Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury

总体--摘要/摘要 原位肝移植(OLT)是终末期肝病患者治疗的金标准。 患有肝源性肿瘤的。然而，器官短缺促使了扩展标准的使用 肝脏特别容易受到缺血再灌注损伤(IRI)的影响，IRI是一种炎症/组织损伤 反应，这在器官采购和保存过程中是不可避免的。我们建议最重要的是 假设肝脏IRI是由于先天(如巨噬细胞依赖)和巨噬细胞之间的调节受损所致 适应性(T细胞驱动)免疫机制。团队的技能和专长互补--精通 器官IRI、基础免疫学、肝脏免疫生物学和器官移植的研究 临床上，被融合在这个PPG倡议中，以更好地理解在肝脏运行的分子机制 先天免疫-适应性免疫接口。项目I关注的是新发现的TIM-3-CEACAM1阴性 IR应激异体原位肝移植天然免疫界面的检查点调节。目标1将澄清 CEACAM1-TIM-3信号转导宿主循环CD4+T细胞促进T细胞功能障碍的机制 IRI-OLT通过类耗竭机制的表型。目标2将调查通过哪些机制 肝细胞特异性CEACAM1的表达可区分无菌炎症/肝细胞 IR应激异位原位肝移植的损伤与细胞保护。项目II将定义同种异体特异性CD4的机制 在临床相关的同种异体原位肝移植中，宿主排斥反应中的T细胞影响肝脏IRI。研究 重点关注先前存在的效应记忆CD4T细胞(TEM)的子集，它们通过 银依赖途径与非银依赖途径，包括重新激活以分泌干扰素-γ或促进CD154. CD40信号。目标1将分析CD4TM对Ag的依赖，而目标2将确定 IR应激异体原位肝移植中的共刺激分子。项目III考察了先天/适应性的相互调节 免疫反应并确定同种免疫记忆对急性脑出血的发生率和严重程度的影响 人原位肝移植中的肝脏IRI目标1将确定DAMPS/PRR信号在激活先天和 IR应激下人肝移植物的适应性免疫。目标2将描绘IRI的病理特征 通过对IRI活检组织的转录剪裁分析进行人类原位肝移植，并表征急性和长期 IRI的促炎性特征。目标3将确定先天和先天之间串扰的分子基础 遭受IR损伤的人原位肝移植中的适应性免疫网络(协同作用：项目I和II)。这3个 项目将得到行政核心(核心A)、肝脏显微外科核心(核心B；支助)的支持 项目I和II)；计算/生物统计核心(核心C；支持所有3个项目)。相关性： 这些整合良好和相互依赖的项目和核心的最终共同目标是在临床上解体 肝移植受者肝脏IRI调节的相关机制。这些应该识别分子作为目标 可能的治疗干预，以对抗IR应激，并促进肝移植患者的细胞保护。

OVERALL – SUMMARY/ABSTRACT Orthotopic liver transplantation (OLT) is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin. However, the organ shortage has prompted the use of extended criteria livers, which are particularly susceptible to ischemia-reperfusion injury (IRI), an inflammation/tissue damage response, which is inevitable during organ procurement and preservation. We propose the overarching hypothesis that liver IRI results from impaired regulation between innate (e.g., macrophage-dependent) and adaptive (T cell-driven) immune mechanisms. Complementary skills and expertise of the team well-versed in the study of organ IRI, basic immunology, liver immunobiology, and organ transplantation, both experimental and clinical, are melded in this PPG initiative to better appreciate molecular mechanisms that operate at the hepatic innate - adaptive immune interface. Project I focuses on a newly discovered TIM-3 – CEACAM1 negative checkpoint regulation of innate – adaptive immune interface in IR-stressed iso-OLT. Aim 1 will elucidate mechanisms by which CEACAM1 – TIM-3 signaling on host circulating CD4+ T cells promotes T cell dysfunction phenotype via exhaustion-like mechanism in IRI–OLT. Aim 2 will investigate mechanisms by which hepatocellular-specific CEACAM1 expression may discriminate between sterile inflammation/liver hepatocellular damage vs. cytoprotection in IR-stressed iso-OLT. Project II will define mechanisms by which allo-specific CD4 T cells during the host rejection response influence liver IRI in clinically-relevant allogeneic OLT settings. Studies focus on a subset of pre-existing effector memory CD4 T cells (TEM), which respond to allograft challenge via Ag-dependent vs. Ag non-dependent pathways, involving reactivation to secrete IFN-γ or to promote CD154 - CD40 signaling. Aim 1 will analyze the Ag-dependence of CD4 TEM, while Aim 2 will ascertain the role of costimulatory molecules in IR-stressed allo-OLT. Project III examines reciprocal regulation of innate/adaptive immune responses and determines the contribution of alloimmune memory on the incidence and severity of hepatic IRI in human OLT. Aim 1 will determine the role of DAMPs/PRR signaling in the activation of innate and adaptive immunity in human liver grafts under IR-stress. Aim 2 will delineate the pathological signature of IRI in human OLT via transcriptomic profiling of IRI biopsies and characterize the acute and long-term pro-inflammatory profile of IRI. Aim 3 will determine the molecular basis for crosstalk between innate and adaptive immune networks in human OLT that suffer from IR-damage (synergy: Project I and II). These 3 Projects will be supported by an Administrative Core (Core A); Liver Microsurgery Core (Core B; supports Project I and II); and Computational/Biostatistics Core (Core C; supports all 3 Projects). Relevance: The ultimate shared goal of these well-integrated and interdependent Projects and Cores is to unravel clinically relevant mechanisms that regulate hepatic IRI in OLT recipients. These should identify molecules as targets for a possible therapeutic intervention against IR-stress, and promote cytoprotection in liver transplant patients.