Modulation of liver fibrosis resolution by dendritic cells

树突状细胞调节肝纤维化消退

• 批准号: 8735008
• 负责人: Costica Aloman
• 金额: $ 15万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735008
• 关键词: Address; Adoptive Transfer; Affect; Animal Model; Antigen-Presenting Cells; Antigens; CD8B1 gene; Cells; Chronic; Cicatrix; Coculture Techniques; Cross Presentation; Data; Dendritic Cell Therapy; Dendritic Cells; Deposition; Development; Dose; Epidemic; Etiology; Event; Excision; Fibrosis; Gelatinase B; Goals; Hepatic; Hepatic Stellate Cell; Homeostasis; Human; ITGAM gene; ITGAX gene; Immune; Immune system; In Vitro; Individual; Inflammation; Inflammation Mediators; Integrins; Interleukin-15; Knockout Mice; Kupffer Cells; Laboratories; Ligands; Liver; Liver Fibrosis; Liver diseases; MMP9 gene; Matrix Metalloproteinases; Mediating; Metalloproteases; Morphology; Mus; Names; Natural History; Natural Immunity; Natural Killer Cells; Pathway interactions; Patients; Play; Population; Production; Proteins; Public Health; Recovery; Regulation; Relative (related person); Reporting; Resolution; Role; Signal Transduction; Staging; T-Lymphocyte; Testing; Vascular Endothelial Growth Factor Receptor-1; adaptive immunity; cancer immunotherapy; cell type; cellular targeting; chronic liver disease; cytokine; defined contribution; fibrogenesis; in vivo; innovation; liver injury; macrophage; mouse model; neutrophil; novel strategies

DESCRIPTION (provided by applicant): Today's epidemic of end-stage liver disease due to hepatic fibrosis has precipitated an urgent need for new therapies and a better understanding of fibrosis regression. Hepatic fibrosis is the result of a tightly regulated interaction between immune and matrix-producing cells. Exciting data establish that fibrosis is reversible in humans and in animal models following removal of etiologic agent. Metalloproteinases (MMPs) released from immune cells are critical to fibrosis regression. Dendritic cells (DC) are the main professional antigen-presenting cells of the immune system, and control innate and adaptive immunity; our data indicate that they produce MMP-9. We have also found that hepatic DC are heterogeneous in their origin, morphology and function. DC development and activity can be amplified by the protein fms-like tyrosine kinase 3 ligand (Flt3L), which has already been tested in humans as cancer immunotherapy. DC also secrete IL-15, which regulates NK and CD8+ T cells, cells that additionally modulate fibrosis. Despite their vital role in hepatic immune homeostasis, the contribution of DC to fibrosis regression is unknown. Our long-term goal is to understand how DC control fibrosis regression in order to develop novel approaches to accelerate liver fibrosis regression. The objective of this project, which is the next step towards our long-term goal, is to characterize the contributions of DC to fibrosis regression and to elucidate underlying mechanisms. Our central hypothesis, therefore, is that a specific DC population leads to liver fibrosis regression. We will test our central hypothesis through the following interrelated Specific Aims: 1. Define the contribution of different DC populations to liver fibrosis regression. In this aim we will validate the optimal dose of Flt3L required for fibrosis regression, identify the most potent DC population that induces regression, and define the contributions of other immune cells that are in turn regulated by DC (NK cells, CD8+T cells, macrophages, neutrophils); 2. Establish the role of MMP-9 in DC-mediated fibrosis regression. In this aim we will characterize the contribution of DC to hepatic MMP-9 production, define the specific DC population(s) that produce MMP-9 and explore the impact of this specific DC population on fibrosis regression; 3. Characterize the role of DC IL15 signaling during fibrosis regression. In this aim, we will characterize IL-15 production by specific DC populations and define the relative importance of IL-15 to fibrosis regression mediated by DC. These studies should uncover new pathways to accelerate fibrosis regression, leading to innovative treatments for patients with advanced fibrosis.

描述（由申请人提供）：由于肝纤维化导致的终末期肝病的流行，迫切需要新的治疗方法和对纤维化消退的更好理解。肝纤维化是免疫细胞和基质生成细胞之间严格调节相互作用的结果。令人兴奋的数据表明，在去除病原体后，纤维化在人类和动物模型中是可逆的。免疫细胞释放的金属蛋白酶（MMPs）对纤维化消退至关重要。树突状细胞（DC）是免疫系统中主要的专业抗原呈递细胞，控制先天免疫和适应性免疫；我们的数据表明它们产生MMP-9。我们还发现肝脏DC在起源、形态和功能上都是异质的。DC的发育和活性可以通过蛋白fms样酪氨酸激酶3配体（Flt3L）来扩增，该配体已经在人类癌症免疫治疗中进行了测试。DC还分泌IL-15，它调节NK和CD8+ T细胞，这些细胞也调节纤维化。尽管它们在肝脏免疫稳态中起着至关重要的作用，但DC对纤维化消退的贡献尚不清楚。我们的长期目标是了解DC如何控制纤维化消退，以便开发加速肝纤维化消退的新方法。这个项目的目标，是我们长期目标的下一步，是表征DC对纤维化消退的贡献，并阐明潜在的机制。因此，我们的中心假设是，特定的DC人群导致肝纤维化消退。我们将通过以下相关的具体目标来检验我们的中心假设：确定不同DC人群对肝纤维化消退的贡献。在此目的中，我们将验证纤维化消退所需的最佳Flt3L剂量，确定诱导消退的最有效DC群体，并确定由DC调节的其他免疫细胞（NK细胞、CD8+T细胞、巨噬细胞、中性粒细胞）的贡献；2. 确定MMP-9在dc介导的纤维化消退中的作用。在这个目标中，我们将描述DC对肝脏MMP-9产生的贡献，定义产生MMP-9的特定DC群体，并探索该特定DC群体对纤维化消退的影响；3. 表征DC IL15信号在纤维化消退过程中的作用。在此目的中，我们将通过特定DC群体表征IL-15的产生，并定义IL-15对DC介导的纤维化消退的相对重要性。这些研究应该揭示加速纤维化消退的新途径，为晚期纤维化患者带来创新治疗。