Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury

总体-摘要 原位肝移植（奥尔特）是终末期肝功能衰竭患者的公认治疗方法， 肝源性肿瘤然而，器官短缺促使人们使用扩展标准的捐赠者， 其对缺血再灌注损伤（IRI）特别敏感。该P01的总体假设 更新是IRI在奥尔特中的结果，供体肝脏特异性和宿主来源的先天性之间的调节受损 免疫力该项目和核心目标以高度协同的方式发挥作用，1/确定新的目标 用于改善供体肝脏质量（器官再生）的分子; 2/提供了新的治疗手段， 急性IR应激，同时促进炎症消退（稳态修复）;和3/预防持续的/ 慢性炎症，以减轻同种异体免疫和改善结果（耐受诱导）。 项目1关注新发现的CEACAM 1（CC 1）负检查点调节IR触发的先天性 免疫激活/无菌性炎症在供肝再生机制中的作用。目标1和2将描述 在供体肝脏（S-同种型）中强制CC 1选择性剪接的机制，或供体来源的 中性粒细胞（L-同种型）在小鼠IRI-OLT中发挥抗炎/细胞保护功能（协同作用：项目2/3）。 目的3将阐明是否/如何调节肝脏CC 1可能改善废弃人的功能， 肝脏（视为不可移植），当受到常温机器保存（协同作用：项目3）。 项目2定义了IR应激小鼠肝脏浸润巨噬细胞重编程的机制， 驻留的异质性KC协调肝组织稳态的恢复。与项目1/3协同， 目的1将确定胚胎与单核细胞来源的KCs促进肝脏的功能机制 IR-炎症消退。目标2将定义肝脏中MerTK介导的促消退效应子途径- 居民卡。目的3将剖析KCs在奥尔特设置中的作用，以及是否/如何解决肝脏炎症 其动力学影响同种免疫的激活和移植耐受的推定获得。 项目3剖析了先天免疫DAMP和相关的辅助因子/PRR驱动骨髓细胞可塑性， 人IRI-OLT患者。与项目1/2协同，目标1将确定TLR 7/NOD 2和TLR 9配体 和介导调节性与炎性巨噬细胞的差异极化的信号传导途径， 与T细胞的串扰。目的2将评估PRR抑制/预处理的治疗潜力， 骨髓细胞活化和OLT-IRI。目的3将阐明DAMP/PRR内型对产生的影响， 同种免疫和移植物结果，以及潜在的移植耐受获得。 这些项目将得到行政核心（核心A）、小鼠/人类肝脏手术核心（核心B）、 计算/生物统计学核心（计算/生物统计学核心C）。这P01统一了一个高度成熟的集体专业知识， 经验丰富的跨学科研究人员，精通器官IRI研究，基础免疫学， 肝脏免疫生物学和器官移植，包括实验和临床。

OVERALL – ABSTRACT Orthotopic liver transplantation (OLT) is the accepted treatment in patients with end-stage liver failure and those with tumors of hepatic origin. However, the organ shortage has prompted the use of extended criteria donors, which are particularly susceptible to ischemia-reperfusion injury (IRI). The overarching hypothesis of this P01 renewal is that IRI in OLT results from impaired regulation between donor liver-specific and host-derived innate immunity. The project and core objectives, functioning in a highly synergistic manner, are to 1/ identify new target molecules for improving donor liver quality (organ rejuvenation); 2/ provide novel therapeutic means against acute IR-stress while promoting inflammation resolution (homeostatic reparation); and 3/ prevent sustained/ chronic inflammation to mitigate alloimmunity and improve outcomes (tolerance induction). Project 1 focuses on a newly discovered CEACAM1 (CC1) negative checkpoint regulation of IR-triggered innate immune activation/sterile inflammation in the mechanism of donor liver rejuvenation. Aim 1 and 2 will delineate mechanisms by which enforced CC1 alternative splicing in the donor liver (S-isoform), or the recipient-derived neutrophils (L-isoform) exert anti-inflammatory/cytoprotective functions in mouse IRI-OLT (synergy: Project 2/3). Aim 3 will elucidate whether/how modulation of hepatic CC1 might improve the function of discarded human livers (deemed untransplantable) when subjected to normothermic machine preservation (synergy: Project 3). Project 2 defines mechanisms by which reprogramming of IR-stressed mouse liver-infiltrating macrophages and resident heterogeneic KCs orchestrate the restoration of hepatic tissue homeostasis. In synergy with Project 1/3, Aim 1 will determine the functional mechanisms by which embryonic vs. monocyte-derived KCs promote liver IR-inflammation resolution. Aim 2 will define MerTK-mediated pro-resolution effector pathways in the liver- resident KCs. Aim 3 will dissect the roles of KCs in OLT settings and whether/how liver inflammation resolution and its kinetics impact the activation of alloimmunity and putative acquisition of transplant tolerance. Project 3 dissects the innate immune DAMPs and associated cofactors/PRRs driving myeloid cell plasticity in human IRI-OLT patients. In synergy with Project 1/2, Aim 1 will determine the TLR7/NOD2 and TLR9 ligands and signaling pathways mediating differential polarization of regulatory vs. inflammatory macrophages and crosstalk with T cells. Aim 2 will assess the therapeutic potential of PRR inhibition/preconditioning to mitigate myeloid cell activation and OLT-IRI. Aim 3 will elucidate the impact of DAMP/PRR endotypes on the generation of alloimmunity and graft outcome, and potential transplantation tolerance acquisition. The Projects will be supported by an Administrative Core (Core A), Mouse/Human Liver Surgery Core (Core B), and Computational/Biostatistics Core (Core C). This P01 unifies the well-proven collective expertise of a highly experienced and interdisciplinary group of investigators, well-versed in the study of organ IRI, basic immunology, liver immunobiology, and organ transplantation, both experimental and clinical.