Novel model of antigen-specific induction of bile duct injury.
OBJECTIVE
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 alpha and interferon gamma.


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.
Buxbaum
James
J
Department of Medicine, University of California, San Francisco, California 94143-0538, USA.
Qian
Peiqing
P
Khuu
Ciera
C
Shneider
Benjamin L
BL
Daikh
David I
DI
Gershwin
M Eric
ME
Allen
Paul M
PM
Peters
Marion G
MG
D019264:Adoptive Transfer / Q000009:adverse effects* / Q000379:methods*; D000818:Animals; D000941:Antigens / Q000276:immunology*; D001649:Bile Duct Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000941:Antigens; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D010047:Ovalbumin