Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury

总体--摘要 原位肝移植(OLT)是终末期肝功能衰竭患者公认的治疗方法。 患有肝源性肿瘤。然而，器官短缺促使使用扩展标准的捐赠者， 它们特别容易受到缺血再灌注损伤(IRI)的影响。这一P01的首要假设 原位肝移植中IRI的更新是由于供体肝脏特异性和宿主来源的先天性之间的调节受损所致 豁免权。以高度协同的方式运作的项目和核心目标是1/确定新目标 改善供体肝脏质量的分子(器官年轻化)；2/提供新的治疗手段 急性IR应激，同时促进炎症消退(动态平衡修复)；以及3/预防持续/ 慢性炎症，以减轻同种异体免疫和改善结果(耐受性诱导)。 项目1的重点是新发现的IR触发的先天性的CEACAM1(CC1)负检查点调节 免疫激活/无菌炎症在供体肝脏复壮机制中的作用目标1和目标2将描述 在供体肝脏(S异构体)或受体来源的肝脏中强制CC1选择性剪接的机制 中性粒细胞(L异构体)在小鼠IRI-OLT中发挥抗炎/细胞保护作用(协同作用：项目2/3)。 目的3将阐明肝脏CC1的调节是否/如何改善废弃人类的功能 经过常温机器保存的肝脏(被认为是不可移植的)(协同效应：项目3)。 项目2定义了IR应激小鼠肝脏浸润性巨噬细胞和 常驻异种KCs协调肝组织内稳态的恢复。在与项目1/3的协同中， 目的1将确定胚胎来源的KCs与单核细胞来源的KCs促进肝脏的功能机制。 IR-炎症消退。AIM 2将在肝脏中定义MerTK介导的前拆分效应通路- 常驻KC。目标3将剖析KCs在原位肝移植设置中的作用，以及是否/如何缓解肝脏炎症 其动力学影响同种异体免疫的激活和移植耐受的可能获得。 项目3剖析了推动髓系细胞可塑性的先天免疫抑制和相关的辅因子/PRRs。 人类IRI-OLT患者。与项目1/2协同，目标1将确定TLR7/NOD2和TLR9配体 和信号通路介导调节性和炎症性巨噬细胞的差异极化 与T细胞的串扰。目标2将评估PRR抑制/预适应的治疗潜力以缓解 髓系细胞活化与原位肝移植-再灌注损伤。目标3将阐明DAMP/PRR内型对世代的影响 同种异体免疫和移植结果，以及潜在的移植耐受获得。 这些项目将由行政核心(核心A)、小鼠/人类肝脏外科核心(核心B)、 和计算/生物统计学核心(核心C)。这一P01统一了一家高度认可的 一群经验丰富的跨学科研究人员，精通器官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。

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.