Modulation of liver fibrosis resolution by dendritic cells

树突状细胞调节肝纤维化消退

• 批准号: 8879115
• 负责人: Costica Aloman
• 金额: $ 15万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879115
• 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，促使人们迫切需要新的治疗方法，并更好地了解纤维化消退。肝纤维化是免疫细胞和基质产生细胞之间严格调控相互作用的结果。令人振奋的数据表明，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)在纤维化消退中起着关键作用。树突状细胞(DC)是免疫系统的主要专职抗原提呈细胞，控制天然免疫和获得性免疫；我们的数据表明，它们产生基质金属蛋白酶-9。我们还发现，肝树突状细胞在来源、形态和功能上具有异质性。DC的发育和活性可以通过FMS样酪氨酸激酶3配体(Flt3L)蛋白来放大，该配体已经在人类身上作为癌症免疫治疗进行了测试。DC还分泌IL-15，它调节NK和CD8+T细胞，这是另外调节纤维化的细胞。尽管DC在肝脏免疫动态平衡中发挥重要作用，但DC在纤维化消退中的作用尚不清楚。我们的长期目标是了解DC如何控制纤维化消退，以便开发新的方法来加速肝纤维化消退。这个项目的目标是确定DC对纤维化消退的贡献，并阐明潜在的机制，这是迈向长期目标的下一步。因此，我们的中心假设是，特定的DC人群会导致肝纤维化消退。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.确定不同DC群体对肝纤维化消退的贡献。为此，我们将验证纤维化消退所需的Flt3L的最佳剂量，确定诱导消退的最有效的DC群体，并确定受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.建立基质金属蛋白酶-9在DC介导的纤维化消退中的作用。为此，我们将研究DC在肝脏基质金属蛋白酶-9产生中的作用，定义产生基质金属蛋白酶-9的特定DC群(S)，并探讨该特定DC群在纤维化消退中的作用；3.研究DC IL15信号在肝纤维化消退中的作用。在这个目标中，我们将确定特定DC群体产生IL-15的特征，并确定IL-15在DC介导的纤维化消退中的相对重要性。这些研究应该会发现加速纤维化消退的新途径，从而导致晚期纤维化患者的创新治疗。

项目成果

Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.

骨桥蛋白缺失将造血干细胞动员驱动向肝脏动员，并增加对酒精性肝病的肝铁。

• DOI: 10.1002/hep4.1116
• 发表时间: 2018-01
• 期刊: Hepatology communications
• 影响因子: 5.1
• 作者: Magdaleno F;Ge X;Fey H;Lu Y;Gaskell H;Blajszczak CC;Aloman C;Fiel MI;Nieto N
• 通讯作者: Nieto N

The dynamic and clinical significance of autoantibodies and immunoglobulins in liver transplant recipients.

肝移植受者自身抗体和免疫球蛋白的动态和临床意义。

• DOI: 10.1111/ctr.12682
• 发表时间: 2016
• 期刊: Clinical transplantation
• 影响因子: 2.1
• 作者: Stanca,CarmenM;Aloman,Costica;Fiel,MariaIsabel;Raja,Kaiser;Uskudar,Oguz;Florman,Sander;Schiano,ThomasD
• 通讯作者: Schiano,ThomasD

Dendritic cells and liver fibrosis.

• DOI: 10.1016/j.bbadis.2013.01.005
• 发表时间: 2013-07
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
• 影响因子: 6.2
• 作者: Rahman, Adeeb H.;Aloman, Costica
• 通讯作者: Aloman, Costica

Increased hepatic progenitor cell response and ductular reaction in patients with severe recurrent HCV post-liver transplantation.

肝移植后严重复发性 HCV 患者的肝祖细胞反应和导管反应增加。

• DOI: 10.1111/ctr.12740
• 发表时间: 2016
• 期刊: Clinical transplantation
• 影响因子: 2.1
• 作者: Sclair,SethN;Fiel,MariaIsabel;Wu,Hai-Shan;Doucette,John;Aloman,Costica;Schiano,ThomasD
• 通讯作者: Schiano,ThomasD

Diurnal variations in intestinal barrier integrity and liver pathology in mice: implications for alcohol binge.

小鼠肠道屏障完整性和肝脏病理学的昼夜变化：对酗酒的影响。

• DOI: 10.1152/ajpgi.00103.2017
• 发表时间: 2018
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Voigt,RobinM;Forsyth,ChristopherB;Shaikh,Maliha;Zhang,Lijuan;Raeisi,Shohreh;Aloman,Costica;Preite,NailliwZ;DonohueJr,TerrenceM;Fogg,Louis;Keshavarzian,Ali
• 通讯作者: Keshavarzian,Ali