PATHOGENESIS OF CHRONIC GRAFT VERSUS HOST LIVER DISEASE

描述：该项目的长期目标是定义机制 T细胞在移植物抗宿主中介导胆管破坏的机制 疾病和原发性胆汁性肝硬变。这个项目是基于鼠标的 移植物抗宿主病模型与胆管破坏的中心假说 移植物抗宿主病是由供者识别小分子的CD4+和CD8+T细胞介导的 宿主胆管上皮细胞中的组织相容性同种异体抗原。这个 第一个特定目标是确定体外辅助性和细胞毒性 移植物抗宿主病小鼠肝脏供体T细胞功能的研究他们会 确定供者T细胞是否识别胆道限制性MIH 抗原和确定T细胞杀死胆管上皮细胞的机制 细胞。具体目的#2是确定纯化的 BALB/c肝内胆管上皮细胞(IBDE)。 他们会将提纯的胆管细胞注射到腹膜内， 并测定B10.D2小鼠的免疫应答。他们会比较T 这个系统中的细胞库是他们的GVHD模型。最后，具体地说 目的#3他们将确定中国人对促炎细胞因子的需求 移植物抗宿主病的发生。他们将通过使用基因敲除来进行这些实验 小鼠及细胞因子对IL-12和INF-γ的中和作用

DESCRIPTION: The long-term goal of this project is to define the mechanisms through which T cells mediate bile duct destruction in graft-versus-host disease and primary biliary cirrhosis. The project is based on a mouse model of GVHD and the central hypothesis that bile duct destruction during GVHD is mediated by donor CD4+ and CD8+ T cells that recognize minor histocompatibility alloantigens in the host bile duct epithelial cells. The first specific aim is to determine the in vitro helper and cytotoxic function of donor T cells isolated from livers of mice with GVHD. They will determine whether the donor T cells recognize bile duct restricted miH antigens and define the mechanism by which T cells kill bile duct epithelial cells. Specific aim #2 is to define the immunopathogenicity of purified BALB/c intrahepatic bile duct epithelial (IBDE) cells in vivo and in vitro. They will take the purified bile duct cells, inject them intraperitoneally, and determine the immune response in B10.D2 mice. They will compare the T cell repertoire in this system to their model of GVHD. Lastly, in specific aim #3 they will determine the requirement of proinflammatory cytokines in the genesis of GVHD. They will perform these experiments by using knockout mice and neutralization of IL12 and INF gamma by treatment with cytokines.