Liver Antigen - Presenting Cells in Hepatic Injury and Transplantation

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，该小组成立于APC功能、肝脏缺血再灌注(I/R)损伤、肝脏免疫生物学和 移植。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：将确定肝脏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：将阐明IRF-1介导的肝损伤的机制；目的III：将确定阻断IRF-1是否可以改善 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)提供支助。和小动物移植手术核心(核心C)。

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 programatic functions, an Imaging and Tissue Pathology Core (Core B). and a small animal Transplantation Surgery Core (Core C).