Role of Dendritic Cell Activation in the Pathogenesis of Liver Fibrosis

树突状细胞激活在肝纤维化发病机制中的作用

• 批准号: 8033822
• 负责人: George Miller
• 金额: $ 15.36万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033822
• 关键词: Accounting; Acute; Antigen-Presenting Cells; Antigens; Area; Basic Science; Benign; Biochemical; CCL11 gene; CCL2 gene; CCL21 gene; CCL22 gene; CCL23 gene; Cause of Death; Cell physiology; Cells; Chronic; Clinical; Clinical Trials; Complex; Data; Dendritic Cells; Dendritic cell activation; Deposition; Development; Dose; Effector Cell; Environment; Extracellular Matrix; Fibrosis; Goals; Group Meetings; Health; Heart Diseases; Hepatic; Hepatic Stellate Cell; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunologist; Immunosuppression; Inflammation; Inflammation Mediators; Inflammatory; Injury; Injury to Liver; Interest Group; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-6; Laboratories; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Liver parenchyma; Lymphoid Tissue; Macrophage Inflammatory Protein-1; Malignant - descriptor; Malignant Neoplasms; Master of Science; Mediator of activation protein; Mentors; Molecular; Natural Immunity; Natural Killer Cells; Nodal; Organ; Pathogenesis; Pathology; Patient Care; Patients; Phenotype; Physicians; Process; Production; Public Health; Research; Research Personnel; Research Proposals; Role; Scientist; Solid; Staging; Surgeon; System; T cell anergy; T-Lymphocyte; TNF gene; Therapeutic; Time; Toxin; Training; Training Programs; Translating; Virus; Work; adaptive immunity; aged; authority; base; career; cell type; chemokine; clinically relevant; cytokine; cytotoxic; effective therapy; immunogenic; immunogenicity; interest; liver allograft; liver function; liver transplantation; multidisciplinary; oral tolerance; programs; research study; response; skills; translational medicine

DESCRIPTION (provided by applicant): I am a surgeon-scientist. My clinical interests are caring for patients with benign and malignant liver disease. My research interests are studying the immunological changes in acute chronic liver disease. More than 75% of my time is spent in the laboratory. My primary career goal is to become an independent investigator in liver immuno-pathology and to be able to translate my bench-work to clinical trials for my patients. My secondary goals are to inspire other young physicians to pursue investigative careers. I have a wonderful mentoring system set-up for my early career. My mentor (Alan Frey) is a leading immunologist and my co-mentor (Bruce Cronstein) is a physician who is a noted authority on the pathogenesis of chronic liver disease. I am fortunate to have a very close personal relationship with both my mentor and co-mentor. My proposed training program is enhanced by limited didactic seminar-style coursework in basic science (years 1 and 2) to enhance my understanding of molecular pathogenesis and a Masters of Science in Clinical Investigation program with a focus in Translational Medicine (years 3 and 4). The latter is a program that is directed by my co-mentor and its aim is to train clinician-scientists in the skills necessary to translate scientific discoveries to clinical settings. The research environment at NYU is extremely supportive for this work. As a highlight, we currently have a multidisciplinary liver-interest group that meets weekly to discuss clinical, basic science, and translational concepts in liver disease. My research proposal aims to study the role of liver dendritic cell activation in the pathogenesis of hepatic fibrosis. The pathogenesis of liver fibrosis is complex and our understanding of the cellular and biochemical factors underlying its development are still rudimentary. Hepatic stellate cells (HSC) are the primary producers of the extracellular matrix in liver fibrosis. After hepatic injury, a diverse interplay of cell types including immune-competent cells, such as T cells and kuppfer [sic] cells, produce an array of cytokines including IL-6, CCL21, TNF-(, and TGF-( which result in HSC activation, extracellular matrix deposition, and eventually progresses to liver fibrosis and cirrhosis. Dendritic cells (DC) are the primary antigen presenting cell in the immune system and initiate innate and adaptive immunity. However, liver DC represent a distinct phenotype that are [sic] prone to induce tolerance rather than immunity. In fact, the inability of liver DC to initiate effective immunity to antigen is a primary factor contributing to both oral tolerance and the acceptance of hepatic allografts with little immune-suppression. While normal liver DC induce T cell anergy and are poor initiators of inflammation, the function of DC in states of hepatic fibrosis - and their contribution to the fibrotic process itself - has not been previously studied. Our preliminary data show that in hepatic fibrosis, liver DC are remarkably effective at engaging both innate and adaptive immunity and; moreover, DC are entirely responsible for the elevated hepatic cytokine milieu in the fibrotic liver. The increased inflammation and enhanced stimulation of T cells and NK cells by liver DC in liver fibrosis is contingent on their elevated production of TNF-(. Based on these observations, we postulate that in states of hepatic fibrosis there is a fundamental shift in liver DC function from weak immunogenicity and initiation of tolerance to potent induction of effector cell immunity and inflammation. Furthermore, we postulate that this shift in DC function toward immunogenicity underlies the inflammatory cascade in the fibrotic liver and is a critical component to the pathogenesis of hepatic fibrosis. Specific aims of this study are (i) To determine whether liver DC convert from inert inducers of tolerance to potent immune-stimulators in liver fibrosis, (ii) To determine the contributory role of DC in the pathogenesis of fibrosis and their direct role in HSC activation, (iii) To determine whether blockade of the immunogenic function of liver DC can mitigate the fibrogenic response to liver injury. Our expected findings will suggest that further studies aimed at countering the effects of liver fibrosis must account for the central role of DC. We expect that our work will also broach a new area of experimental therapeutics in the treatment of hepatic fibrosis. PUBLIC HEALTH RELEVANCE: In USA, 27,000 people die annually from liver cirrhosis. Worldwide, liver fibrosis and cirrhosis is the third most common cause of death after heart disease and cancer among people aged 45 to 65. There is no currently available effective therapy for liver fibrosis. Furthermore, the cellular and biochemical pathogenesis of hepatic stellate cell activation in hepatic fibrosis is poorly understood. Targeting dendritic cells in the pathogenesis of liver fibrosis would have wide clinical relevance for new experimental therapeutics.

描述（由申请人提供）： 我是一名外科医生兼科学家。我的临床兴趣是护理良性和恶性肝病患者。我的研究兴趣是研究急性慢性肝病的免疫学变化。我75%以上的时间都在实验室度过。我的主要职业目标是成为肝脏免疫病理学的独立研究者，并能够将我的实验室工作转化为患者的临床试验。我的次要目标是激励其他年轻医生从事研究职业。我为我的早期职业生涯设置了一个很棒的指导系统。我的导师（艾伦·弗雷）是一位领先的免疫学家，我的搭档（布鲁斯·克朗斯坦）是一位医生，他是慢性肝病发病机制的著名权威。我很幸运与我的导师和共同导师都有非常密切的个人关系。我提议的培训计划通过有限的基础科学研讨会式课程（第一年和第二年）得到加强，以增强我对分子发病机制的理解，以及以转化医学为重点的临床研究理学硕士课程（第三年和第四年） 。后者是由我的合作导师指导的一个项目，其目的是培训临床医生科学家将科学发现转化为临床环境所需的技能。纽约大学的研究环境非常支持这项工作。作为一个亮点，我们目前有一个多学科肝脏兴趣小组，每周举行一次会议，讨论肝脏疾病的临床、基础科学和转化概念。 我的研究计划旨在研究肝树突状细胞活化在肝纤维化发病机制中的作用。肝纤维化的发病机制很复杂，我们对其发展背后的细胞和生化因素的了解仍然很初级。肝星状细胞（HSC）是肝纤维化过程中细胞外基质的主要产生者。肝损伤后，包括免疫活性细胞（如 T 细胞和 kuppfer [原文如此] 细胞）在内的多种细胞类型相互作用，产生一系列细胞因子，包括 IL-6、CCL21、TNF-( 和 TGF-()，从而导致HSC 激活、细胞外基质沉积，并最终进展为肝纤维化和肝硬化。树突状细胞 (DC) 是免疫系统中的主要抗原呈递细胞，可启动先天性和适应性免疫。然而，肝 DC 代表了一种独特的表型，易于诱导耐受性而不是免疫性。事实上，肝 DC 无法启动对抗原的有效免疫是导致口服耐受和肝同种异体移植物接受的主要因素。虽然正常肝脏 DC 会诱导 T 细胞无反应并且是炎症的不良引发剂，但 DC 在肝纤维化状态下的功能以及它们对纤维化过程本身的贡献尚未被研究过。初步数据表明，在肝纤维化过程中，肝 DC 在参与先天性和适应性免疫方面非常有效；此外，DC 完全负责纤维化肝脏中肝细胞因子环境的升高。肝纤维化过程中肝 DC 的炎症增加以及对 T 细胞和 NK 细胞的刺激增强取决于它们产生的 TNF-(。基于这些观察结果，我们假设在肝纤维化状态下，肝 DC 发生根本性转变功能从弱免疫原性和耐受性的启动到有效诱导效应细胞免疫和炎症。此外，我们推测DC功能向免疫原性的转变是纤维化肝脏中炎症级联的基础，并且是纤维化肝脏中炎症级联反应的关键组成部分。本研究的具体目的是 (i) 确定肝 DC 是否从惰性耐受诱导剂转化为肝纤维化中的有效免疫刺激剂，(ii) 确定 DC 在肝纤维化发病机制中的贡献作用和(iii) 确定阻断肝 DC 的免疫原性功能是否可以减轻对肝损伤的纤维化反应。我们的预期结果表明，旨在对抗肝纤维化影响的进一步研究必须考虑 DC 的核心作用。我们期望我们的工作也将开辟肝纤维化治疗实验治疗的新领域。 公共卫生相关性： 在美国，每年有 27,000 人死于肝硬化。在全球范围内，肝纤维化和肝硬化是 45 至 65 岁人群中继心脏病和癌症之后的第三大常见死因。目前还没有针对肝纤维化的有效治疗方法。此外，肝纤维化中肝星细胞活化的细胞和生化发病机制尚不清楚。针对肝纤维化发病机制中的树突状细胞对于新的实验疗法具有广泛的临床意义。