Liver Antigen - Presenting Cells in Hepatic Injury and Transplantation

描述(由申请人提供)： 我们提出了一个重要的假设，即肝脏非实质抗原提呈细胞(ARC)是肝脏炎症/免疫反应的关键调节细胞。拟议的计划项目将汇集经验丰富和互动的跨学科研究人员小组的集体专业知识，该小组在APC功能、肝脏缺血再灌注(I/R)损伤、肝脏免疫生物学和移植研究中建立。该团队的互补技能和专业知识将被融合在一起，以阐明机制和解决特定肝脏APC群体在先天性免疫和适应性免疫调节中的独特作用所潜在的明显矛盾。有很大的潜力开发新的治疗策略来改善同种异体肝移植的结果。该计划的目标是通过协作互动，了解特定的肝脏APC在调节与移植结果相关的肝脏损伤和肝脏免疫方面的潜在作用机制，这种作用通常会抑制对肠源性AGS的系统免疫反应。项目1将侧重于肝细胞衍生的转录因子干扰素调节因子-1(IRF-1)和肝细胞损伤如何压倒肝脏在肝I/R损伤后抑制炎症/免疫反应的自然趋势的机制。目的I：明确肝脏APC(DC、Kupffer细胞和星状细胞)在调节肝脏IRF-1表达中的信号通路和作用；目的II：阐明肝脏IRF-1介导的肝损伤的机制；目的III：确定阻断IRF-1是否能减轻肝移植I/R损伤。项目2将侧重于调节肝脏DC成熟和功能的机制，并确定它们在启动和调节T细胞功能和肝脏移植结果中的作用。目的I：将阐明Toll样受体(TLR)信号诱导调节因子在肝DC内毒素耐受中的作用；目的II：将确定在稳态和I/R损伤过程中表达的特异性促炎和抗炎细胞因子在肝DC内毒素耐受中的作用。目的III：将确定供者DC、TLR4和肝脏DC中TLR信号的负调控因子在实验性肝移植后对T细胞应答的作用；目的IV：将确定肝DC的成熟状态，包括成熟负调控因子的表达，与人类肝移植结果的关系。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。目的I：确定肝星状细胞对IRF-1和肝脏I/R损伤的影响；目的II：确定肝星状细胞调节DC和T淋巴细胞功能的机制；目的III：确定肝星状细胞在肝移植预后调节中的作用。这三个项目将由一个协调方案职能的行政核心(核心A)、一个成像和组织病理学核心(核心B)和一个小动物移植手术核心提供支助 (核心C)。相关性：这些高度整合和相互依赖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获得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 Geller对肝脏炎症反应的调节。 项目1描述(申请人提供)： 移植肝保存损伤是肝移植的主要并发症。保存损伤是一种低温缺血/再灌注损伤。虽然所有供体肝脏都表现出不同程度的保存损伤，但接受保存损伤严重的移植物的患者早期肝功能较差，更容易发生各种并发症。对造成局部器官损害的启动事件只有部分了解。干扰素调节因子-1(IRF-1)是一种核转录因子，最初被认为是干扰素β基因表达(IFNB)的关键因子之一，与其他干扰素诱导基因一样。现已知，IRF-1可以调节与先天免疫和获得性免疫相关的一些基因的表达。我们课题组的最新数据表明，在低氧刺激下，IRF-1在原代人肝细胞中表达上调。此外，我们确定了TLR4和HMGB1在IRF-1中在肝移植损伤中的新角色。我们的假设是，IRF-1是肝移植I/R所致炎症反应的关键调节因子。此外，我们认为非实质抗原提呈细胞(ACP)对于激活肝细胞IRF-1的表达是至关重要的，从而导致肝移植损伤。

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.