Liver Antigen - Presenting Cells in Hepatic Injury and Transplantation

描述（由申请人提供）： 我们提出了一个总体假设，即肝脏非实质性抗原呈递细胞（ARC）是基于肝脏的炎症/免疫反应的关键调节因子。拟议的计划项目将汇集一个经验丰富，互动，跨学科的研究小组的集体专业知识，建立在APC功能，肝缺血再灌注（I/R）损伤，肝脏免疫生物学和移植的研究。该团队的互补技能和专业知识将融合在一起，以阐明机制并解决特定肝脏APC群体在先天免疫和适应性免疫调节中的独特作用的明显矛盾。开发新的治疗策略以改善肝移植结局具有很大的潜力。该计划的目标是通过协作互动来了解特定肝脏APC的作用机制，该机制通常抑制对肠道来源的Ags的全身免疫反应，调节与移植结果相关的肝损伤和肝脏免疫。项目1将重点关注肝细胞衍生的转录因子干扰素调节因子-1（IRF-1）和肝细胞损伤压倒肝脏I/R损伤后肝脏抑制炎症/免疫反应的自然趋势的机制。目标一：目的二：阐明IRF-1介导的肝损伤机制;目的三：探讨IRF-1阻断是否能改善肝移植I/R损伤。项目2将重点关注调节肝DC成熟和功能的机制，并确定其在启动和调节T细胞功能和肝移植结果中的作用。目标一：将阐明Toll样受体（TLR）信号传导的诱导调节因子在肝DC内毒素耐受性中的作用;目的II：将确定在稳态和I/R损伤期间表达的特异性促炎和抗炎细胞因子对肝DC内毒素耐受性的贡献。目标三：将建立供体DC、TLR 4和肝DC中TLR信号传导的负调节因子对实验性肝移植后T细胞应答的贡献;目的IV：将确定肝DC的成熟状态，包括成熟负调节因子的表达，与人肝移植结果的关系。项目3将确定肝星状细胞参与I/R损伤的机制，并调节DC和T淋巴细胞的功能与肝移植结果的关系。目标一：目的二：确定肝星状细胞对IRF-1和肝I/R损伤的影响;目的三：确定肝星状细胞调节DC和T淋巴细胞功能的机制;目的四：确定肝星状细胞在调节肝移植结局中的作用。这三个项目将由一个行政核心（核心A）、一个成像和组织病理学核心（核心B）以及一个小动物移植外科核心提供支持，行政核心将协调方案职能 (Core C）。相关性：这些高度整合且相互依存的项目和核心的最终共同目标是发现调节影响肝脏的先天和适应性免疫反应结果的机制，并可能为移植治疗干预提供新的靶点。 项目1：IRF-1对肝脏炎症反应的调节 Geller，大卫A. 项目1描述（由申请人提供）： 供肝保存性损伤是肝移植术后面临的主要问题。保存性损伤代表低温缺血/再灌注（I/R）损伤。虽然所有供体肝脏都表现出一定程度的保存损伤，但接受严重保存损伤移植物的患者早期肝功能较差，更容易发生各种并发症。导致局部器官损伤的起始事件仅被部分理解。干扰素调节因子-1（IRF-1）是一种核转录因子，最初被鉴定为负责干扰素β基因表达（IFNB）以及其他干扰素诱导基因的关键因子之一。现在已知IRF-1调节参与先天性和获得性免疫的许多基因的表达。我们组的最新数据表明，IRF-1在缺氧刺激后的原代人肝细胞中上调。此外，我们确定了TLR 4和HMGB 1在IRF-1中在肝移植损伤中的新作用。我们的假设是，IRF-1是肝移植I/R导致的炎症反应的关键调节因子。此外，我们认为，非实质抗原呈递细胞（ACP）是至关重要的肝细胞IRF-1表达的激活，然后有助于肝移植损伤。

DESCRIPTION (provided by applicant): We propose the overarching hypothesis that liver non-parenchymal, antigen-presenting cells (ARC) serve as key regulators of hepatic-based inflammatory/immune responses. The proposed Program Project will bring together the collective expertise of a highly-experienced and interactive, interdisciplinary group of investigators, established in the study of APC function, hepatic ischemia-reperfusion (I/R) injury, liver immunobiology, and transplantation. Complementary skills and expertise of the team will be melded to elucidate mechanisms and resolve apparent paradoxes underlying the distinctive role of specific liver APC populations in innate immunity and regulation of adaptive immunity. There is strong potential for development of novel therapeutic strategies to improve liver allograft outcome. The Program's goal is to understand, through collaborative interaction, mechanisms underlying the role of specific liver APC, that generally dampen systemic immune responses to gut-derived Ags, in regulation of liver injury and hepatic immunity relevant to transplant outcome. Project 1 will focus on mechanisms by which the hepatocyte-derived transcription factor interferon regulatory factor-1 (IRF-1) and hepatocyte injury overwhelm the natural tendency of the liver to suppress inflammatory/immune responses after liver I/R injury. Aim I: will identify the signaling pathways and role of liver APC (DCs, Kupffer cells and stellate cells) in regulation of hepatic IRF-1 expression; Aim II: will elucidate the mechanisms of hepatic IRF-1-mediated liver injury; Aim III: will determine whether IRF-1 blockade can ameliorate liver transplant I/R injury. Project 2 will focus on mechanisms that regulate liver DC maturation and function and determine their role in the initiation and regulation of T cell function and liver transplant outcome. Aim I: will elucidate the role of inducible regulators of Toll-like receptor (TLR) signaling in endotoxin tolerance in liver DC; Aim II: will ascertain the contribution of specific pro- and anti-inflammatory cytokines, expressed in the steady-state and during I/R injury, to endotoxin tolerance in liver DC. Aim III: will establish the contribution of donor DC, TLR4 and negative regulators of TLR signaling in liver DC to T cell responses following experimental liver transplantation; Aim IV: will determine the maturation status of hepatic DC, including expression of negative regulators of maturation, in relation to human liver transplant outcome. Project 3 will define mechanisms by which hepatic stellate cells participate in I/R injury and regulate the function of DC and T lymphocytes in relation to liver transplant outcome. Aim I: will ascertain the influence of hepatic stellate cells on IRF-1 and liver I/R injury; Aim II: will determine mechanisms underlying the regulation of DC and T lymphocyte function by hepatic stellate cells; Aim III: will ascertain the role of hepatic stellate cells in the regulation of liver allograft outcome. These three Projects will be supported by an Administrative Core (Core A), that will co-ordinate programmatic functions, an Imaging and Tissue Pathology Core (Core B) and a small animal Transplantation Surgery Core (Core C). Relevance: The ultimate shared goal of these highly-integrated and interdependent Projects and Cores is to discover mechanisms that regulate the outcome of innate and adaptive immune responses affecting the liver, and that may provide new targets for therapeutic intervention in transplantation. PROJECT 1: Regulation of the Liver Inflammatory Response by IRF-1 Geller, David A. PROJECT 1 DESCRIPTION (provided by applicant): Liver graft preservation injury is a major problem complicating liver transplantation. Preservation injury represents a hypothermic ischemia/reperfusion (I/R) injury. Although all donor livers exhibit some degree of preservation damage, patients receiving grafts with severe preservation injury have poor early liver function and are more susceptible to a variety of complications. The initiating events that account for local organ damage are only partially understood. Interferon regulatory factor-1 (IRF-1) is a nuclear transcription factor originally identified as one of the key factors responsible for interferon beta gene expression (IFNB), as well as other interferon-inducible genes. IRF-1 is now known to regulate the expression of a number of genes involved in both innate and acquired immunity. Recent data from our group demonstrates that IRF-1 is upregulated in primary human hepatocytes after hypoxic stimulation. Further, we identify novel roles for TLR4 and HMGB1 in the IRF-1 in liver transplant injury. Out hypothesis is that IRF-1 is a key regulator of the inflammatory response that occurs as a result of liver transplant I/R. Further, we believe that the non-parenchymal antigen-presenting cells (ACP) are crucial for the activation of hepatocellular IRF-1 expression, which then contributes to the liver graft injury.