Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury

肝移植缺血/再灌注损伤中的先天适应性免疫调节

• 批准号: 10622451
• 负责人: Jerzy W Kupiec-Weglinski
• 金额: $ 194.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622451
• 关键词: Acute; Address; Alternative Splicing; Anti-Inflammatory Agents; Automobile Driving; Biostatistics Core; CEACAM1; Cessation of life; Chronic; Clinical; Collaborations; Cytoprotection; Donor person; Embryo; Funding; Generations; Genetic; Hepatic; Hepatic Tissue; Hepatocyte; Homeostasis; Human; Immune; Immunobiology; Immunology; Impairment; Inferior; Infiltration; Inflammation; Inflammatory; Ischemia; Journals; Kinetics; Kupffer Cells; Ligands; Liver; Liver neoplasms; Macrophage; Mediating; Molecular; Monitor; Morbidity - disease rate; Mus; Myeloid Cell Activation; Myeloid Cells; Natural Immunity; Neutrophil Infiltration; Operative Surgical Procedures; Organ; Organ Donor; Organ Transplantation; Outcome; Pathology; Pathway interactions; Patients; Peer Review; Phenotype; Predisposition; Process; Productivity; Progress Reports; Protein Isoforms; Publications; Publishing; Regulation; Rejuvenation; Reperfusion Injury; Reporting; Research Personnel; Resolution; Risk; Role; Scientist; Signal Pathway; Solid; Sterility; Stress; Syndrome; T-Lymphocyte; TLR4 gene; TLR7 gene; Therapeutic; Therapeutic Intervention; Tissues; Translational Research; Transplant Recipients; Transplantation; Transplantation Tolerance; cofactor; end stage liver disease; experience; functional improvement; immune activation; immunoregulation; improved; improved outcome; innovative technologies; isoimmunity; liver inflammation; liver ischemia; liver transplantation; monocyte; mouse model; neutrophil; notch protein; novel therapeutic intervention; novel therapeutics; originality; personalized medicine; preconditioning; preservation; prevent; programs; response; restoration; retransplantation; success; synergism; tool

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.

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，以减轻同种免疫并改善结果（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将描绘 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。

项目成果

Apheresis of Deceased Donors as a New Source of Mobilized Peripheral Blood Hematopoietic Stem Cells for Transplant Tolerance.

已故捐献者的血浆分离术作为动员外周血造血干细胞的新来源以实现移植耐受。

• DOI: 10.1097/tp.0000000000004288
• 发表时间: 2023
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Sosa,RebeccaA;Mone,Thomas;Naini,BitaV;Kohn,DonaldB;Reed,ElaineF;Wheeler,Kristina;Campo-Fernandez,Beatriz;Davila,Alejandra;Chaffin,DonaldJ;DiNorcia,Joseph;Kaldas,FadyM;Cohen,Aaron;Lum,ErikL;Veale,JeffreyL;Kogut,NeilM
• 通讯作者: Kogut,NeilM

Donor Hepatic Occult Collagen Deposition Predisposes to Peritransplant Stress and Impacts Human Liver Transplantation.

• DOI: 10.1002/hep.32030
• 发表时间: 2021-11
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Hirao, Hirofumi;Ito, Takahiro;Kadono, Kentaro;Kojima, Hidenobu;Naini, Bita, V;Nakamura, Kojiro;Kageyama, Shoichi;Busuttil, Ronald W.;Kupiec-Weglinski, Jerzy W.;Kaldas, Fady M.
• 通讯作者: Kaldas, Fady M.