Role of Cytokines and Autoimmunity in Murine BA

描述(由申请人提供)： 胆道闭锁(BA)似乎是由慢性、进行性炎性介质对肝外和肝内胆管的破坏所致，导致一些人将其称为“婴儿闭塞性胆管病”。已经提出BA的发病机制是由于病毒诱导的、随后免疫介导的胆管破坏。大多数患有BA的儿童需要肝移植才能存活。了解这种疾病的免疫病理机制是非常重要的，以便提供可能延迟或消除移植需要的治疗方案。 轮状病毒(RRV)诱导的小鼠BA模型正被用作研究BA发病机制中早期事件的工具。这项研究的假设是，持续的CD4+Th1细胞介导的炎症是胆管上皮细胞死亡和肝外胆管梗阻的原因。此外，慢性T细胞介导的导管炎症和损伤可能继发于自身反应性胆管上皮抗原特异性T细胞。将研究Th1细胞免疫中的关键分子(IP-10、干扰素-γ和肿瘤坏死因子-α)的作用。将通过使用缺乏感兴趣的细胞因子或趋化因子的基因敲除小鼠来寻求预防疾病的发生。黄疸发作后胆道疾病的消除或改善将通过使用细胞因子或趋化因子中和抗体来确定。利用RRV病小鼠和受体T细胞缺陷SCID小鼠的供体肝脏T细胞进行过继转移研究，将确定是否存在胆管上皮特异的自体反应性T细胞。明确胆道闭锁的免疫病理学将有助于更好地了解其病因，并为未来的治疗方案提供洞察力。

DESCRIPTION (provided by applicant): Biliary atresia (BA) appears to result from a chronic, progressive inflammatory mediated destruction of extrahepatic and intrahepatic bile ducts, leading some to call it "infantile obliterative cholangiopathy". It has been proposed that the pathogenesis of BA is due to a virus-induced, subsequent immune mediated destruction of bile ducts. The majority of children with BA require liver transplantation for survival. It is of utmost importance to understand the immunopathology of this disease in order to provide treatment options which may delay or eliminate the need for transplantation. The rotavirus (RRV)-induced murine model of BA is being used as a tool to study the early events in the pathogenesis of BA. The hypotheses to be examined in this study are that persistent CD4+ Th1-cell mediated inflammation is responsible for bile duct epithelial death and extrahepatic bile duct obstruction. Furthermore, chronic T cell mediated ductal inflammation and injury may be secondary to autoreactive bile duct epithelial antigen-specific T cells. The role of key players in Th1 cell mediated immunity (IP-10, IFN-gamma and TNF-alpha) will be investigated. Prevention of disease onset will be sought through the use of knockout mice which are deficient in the cytokine or chemokine of interest. Abrogation or amelioration of the biliary disease after the onset of jaundice will be determined by the use of cytokine or chemokine neutralizing antibodies. Determination of the presence of autoreactive T cells specific to bile duct epithelium will be performed through adoptive transfer studies utilizing donor liver T cells from RRV-diseased mice and recipient T cell deficient SCID mice. Defining the immunopathology in biliary atresia will lead to a better understanding of the etiopathogenesis and provide insight into future therapeutic options.