TIM-3 Negative Costimulation Signaling at the Innate-Adaptive Immune interface in Liver Transplant Ischemia-Reperfusion Injury

肝移植缺血再灌注损伤中先天适应性免疫界面的 TIM-3 负共刺激信号

• 批准号: 9198218
• 负责人: Jerzy W Kupiec-Weglinski
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198218
• 关键词: Ablation; Address; Adhesions; Adoptive Transfer; Affect; Antioxidants; Autophagocytosis; Biological; Bone Marrow; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Clinical; Coculture Techniques; Cryopreservation; Cytoprotection; Data; Development; Endothelial Cells; Foundations; Galactose Binding Lectin; Galectin 3; HMGB1 Protein; Hepatic; Hepatocyte; Homeostasis; Hydrogen Peroxide; ITGAM gene; Immune; Immune Tolerance; Immunity; Immunoglobulins; In Situ; In Vitro; Inflammation; Injury; Ischemia; Label; Ligands; Ligation; Liver; Liver diseases; Liver neoplasms; Liver parenchyma; Macrophage Activation; Modeling; Molecular; Mucins; Mus; Organ; Organ Donor; Organ Transplantation; Outcome; Oxidation-Reduction; PPBP gene; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Population; Process; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Resistance; Response Elements; Sentinel; Signal Pathway; Signal Transduction; Sterility; Stress; System; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TLR4 gene; Testing; Therapeutic Intervention; Tissues; Transplant Recipients; Warm Ischemia; allograft rejection; clinically relevant; conditioning; experimental study; immunoregulation; improved; in vivo; liver ischemia; liver transplantation; macrophage; mouse model; novel; novel strategies; novel therapeutics; p65; preconditioning; programs; public health relevance; receptor; response; success; targeted treatment; trafficking

 DESCRIPTION (provided by applicant): Ischemia-reperfusion injury (IRI) remains the primary obstacle limiting the success of orthotopic liver transplantation (OLT) in patients with end-stage liver disease and those with tumors of hepatic origin. Our group has pioneered the concept that hepatic IRI, an exogenous Ag-independent, innate immune-dominated sterile inflammation response, requires activated CD4+ T cells to facilitate tissue damage. T cell Immunoglobulin Mucin (TIM)-3 receptor has been recognized as a central regulator of T cell activation in a number of auto- / allo-immunity pathologies and organ transplantation. We reported that disruption of TIM-3 - Gal-9 pathway exacerbated hepatocellular injury in mouse livers subjected to warm IR. Then, we found that recipient CD4+TIM-3+ cells conferred resistance against liver IRI, suggesting a discrete host T cell subset should be spared while applying T cell-targeted therapy in transplant recipients. This proposal explores the function of TIM-3 signaling pathway in the mechanism of hepatic IRI in a clinically relevant mouse model of extended cold storage followed by orthotopic liver transplantation (OLT). First, we found that stressed hepatocytes express Gal-9 and HMGB1, i.e., known TIM-3 ligands. Second, we discovered robust expression of TIM-3 on activated liver endothelial cells (LEC). These preliminary data have led us to a central hypothesis that negative regulation between hepatocellular-derived Gal-9/HMGB1 and TIM-3 expressed on host circulating CD4+ T cells/graft LEC is essential to control tissue injury, and impose cytoprotective phenotype in IR-stressed OLT. Two interlocked specific aims will test this hypothesis: Aim 1: Define molecular mechanisms by which hepatocyte Gal-9 - CD4+ T cell TIM-3 negative regulation confers OLT resistance against IR stress. Aim 1.1. Hypothesis: Gal-9 - TIM-3 signaling triggers anti-oxidant response in which amplified Nrf2 activity represses macrophage NFB/inflammation responses. Aim 1.2. Hypothesis: Gal-9 - TIM-3 signaling enhances hepatocyte autophagy via Keap1/Nrf2 redox network. Aim 2: Define molecular mechanisms by which hepatocellular HMGB1 - endothelial TIM-3 negative regulation alleviates IRI in OLT. Aim 2.1. Hypothesis: HMGB1 conditioning prior to IR insult triggers activation of liver endothelial TIM-3 to repress macrophage trafficking and sequestration in OLT. Aim 2.2. Hypothesis: Hepatocellular HMGB1 - endothelial TIM-3 signaling promotes LEC protective phenotype. These studies will discern novel mechanisms at the innate-adaptive immune interface, which control organ damage/promote homeostasis in IR-stressed OLT; and should contribute to the development of new therapies to increase donor organ pool and improve clinical outcomes.

 描述（由适用提供）：缺血 - 再灌注损伤（IRI）仍然是限制末期肝病患者原位肝移植（OLT）成功的主要障碍，以及患有肝素肿瘤的患者。我们的小组开创了一个概念，即肝脏IRI是一种外源性AG独立的，先天免疫主导的无菌感染反应，需要激活的CD4+ T细胞来促进组织损伤。 T细胞免疫球蛋白粘蛋白（TIM）-3接收器已被公认为在许多自身 / Allo- / Allo免疫性病理和器官移植中被​​认为是T细胞激活的中心调节剂。 We reported that disruption of TIM-3 - Gal-9 pathway exacerbated hepatocellular injury in mouse lives subjected to warm IR.然后，我们发现受体CD4+ TIM-3+细胞赋予对肝脏IRI的耐药性，这表明在移植受者中应用T细胞靶向治疗时，应保留离散的宿主T细胞子集。该提案探讨了TIM-3信号通路在肝IRI机理中的功能，在临床相关的延长冷藏的小鼠模型中，然后是原位肝移植（OLT）。首先，我们发现应力的肝细胞表达GAL-9和HMGB1，即已知的TIM-3配体。 Second, we discovered robust expression of TIM-3 on activated live endothelial cells (LEC).这些初步数据使我们提出了一个中心假设，即肝细胞衍生的GAL-9/HMGB1和在宿主循环CD4+ T细胞/移植物LEC上表达的TIM-3之间的负调节对于控制组织损伤至关重要，并在IR折磨的OLT中施加了细胞型。两个互锁的特定目的将检验以下假设：目标1：定义分子机制，肝细胞GAL-9-CD4+ T细胞TIM-3阴性调节承认OLT对IR应激的抗性。目标1.1。假设：GAL-9-TIM-3信号传导触发抗氧化反应，其中扩增的NRF2活性反映了巨噬细胞NFB/炎症反应。目标1.2。假设：GAL-9-TIM-3信号传导通过KEAP1/NRF2氧化还原网络增强了肝细胞自噬。 AIM 2：定义肝细胞HMGB1-内皮TIM -3阴性调节减轻IRI的分子机制。目标2.1。假设：IR损伤之前的HMGB1调节会触发肝内皮TIM-3的激活，以反映OLT中的巨噬细胞运输和隔离。目标2.2。假设：肝细胞HMGB1-内皮TIM -3信号传导促进LEC保护表型。这些研究将辨别先天自适应免疫界面的新型机制，该机制控制器官损害/促进IR压力OLT中的稳态；并应有助于开发新疗法，以增加供体器官池并改善临床结果。