TLRs介导的固有免疫通路在肝移植术后早期移植物失功中的作用及其对缺血型胆道病变的影响和机制研究

项目名称： TLRs介导的固有免疫通路在肝移植术后早期移植物失功中的作用及其对缺血型胆道病变的影响和机制研究

项目编号： No.81470900

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 傅志仁

作者单位： 中国人民解放军第二军医大学

项目金额： 73万元

中文摘要： 肝移植术后缺血型胆道病变（ITBL）发生率高达15%-31%，其中15%的ITBL需行再次移植。临床肝癌肝移植分析显示：术后长期服用索拉非尼的受者ITBL发生率明显偏低。索拉非尼作为多激酶抑制剂，其重要的机制是抑制MEK信号传导。而我们在预实验中通过表达谱测序分析和流式检测发现，发生早期移植物失功（EAD）的患者移植肝和外周血样本中MEK下游信号激活，且固有免疫细胞亚群改变明显。我们推测：肝移植术后EAD与ITBL可能是一个连续的过程，EAD中发生的固有免疫持续存在并对移植肝尤其是胆道系统造成慢性损伤，最终导致ITBL。因此，我们拟通过热缺血和冷缺血诱发ITBL 模型，采用TLRs和RIG-I缺陷小鼠寻找ITBL涉及的固有免疫通路，进一步通过体外实验研究相关通路下游蛋白和分子在EAD和ITBL发生中的作用机制。该研究将为肝移植术后ITBL提供潜在的预防治疗靶点，更有效的防止移植物丢失。

中文关键词： 固有免疫；肝移植；早期移植物失功；toll样受体；缺血型胆道病变

英文摘要： The incidence of ischemic-type biliary lesions (ITBL) after liver transplantation is as high as 15%-30%. And 15% of ITBL recipients need retransplantation. Clinical analysis showed lower morbidity of ITBL for hepatocellular carcinoma patients long-term using sorafenib after liver transplantationc. As a multikinase inhibitor, sorafenib can suppress the MEK signaling. Besides, we found in preliminary experiment that MEK downstream signaling events were activated and subset of innate immune cells changed significantly in liver graft and periferal blood of patients with occurrence of early allograft dysfunction (EAD), using expression profiles sequencing analysis and flow cytomery. We hypothesized that EAD and ITBL after liver transplantation was likely to be a continuous process, in which the innate immunity in the EAD persisted and led chronic damage to liver graft, especially to the biliary system, eventually gave rise to ITBL. In the current project, we will establish warm and cold ischemia induced ITBL models, and explore the potential innate immune pathways involved in the ITBL using TLRs-/- and RIG-I-/- mice. We will also make a further research on mechanism of downstream proteins and molecules, in related pathways, on EAD and ITBL. The study will provide potential targets for ITBL prevention and treatment, more effectively decreasing graft loss.

英文关键词： innate immunity;liver transplantation;early allograft dysfunction;toll-like receptors;ischemic-type biliary lesions