Modulation of liver fibrosis resolution by dendritic cells

描述（由申请人提供）：当今由于肝纤维化导致的终末期肝脏疾病的流行，迫切需要新的疗法和更好地了解纤维化消退。肝纤维化是免疫细胞和基质生成细胞之间相互作用的结果。令人兴奋的数据表明，在人类和动物模型中，去除病原体后，纤维化是可逆的。从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）是免疫系统的主要专职抗原呈递细胞，控制先天性和适应性免疫;我们的数据表明它们产生MMP-9。我们还发现，肝DC的起源，形态和功能是异质性的。DC的发育和活性可以通过蛋白质fms样酪氨酸激酶3配体（Flt 3L）来放大，该配体已经在人类中作为癌症免疫疗法进行了测试。DC还分泌IL-15，其调节NK和CD 8 + T细胞，这些细胞另外调节纤维化。尽管它们在肝脏免疫稳态中起重要作用，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，以开发加速肝纤维化消退的新方法。该项目是我们实现长期目标的下一步，其目标是描述DC对纤维化消退的贡献并阐明潜在机制。因此，我们的中心假设是特定的DC群体导致肝纤维化消退。我们将通过以下相互关联的具体目标来检验我们的中心假设：1.定义不同DC群体对肝纤维化消退的贡献。在这个目标中，我们将验证纤维化消退所需的Flt 3L的最佳剂量，鉴定诱导消退的最有效的DC群体，并确定反过来由DC调节的其他免疫细胞（NK细胞、CD 8 +T细胞、巨噬细胞、嗜中性粒细胞）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，我们将表征DC对肝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 IL 15信号传导在纤维化消退期间的作用。在这个目标中，我们将通过特定的DC群体来表征IL-15的产生，并确定IL-15对DC介导的纤维化消退的相对重要性。这些研究应该发现加速纤维化消退的新途径，从而为晚期纤维化患者提供创新治疗。

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.