Role of Dendritic Cell Activation in the Pathogenesis of Liver Fibrosis

描述(由申请人提供)： 我是外科医生兼科学家。我的临床兴趣是照顾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%以上的时间是在实验室里度过的。我的主要职业目标是成为一名肝脏免疫病理学的独立研究员，并能够将我的工作台上的工作转化为我的病人的临床试验。我的次要目标是激励其他年轻医生追求调查职业。在我早期的职业生涯中，我有一套很棒的指导体系。我的导师(艾伦·弗雷饰)是一位著名的免疫学家，我的另一位导师(布鲁斯·克朗斯坦饰)是一位内科医生，在慢性肝病的发病机制方面是著名的权威人士。我很幸运地与我的导师和共同导师都有非常密切的私人关系。我建议的培训计划是通过有限的基础科学教学研讨会式的课程(1年级和2年级)来加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(3年级和4年级)。后者是一个由我的共同导师指导的项目，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必需的技能。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的肝脏兴趣小组，每周开会讨论肝脏疾病的临床、基础科学和翻译概念。 我的研究计划旨在研究肝脏树突状细胞激活在肝纤维化发病机制中的作用。肝纤维化的发病机制是复杂的，我们对其发生的细胞和生化因素的了解仍处于初级阶段。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，多种细胞类型相互作用，包括免疫活性细胞，如T细胞和枯否细胞，产生一系列细胞因子，包括IL-6、CCL21、肿瘤坏死因子和转化生长因子-α，导致HSC激活，细胞外基质沉积，最终发展为肝纤维化和肝硬变。树突状细胞(DC)是免疫系统中的主要抗原提呈细胞，启动先天免疫和获得性免疫。然而，肝脏树突状细胞代表了一种独特的表型，容易诱导耐受而不是免疫。事实上，肝树突状细胞不能启动对抗原的有效免疫是导致口服耐受和几乎没有免疫抑制的同种异体肝移植接受的主要因素。虽然正常肝脏树突状细胞诱导T细胞无能，是炎症的不良始发者，但在肝纤维化状态下树突状细胞的功能及其在纤维化过程中的作用尚未被研究过。我们的初步数据显示，在肝纤维化中，DC在启动天然免疫和获得性免疫方面非常有效；此外，DC是肝纤维化肝脏细胞因子环境升高的全部原因。在肝纤维化过程中，肝树突状细胞对T细胞和NK细胞的炎症反应和刺激作用的增强依赖于其产生的肿瘤坏死因子。基于这些观察，我们推测在肝纤维化状态下，肝脏DC功能发生了根本性的转变，从弱的免疫原性和开始的耐受转变为有效的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炎症级联反应的基础，是肝纤维化发病机制的关键组成部分。本研究的具体目的是(I)确定肝DC是否在肝纤维化中从惰性的耐受诱导者转变为强大的免疫刺激因子，(Ii)确定DC在肝纤维化发病机制中的作用及其在HSC激活中的直接作用，(Iii)确定阻断肝DC的免疫原性功能是否可以减轻肝损伤的纤维化反应。我们的预期结果将表明，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为肝纤维化的治疗开辟一个新的实验治疗领域。 公共卫生相关性： 在美国，每年有27,000人死于肝硬变。在全球范围内，在45岁至65岁的人群中，肝纤维化和肝硬变是仅次于心脏病和癌症的第三大常见死亡原因。目前尚无有效的治疗肝纤维化的方法。此外，肝星状细胞激活在肝纤维化中的细胞和生化发病机制尚不清楚。靶向树突状细胞在肝纤维化发病机制中的作用将为新的实验治疗方法提供广泛的临床意义。

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.