIL mice led to biliary-centered necroinflammatory damage in a dose-dependent manner. This inflammation absolutely required CD8+ T cells and was augmented by CD4+ T cells. Adoptively transferred OVA CD8+ cells homed to and proliferated in the liver but not the spleen. These activated, adoptively transferred cytotoxic T lymphocytes produced elevated levels of tumor necrosis factor α and interferon γ. Conclusions: T-cell recognition of antigen aberrantly expressed on bile duct epithelium induced an acute necroinflammatory response specific to the liver, with activation, proliferation, and cytokine production predominantly by the OVA-specific cytotoxic T cells. Thus, OVA BIL represents an antigen-specific animal model of inflammatory bile duct injury.

Original languageEnglish
Pages (from-to)1899-1906
Number of pages8
JournalGastroenterology
Volume131
Issue number6
DOIs
StatePublished - Dec 2006

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    Buxbaum, J., Qian, P., Khuu, C., Shneider, B. L., Daikh, D. I., Gershwin, M. E., Allen, P. M., & Peters, M. G. (2006). Novel Model of Antigen-Specific Induction of Bile Duct Injury. Gastroenterology, 131(6), 1899-1906. https://doi.org/10.1053/j.gastro.2006.10.020