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

基本信息

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
项目类别：
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

项目摘要

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/组织损伤这是器官获取和保存过程中不可避免的反应，我们提出总体要求。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）和精通适应性（T 细胞驱动）免疫机制的团队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项目 I 重点研究新发现的 TIM-3 – CEACAM1 阴性。 IR 应激的 iso-OLT 中先天-适应性免疫界面的检查点调节将阐明。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将研究其机制。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 研究中，宿主排斥反应期间的 T 细胞会影响肝脏 IRI。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 CD40 信号传导的作用。 IR应激allo-OLT中的共刺激分子项目III检查先天/适应性的相互调节。免疫反应并确定同种免疫记忆对疾病发生率和严重程度的贡献人类 OLT 中的肝脏 IRI 目标 1 将确定 DAMPs/PRR 信号传导在先天和肝脏激活中的作用。 IR 应激下人类肝移植物的适应性免疫目标 2 将描绘 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 的促炎特性将决定先天性和炎症性之间的串扰的分子基础。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）。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 I 和 II)；以及计算/生物统计学核心（核心 C；支持所有 3 个项目）。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 OLT 受体中调节肝脏 IRI 的相关机制应将分子识别为靶点。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。