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: 9005628
• 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/9005628
• 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; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Population; Process; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Resistance; Response Elements; Sentinel; Signal Pathway; Signal Transduction; Staging; Sterility; Stress; System; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TLR4 gene; Testing; Therapeutic Intervention; Time; Tissues; Transplant Recipients; Warm Ischemia; allograft rejection; clinically relevant; conditioning; improved; in vivo; liver ischemia; liver transplantation; macrophage; mouse model; novel; novel strategies; novel therapeutics; p65; preconditioning; programs; public health relevance; receptor; research study; 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（由申请人提供）：缺血再灌注损伤（IRI）仍然是限制终末期肝病和肝源性肿瘤患者原位肝移植（OLT）成功的主要障碍，我们的团队率先提出了这一概念。肝脏 IRI 是一种不依赖于外源性 Ag 的、先天免疫主导的无菌炎症反应，需要激活的 CD4+ T 细胞来促进组织损伤。粘蛋白 (TIM)-3 受体已被认为是许多自身/同种免疫病理和器官移植中 T 细胞激活的中心调节因子。我们报道，TIM-3 - Gal-9 通路的破坏会加剧肝细胞损伤。然后，我们发现受体 CD4+TIM-3+ 细胞对肝脏 IRI 具有抵抗力，这表明在移植受体中应用 T 细胞靶向治疗时，应保留离散的宿主 T 细胞亚群。该提案探讨了 TIM-3 信号通路在临床相关的长期冷藏小鼠原位肝移植（OLT）模型中的肝脏 IRI 机制中的功能。首先，我们发现应激肝细胞表达 Gal-9 和 HMGB1，即 HMGB1。 ，已知的 TIM-3 配体 其次，我们发现 TIM-3 在活化的肝内皮细胞 (LEC) 上强烈表达。这些初步数据使我们得出一个中心假设，即 TIM-3 之间的负调节。宿主循环 CD4+ T 细胞/移植物 LEC 上表达的肝细胞来源的 Gal-9/HMGB1 和 TIM-3 对于控制组织损伤至关重要，并在 IR 应激的 OLT 中施加细胞保护表型，两个相互关联的具体目标将检验这一假设：目标 1。 ：定义肝细胞 Gal-9 - CD4+ T 细胞 TIM-3 负调节赋予 OLT 对 IR 应激的抵抗力的分子机制 假设： Gal-9 - TIM-3 信号传导触发抗氧化反应，其中放大的 Nrf2 活性抑制巨噬细胞 NF+B/炎症反应。 假设：Gal-9 - TIM-3 信号传导通过 Keap1/Nrf2 氧化还原网络增强肝细胞自噬。目标 2：明确肝细胞 HMGB1 - 内皮 TIM-3 负调节的分子机制目标 2.1. 假设：IR 损伤之前的 HMGB1 温和调节会触发肝内皮 TIM-3 的激活，以抑制 OLT 中的巨噬细胞运输和隔离。 假设：肝细胞 HMGB1 - 内皮 TIM-3 信号传导促进 LEC 保护表型。识别先天适应性免疫界面的新机制，该机制控制器官损伤/促进 IR 应激 OLT 的稳态；并应有助于开发新疗法，以增加供体器官库并改善临床结果。