Liver Dendritic Cells in Tolerance and Immunity

肝树突状细胞的耐受性和免疫

• 批准号: 8101861
• 负责人: Ronald P Dematteo
• 金额: $ 39.17万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101861
• 关键词: Adoptive Transfer; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Brain; Cells; DNA; Data; Dendritic Cells; Diphtheria Toxin; Environment; Funding; HMGB1 gene; Heart; Hepatic; Hepatocyte; Human; Hypovolemic Shock; ITGAX gene; Imatinib; Imatinib mesylate; Immune; Immune response; Immunity; Immunologics; In Vitro; Inflammation; Inflammatory Response; Injury; Interferons; Interleukin-10; Investigation; Ischemia; Kidney; Knockout Mice; Knowledge; Lead; Ligands; Liver; Lung; Mediating; Mediator of activation protein; Molecular; Monoclonal Antibodies; Mus; Natural Immunity; Necrosis; Nucleic Acids; Organ; Partial Hepatectomy; Pattern; Play; Production; Proteins; RNA; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; T-Lymphocyte; TLR4 gene; Testing; Toll-like receptors; Transgenic Organisms; Tyrosine Kinase Inhibitor; effective therapy; human disease; in vitro Model; in vivo; inhibitor/antagonist; liver ischemia; liver transplantation; man; pathogen; protective effect; public health relevance; receptor; research study; response; treatment strategy

DESCRIPTION (provided by applicant): Liver ischemia reperfusion (I/R) induces an untoward hyperinflammatory response following partial hepatectomy, liver transplantation, and hypovolemic shock. Currently, there are no effective therapies. While dendritic cells (DCs) are now recognized as the principal mediators of immunity and inflammation throughout the body, our understanding of liver DCs has been rudimentary. During our first 5 years of funding, we primarily established the T cell stimulating capacity of freshly isolated mouse and human liver DCs. In this competitive renewal application for an additional 5 years of funding, we will investigate the innate role of hepatic DCs in liver inflammation. Toll-like receptors (TLRs) are evolutionarily conserved proteins present on immune cells that recognize pathogens, immunologic danger signals and endogenous nucleic acids and subsequently activate innate immunity. We have discovered that TLR9, the intracellular receptor that detects hypomethylated bacterial CpG motifs and endogenous DNA, modulates anti-inflammatory responses by conventional DCs in liver I/R. Additionally, we have discovered that plasmacytoid DCs exert protective effects in I/R. Thus, we hypothesize that endogenous ligands regulate DCs in the immunopathogenesis of liver I/R injury. In Aim 1, we will determine the regulation of liver I/R by conventional DCs in response to endogenous ligands. In Aim 2, we will establish the mechanism of protection by plasmacytoid DCs in liver I/R. In Aim 3, we will establish the TLR requirements for injury in an in vitro model of human liver I/R. The proposed experiments will increase our knowledge regarding the mechanisms of hepatic inflammation. Our investigation has direct relevance to human disease and may lead to the use of TLR blockade for the treatment of hu- man I/R that involves the liver and other organs, such as the heart, kidney, lung, and brain. PUBLIC HEALTH RELEVANCE: In this proposal, we will investigate the role of liver dendritic cells and danger signals released by the host during liver inflammation in mice and humans. Our investigations will be useful in identifying new therapies to treat ischemia reperfusion injury that occurs in humans.

描述（由申请人提供）：肝脏缺血再灌注（I/R）在部分肝切除术，肝移植和低血容量减震后引起不良过度炎症反应。目前，没有有效的疗法。虽然现在将树突状细胞（DC）公认为是整个体内免疫和炎症的主要介体，但我们对肝脏DC的理解是基本的。在我们的最初5年资金中，我们主要建立了新鲜分离的小鼠和人肝DC的T细胞刺激能力。在这项竞争性更新的申请中，我们还将调查肝DC在肝脏炎症中的先天作用。 Toll样受体（TLR）是存在于识别病原体，免疫学危险信号和内源性核酸的免疫细胞上的进化保守蛋白，随后激活了先天免疫。我们发现TLR9是检测到降压细菌CpG基序和内源性DNA的细胞内受体，可调节肝I/R中常规DCS的抗炎反应。此外，我们发现纤溶酶滴定DC在I/R中发挥保护作用。因此，我们假设内源配体在肝I/R损伤的免疫发病中调节DC。在AIM 1中，我们将通过常规DC确定肝脏I/R的调节，以响应内源性配体。在AIM 2中，我们将在肝I/R中建立通过质子乳剂DC的保护机理。在AIM 3中，我们将在人肝I/R的体外模型中建立TLR损伤的要求。提出的实验将增加我们对肝炎症机制的了解。我们的调查与人类疾病有直接相关性，并可能导致使用TLR阻滞来治疗涉及肝脏和其他器官的Human I/R，例如心脏，肾脏，肺和大脑。 公共卫生相关性：在此提案中，我们将研究肝脏和人类肝脏炎症期间释放的肝脏树突状细胞的作用和危险信号。我们的研究将有助于确定人类发生的缺血再灌注损伤的新疗法。