Buxbaum James, Qian Peiqing, Khuu Ciera, Shneider Benjamin L, Daikh David I, Gershwin M Eric, Allen Paul M, Peters Marion G
Department of Medicine, University of California, San Francisco, California 94143-0538, USA.
Gastroenterology. 2006 Dec;131(6):1899-906. doi: 10.1053/j.gastro.2006.10.020. Epub 2006 Oct 14.
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.
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.
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.
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.
胆汁定向性炎症是急慢性肝病的重要病因。我们构建并鉴定了一种免疫介导的肝胆损伤转基因小鼠模型。
利用3.0千碱基的大鼠顶端钠依赖性胆汁酸转运体启动子构建卵清蛋白（OVA）-BIL小鼠，以驱动卵清蛋白（OVA）膜形式在胆管上皮细胞上异常表达。肝脏炎症由OVA特异性T细胞的过继转移引起。通过评估活化、增殖和细胞内细胞因子表达来鉴定肝脏免疫细胞，以确定反应机制。
OVA-BIL转基因小鼠对OVA耐受，无肝病证据。将OVA特异性CD4+和CD8+T细胞过继转移到未致敏的OVA-BIL小鼠中，以剂量依赖方式导致以胆管为中心的坏死性炎症损伤。这种炎症绝对需要CD8+T细胞，且CD4+T细胞会增强炎症。过继转移的OVA CD8+细胞归巢至肝脏并在肝脏中增殖，但不在脾脏中增殖。这些活化的、过继转移的细胞毒性T淋巴细胞产生升高水平的肿瘤坏死因子α和干扰素γ。
T细胞对胆管上皮细胞异常表达的抗原的识别诱导了肝脏特异性的急性坏死性炎症反应，主要由OVA特异性细胞毒性T细胞活化、增殖并产生细胞因子。因此，OVA BIL代表了一种炎症性胆管损伤的抗原特异性动物模型。
