Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury

总体-总结/摘要 原位肝移植（奥尔特）是终末期肝病患者的金标准治疗， 肝源性肿瘤患者。然而，器官短缺促使使用扩展标准 肝脏，特别容易受到缺血再灌注损伤（IRI），一种炎症/组织损伤 这在器官获取和保存过程中是不可避免的。我们建议， 假设肝脏IRI是由先天性（例如，巨噬细胞依赖性）和 适应性（T细胞驱动）免疫机制。精通该领域的团队的互补技能和专业知识 研究器官IRI，基础免疫学，肝脏免疫生物学和器官移植，包括实验和 临床上，融合在这个PPG倡议，以更好地了解分子机制，在肝 先天-适应性免疫界面项目I关注新发现的TIM-3 -CEACAM 1阴性 IR应激的iso-OLT中先天-适应性免疫界面的检查点调节。目标1将阐明 宿主循环CD 4 + T细胞上的CEACAM 1- TIM-3信号传导促进T细胞功能障碍的机制 IRI-OLT中通过耗竭样机制的表型。目标2将研究 肝细胞特异性CEACAM 1表达可区分无菌性炎症/肝细胞 IR应激的iso-OLT中的损伤与细胞保护。项目II将定义同种异体特异性CD 4 在临床相关的同种异体奥尔特环境中，宿主排斥反应期间的T细胞影响肝脏IRI。研究 关注预先存在的效应记忆CD 4 T细胞（TEM）的亚群，其通过以下途径对同种异体移植物激发作出反应： Ag依赖性与Ag非依赖性途径，涉及再活化以分泌IFN-γ或促进CD 154- CD 40信号转导。目标1将分析CD 4 TEM的Ag依赖性，而目标2将确定 IR应激allo-OLT中的共刺激分子。项目III研究先天/适应性的相互调节 免疫反应，并确定同种免疫记忆对发病率和严重程度的贡献 人奥尔特中肝IRI目的1将确定DAMPs/PRR信号转导在先天性和先天性神经元激活中的作用， IR应激下人肝移植物的适应性免疫。目的2将描述IRI的病理特征， 通过IRI活组织检查的转录组学分析， IRI的促炎性特征。目标3将确定先天性和非先天性之间串扰的分子基础。 适应性免疫网络在人类奥尔特遭受IR损伤（协同作用：项目I和II）。这3 项目将得到行政核心（核心A）、肝脏显微外科核心（核心B）和支持 计算/生物统计核心（核心C;支持所有3个项目）。相关性：The 这些整合良好且相互依存的项目和核心的最终共同目标是在临床上解决 调节奥尔特受者肝脏IRI的相关机制。这些应该可以识别出作为靶点的分子， 可能的治疗干预对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.