Cytokines and Autoimmunity in Murine Biliary Atresia

小鼠胆道闭锁的细胞因子和自身免疫

• 批准号: 6859965
• 负责人: CARA LYNN MACK
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859965
• 关键词: IP 10 protein; SCID mouse; autoimmunity; bile ducts; biliary atresia; cytokine; disease /disorder etiology; genetically modified animals; helper T lymphocyte; immunopathology; inflammation; laboratory mouse; neutralizing antibody; passive immunization; pathologic process; virus cytopathogenic effect

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.

描述（由申请人提供）： 胆道闭锁（BA）似乎是由慢性、进行性炎症介导的肝外和肝内胆管破坏引起的，导致一些人称其为“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BA患儿需要肝移植才能生存。了解这种疾病的免疫病理学是至关重要的，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BA小鼠模型被用作研究BA发病机制中的早期事件的工具。在这项研究中要检查的假设是，持续的CD 4 + Th 1细胞介导的炎症是负责胆管上皮细胞死亡和肝外胆管梗阻。此外，慢性T细胞介导的胆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Th 1细胞介导的免疫（IP-10、IFN-γ和TNF-α）中关键参与者的作用。将通过使用缺乏感兴趣的细胞因子或趋化因子的敲除小鼠来寻求疾病发作的预防。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。将通过过继转移研究确定胆管上皮特异性自身反应性T细胞的存在，过继转移研究使用来自RRV患病小鼠和受体T细胞缺陷型SCID小鼠的供体肝T细胞。明确胆道闭锁的免疫病理机制将有助于更好地理解其发病机制，并为未来的治疗方案提供参考。