Regulation of Innate Immune Responses by Alloimmunity in Liver Ischemia-Reperfusion Injury

肝脏缺血再灌注损伤中同种免疫对先天免疫反应的调节

• 批准号: 9975699
• 负责人: YUAN ZHAI
• 金额: $ 38.23万
• 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/9975699
• 关键词: Acute; Address; Alloantigen; Allogenic; Allografting; Animal Model; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Clinical; Comprehension; Cryopreservation; Cytoprotection; Data; Disease; Event; Experimental Models; Functional disorder; Graft Rejection; Hepatic; Hepatocellular Damage; Homologous Transplantation; Immune; Immune response; Immunobiology; Immunosuppression; In Situ; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Interferon Type II; Interferons; Isogenic transplantation; Kinetics; Knockout Mice; Lead; Life; Liver; Lymphocyte; Memory; Modeling; Mus; Necrosis; Nude Mice; Organ; Organ Procurements; Pathogenesis; Pathway interactions; Process; Rattus; Regulation; Reperfusion Injury; Reperfusion Therapy; Resistance; Role; Signal Pathway; Specific qualifier value; Specificity; Stress; T cell response; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Tissues; Transgenic Organisms; Transplantation; Tumor-infiltrating immune cells; University of Wisconsin-lactobionate solution; Warm Ischemia; adaptive immunity; cellular targeting; cytotoxicity; effector T cell; graft function; immune activation; immunoregulation; insight; isoimmunity; liver injury; liver ischemia; liver transplantation; memory CD4 T lymphocyte; novel; preservation; receptor; reconstitution; response; response to injury; terminally differentiated effector memory (TEM) T cells; tissue injury; transplant model

PROJECT II – PROJECT SUMMARY/ABSTRACT Ischemia-reperfusion injury (lRI) may lead to poor early graft function, primary non-function and predisposes the graft to acute and/or chronic rejection. The pathophysiology of liver IRI has been investigated in animal models, primarily in the setting of hepatic partial warm ischemia in situ, and cold storage/syngeneic Tx, with mechanistic emphasis on innate immune responses. Clearly, there are major discrepancies between these experimental models and the clinical scenario, which may cause deficiencies in our comprehension of the disease mechanism. In this regard, the question of whether and how allo-antigens (Ag)/adaptive allo-immunity impact tissue inflammatory response and injury against IR is of high significance. We have compared liver IRI between syngeneic and allogeneic transplants in both rat and mouse orthotropic liver transplantation (OLT) models. Results showed unequivocally that allografts developed significantly more severe tissue injuries than isografts under the same preservation condition in the early stage of reperfusion, which were distinctive kinetically from rejection. Lymphocytes and their functional mechanisms involved in the liver IRI of allografts are clearly different from those in isografts. This project focuses on the role of CD4 T cells in liver IRI of allo-, vs. iso-OLTs after extended cold storage. We have found in a liver partial warm ischemia model that the effector memory (TEM) subset (CD44highCD62Llow), but not naïve, CD4 T cells were able to function in Ag non- specific manner via a CD154 dependent, but IFN-γ independent mechanism. In the OLT setting, our recent data specified functions of IFN-γ in liver IRI of allo-, but not iso-grafts. We hypothesize that recipient pre- existing CD4 TEM cells are responding to liver IR immediately post Tx. They function via both Ag-specific and non-specific pathways involving distinctive effector mechanisms. We have documented that liver CD4 TEM expressed CD154 constitutively and enhanced innate inflammatory immune activation via CD40, independent of their Ag-specificities. In allo-OLTs, we propose that donor allo-Ags may, additionally, activate recipient infiltrating alloreactive CD4 TEM cells to produce IFN-γ, which is responsible for the enhanced inflammatory immune activation and hepatocellular damage, as compared with those in iso-OLTs. Thus, CD4 TEM cells may promote liver IRI by Ag-specific reactivation to secrete IFN-γ and Ag non-specific interaction via CD154 with CD40 on innate immune cells. We will address our hypothesis in two specific aims to determine Ag- specificities and effector mechanisms of CD4 T cells in IRI of OLTs. These studies will be the first to specifically address the fundamental immunobiology question of liver IRI in allogeneic vs. syngeneic transplantation. Results will not only fulfill the gap in our understanding of the disease pathogenesis in real clinical setting, but also provide us novel insight into the role of adaptive immunity in regulating tissue innate inflammatory immune responses.

项目二--项目摘要/摘要 缺血再灌注损伤(LRI)可导致早期移植物功能不良、原发无功能和易患 移植到急性和/或慢性排斥反应。肝脏IRI的病理生理学已经在动物身上进行了研究 模型，主要在肝脏原位部分热缺血和冷保存/同基因TX的背景下， 机械论强调先天免疫反应。显然，它们之间有很大的差异 实验模型和临床情景，这可能会导致我们对 疾病机制。在这方面，是否以及如何同种抗原(Ag)/适应性同种免疫的问题 影响组织炎症反应和损伤对IR具有很高的意义。我们比较了肝脏IRI 同种异体肝移植在大鼠和小鼠正交异性肝移植中的应用 模特们。结果明确地显示，同种异体移植物发生的组织损伤明显比 在再灌流早期，相同保存条件下的同种异体移植物 从拒绝中获得动力。淋巴细胞及其参与同种异体移植肝IRI的作用机制 显然与同种异种的不同。本课题旨在探讨CD4T细胞在异体小鼠肝脏IRI中的作用。 与延长冷藏后的ISO-OLTS的比较。我们在肝脏部分热缺血模型中发现 效应记忆(TEM)亚群(CD44HighCD62Llow)，但不是幼稚的，CD4T细胞能够在非Ag- 特异性通过CD154CD154依赖，但干扰素-γ非依赖机制。在OLT环境中，我们最新的 资料表明干扰素-γ在同种异体肝缺血再灌注损伤中的作用，而不是同种异体肝缺血再灌注损伤。我们假设接受者预先- 现有的CD4TM细胞在TX后立即对肝脏IR有反应。它们通过银特异的和 涉及独特效应器机制的非特定途径。我们已经记录了肝脏CD4的透射电子显微镜 通过CD40结构性表达CD154并增强先天炎症免疫活性，不依赖于 它们的银特异性。在allo-olts中，我们建议供者allo-ags可以另外激活接受者 渗入同种异体反应的CD4TM细胞产生干扰素-γ，这是导致炎症增强的原因 免疫激活和肝细胞损伤，与异体肝移植组相比。因此，CD4TM细胞可以 抗原特异性激活分泌干扰素-γ促进肝脏缺血再灌注损伤 CD40在先天性免疫细胞上的表达。我们将在两个特定的目标中解决我们的假设，以确定Ag- CD4T细胞在OLTS IRI中的特异性及其作用机制这些研究将是第一次 在同种异体对照中具体解决肝脏IRI的基本免疫生物学问题 移植。结果不仅填补了我们对疾病发病机制的认识上的空白 临床背景，但也为我们提供了对适应性免疫在调节组织天然中的作用的新的见解 炎性免疫反应。