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: 9359428
• 负责人: Jerzy W Kupiec-Weglinski
• 金额: $ 168.58万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9359428
• 关键词: Acute; Address; Affect; Allogenic; Allografting; Biopsy; Biostatistics Core; CD4 Positive T Lymphocytes; CEACAM1; Cessation of life; Clinic; Clinical; Complex; Cytoprotection; Dependence; Development; Environment; Event; Functional disorder; Goals; Gold; Hepatic; Hepatocellular Damage; Hepatocyte; Human; Immune; Immunobiology; Immunogenetics; Immunologics; Immunology; Impairment; Incidence; Inferior; Inflammation; Inflammatory; Interferon Type II; Knowledge; Laboratories; Life; Liver; Liver diseases; Liver neoplasms; Memory; Microsurgery; Molecular; Monitor; Mus; Natural Immunity; Organ; Organ Donor; Organ Preservation; Organ Procurements; Organ Transplantation; Outcome; Pathologic; Pathology; Pathway interactions; Patient Care; Patients; Phenotype; Process; Regulation; Reperfusion Injury; Research Personnel; Role; Savings; Sentinel; Severities; Signal Transduction; Solid; Specificity; Sterility; Stress; Sum; T-Cell Activation; T-Lymphocyte; TLR4 gene; TNFRSF5 gene; TNFSF5 gene; Therapeutic; Therapeutic Intervention; Tissues; Translational Research; Transplant Recipients; Transplantation; adaptive immune response; adaptive immunity; clinically relevant; exhaustion; experience; immunoregulation; improved; innovative technologies; liver allograft; liver inflammation; liver ischemia; liver transplantation; macrophage; member; memory CD4 T lymphocyte; mouse model; novel; programs; response; skills; standard of care; success; synergism; tool; transcriptomics; Acute; Address; Affect; Allogenic; Allografting; Biopsy; Biostatistics Core; CD4 Positive T Lymphocytes; CEACAM1; Cessation of life; Clinic; Clinical; Complex; Cytoprotection; Dependence; Development; Environment; Event; Functional disorder; Goals; Gold; Hepatic; Hepatocellular Damage; Hepatocyte; Human; Immune; Immunobiology; Immunogenetics; Immunologics; Immunology; Impairment; Incidence; Inferior; Inflammation; Inflammatory; Interferon Type II; Knowledge; Laboratories; Life; Liver; Liver diseases; Liver neoplasms; Memory; Microsurgery; Molecular; Monitor; Mus; Natural Immunity; Organ; Organ Donor; Organ Preservation; Organ Procurements; Organ Transplantation; Outcome; Pathologic; Pathology; Pathway interactions; Patient Care; Patients; Phenotype; Process; Regulation; Reperfusion Injury; Research Personnel; Role; Savings; Sentinel; Severities; Signal Transduction; Solid; Specificity; Sterility; Stress; Sum; T-Cell Activation; T-Lymphocyte; TLR4 gene; TNFRSF5 gene; TNFSF5 gene; Therapeutic; Therapeutic Intervention; Tissues; Translational Research; Transplant Recipients; Transplantation; adaptive immune response; adaptive immunity; clinically relevant; exhaustion; experience; immunoregulation; improved; innovative technologies; liver allograft; liver inflammation; liver ischemia; liver transplantation; macrophage; member; memory CD4 T lymphocyte; mouse model; novel; programs; response; skills; standard of care; success; synergism; tool; transcriptomics

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.

总体 - 摘要/摘要 原位肝移植（OLT）是末期肝病和 那些具有肝脏起源肿瘤的人。但是，器官短缺促使使用了扩展条件 肝脏特别容易受到缺血 - 再灌注损伤（IRI），注射/组织损伤 反应，这是器官采购和保存过程中不可避免的。我们提出了总体 假设肝脏IRI是由于先天性（例如巨噬细胞依赖性）和 自适应（T细胞驱动）免疫机制。团队的互补技能和专业知识精通 器官IRI，基本免疫学，肝脏免疫生物学和器官移植的研究，包括实验和 在该PPG计划中融合了临床，以更好地理解在肝的分子机制 先天 - 自适应免疫接口。我重点介绍了新发现的TIM-3 - CEACAM1负面 先天性的检查点调节 - IR压力ISO-olt中的自适应免疫接口。 AIM 1将阐明 CEACAM1 - 宿主循环CD4+ T细胞上的TIM-3信号传导促进T细胞功能障碍的机制 通过IRI – olt中的精疲力尽机理表型。 AIM 2将调查通过的机制 肝细胞特异性CEACAM1表达可能会区分无菌炎症/肝肝细胞 IR胁迫的ISO-OLT中的损伤与细胞保护。项目II将定义Allo特异性CD4的机制 宿主排斥反应期间的T细胞会影响与临床相关的同种异体OLT环境中的肝脏IRI。研究 专注于先前存在的效应器存储器CD4 T细胞（TEM）的子集，该细胞通过 Ag依赖性与Ag非依赖性途径，涉及对秘密IFN-γ的重新激活或促进CD154- CD40信号传导。 AIM 1将分析CD4 TEM的Ag依赖性，而AIM 2将确定 IR胁迫的allo-olt中的共刺激分子。项目III考试与先天/适应性的相互调节 免疫反应并确定同种异体记忆对事件和严重程度的贡献 人类OLT中的肝脏IRI。 AIM 1将确定潮湿/PRR信号在先天激活中的作用 IR应力下的人肝移植物的适应性免疫。 AIM 2将描述IRI的病理签名 人类OLT通过IRI活检的转录组分析，并表征急性和长期 IRI的促炎性概况。 AIM 3将确定先天和串扰的分子基础 人类OLT的自适应免疫网络患有IR损伤（Synergy：II和II项目）。这3 项目将由行政核心（核心A）支持；肝微外科核心（核心B；支持 项目I和II）；和计算/生物统计学核心（核心C;支持所有3个项目）。相关性： 这些良好整合和相互依存的项目和核心的最终共同目标是在临床上解开 在OLT接受者中调节肝脏IRI的相关机制。这些应该识别分子为A的靶标 可能针对IR应力的热干预，并促进肝移植患者的细胞保护。