Intrahepatic T cell responses to hepatotropic viruses in transgenic mice with inducible viral gene expression in the liver

肝脏中可诱导病毒基因表达的转基因小鼠肝内 T 细胞对亲肝病毒的反应

• 批准号: 5432794
• 负责人: Professorin Dr. Dagmar Wirth
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2004
• 资助国家: 德国
• 起止时间: 2003-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5432794?language=en
• 关键词: Intrahepatic; cell; responses; hepatotropic; viruses

The clearance of the acute infection of hepatotropic viruses (HBV, HCV) is CD8+ T cell-dependent. The failure of this anti-viral T cell response leads to chronic virus infection; and the reconstitution of this T cell reactivity is the key objective of therapeutic vaccination. Informative preclinical models are required to develop vaccination strategies that prime CD8+ T cell responses with functional anti-viral activity in the liver. The objective of this application is to achieve the select ble (transient) expression of viral genes in the liver using transgenic mice to mimic viral infection. These mice will be generated by crossing two mouse lines: the first line expresses a tamoxifen-inducible Cre recombinase/human estrogen receptor (hEr) fusion protein selectively in the liver from an approved albumin promoter/a-fetoprotein enhancer control region. The second line carries a 'knock in' into the ubiquitously expressed ROSA26 locus of an antigen cassette which requires a Cre-mediated recombination step for activation. The antigen cassette will be tagged by FRT sites, which facilitates the efficient exchange of antigens in ES cells. Crossing both lines will generate a double transgenic line, in which expression of the viral genes is restricted to the liver and inducible. This system will provide a novel preclinical research tool to study priming, or homing of primed anti-viral CD8+ T cells in the liver that transiently expresses antigens of HBV and HCV. The system can be readily modified to study the influence of cytokines (or their signals) in the establishment of functional CD8+ T cell immunity in the liver.

嗜肝病毒（HBV、HCV）急性感染的清除依赖于 CD8+ T 细胞。这种抗病毒 T 细胞反应失败会导致慢性病毒感染；重建这种 T 细胞反应性是治疗性疫苗接种的关键目标。需要信息丰富的临床前模型来开发疫苗接种策略，以在肝脏中启动具有功能性抗病毒活性的 CD8+ T 细胞反应。该应用的目的是使用转基因小鼠模拟病毒感染，实现病毒基因在肝脏中的选择性 ble（瞬时）表达。这些小鼠将通过两个小鼠系杂交产生：第一个系在肝脏中从批准的白蛋白启动子/甲胎蛋白增强子控制区选择性表达他莫昔芬诱导的 Cre 重组酶/人雌激素受体 (hEr) 融合蛋白。第二条线路携带“敲入”抗原盒中普遍表达的 ROSA26 基因座，这需要 Cre 介导的重组步骤才能激活。抗原盒将被FRT位点标记，这有利于ES细胞中抗原的有效交换。两个品系杂交将产生双转基因品系，其中病毒基因的表达仅限于肝脏并且是可诱导的。该系统将提供一种新颖的临床前研究工具，用于研究肝脏中瞬时表达 HBV 和 HCV 抗原的启动抗病毒 CD8+ T 细胞的启动或归巢。该系统可以很容易地进行修改，以研究细胞因子（或其信号）对肝脏中功能性 CD8+ T 细胞免疫建立的影响。