PATHOGENESIS OF CHRONIC GRAFT VERSUS HOST LIVER DISEASE

描述：本项目的长期目标是定义 T细胞通过其介导移植物抗宿主中的胆管破坏 原发性胆汁性肝硬化 该项目是基于鼠标 GVHD模型和中心假设， GVHD是由供体CD4+和CD8 + T细胞介导的， 组织相容性同种异体抗原在宿主胆管上皮细胞。 的 第一个具体目的是确定体外辅助和细胞毒性 从患有GVHD的小鼠的肝脏分离的供体T细胞的功能。 他们将 确定供体T细胞是否识别胆管限制性miH 抗原，并确定T细胞杀死胆管上皮细胞的机制 细胞 具体目标#2是定义纯化的免疫原性。 BALB/c肝内胆管上皮（IBDE）细胞在体内和体外。 他们将提取纯化的胆管细胞，注入腹腔， 并测定B10.D2小鼠的免疫应答。 他们会比较T 细胞库与GVHD模型相匹配。 最后，具体而言， 目的#3他们将确定促炎细胞因子的需求， GVHD的起源 他们将用基因敲除技术 小鼠和通过用细胞因子处理中和IL 12和INF γ。

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.