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

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——总结/摘要 原位肝移植（OLT）是终末期肝病患者的金标准 患有肝源性肿瘤的人。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）的影响，这是一种炎症/组织损伤 器官获取和保存过程中不可避免的反应。我们建议总体 假设肝脏 IRI 是由先天性（例如巨噬细胞依赖性）和先天性（例如巨噬细胞依赖性）和 适应性（T 细胞驱动）免疫机制。团队精通的互补技能和专业知识 器官 IRI、基础免疫学、肝脏免疫生物学和器官移植的研究，包括实验和 临床，都融入到这个 PPG 计划中，以更好地理解在肝脏中运作的分子机制 先天-适应性免疫界面。项目 I 重点关注新发现的 TIM-3 – CEACAM1 阴性 IR 应激 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 CD4+ T 细胞上的 CEACAM1 – TIM-3 信号传导促进 T 细胞功能障碍的机制 IRI-OLT 中通过类似耗竭机制的表型。目标 2 将研究机制 肝细胞特异性 CEACAM1 表达可区分无菌炎症/肝脏肝细胞 IR 应激 iso-OLT 中的损伤与细胞保护。项目 II 将定义同种异体特异性 CD4 的机制 在临床相关的同种异体 OLT 环境中，宿主排斥反应期间的 T 细胞会影响肝脏 IRI。研究 重点关注预先存在的效应记忆 CD4 T 细胞 (TEM) 的子集，它们通过以下方式响应同种异体移植挑战 Ag 依赖性途径与 Ag 非依赖性途径，涉及重新激活以分泌 IFN-γ 或促进 CD154 - CD40 信号传导。目标 1 将分析 CD4 TEM 的 Ag 依赖性，而目标 2 将确定 IR应激的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免疫反应的发生率和严重程度的贡献 人 OLT 中的肝脏 IRI。目标 1 将确定 DAMPs/PRR 信号传导在先天性和 红外应激下人肝移植物的适应性免疫。目标 2 将描述 IRI 的病理特征 通过 IRI 活检的转录组学分析进行人类 OLT 分析，并表征急性和长期 IRI 的促炎特征。目标 3 将确定先天和先天之间串扰的分子基础 人类 OLT 中遭受 IR 损伤的适应性免疫网络（协同作用：项目 I 和 II）。这3个 项目将得到行政核心（核心 A）的支持；肝脏显微外科核心（核心 B；支持 项目一和二）；和计算/生物统计核心（核心 C；支持所有 3 个项目）。相关性： 这些充分整合且相互依赖的项目和核心的最终共同目标是在临床上解决问题 调节 OLT 受者肝脏 IRI 的相关机制。这些应该将分子识别为目标 可能的针对IR应激的治疗干预，并促进肝移植患者的细胞保护。