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.

Public Health Relevance

Liver fibrosis, or scarring, is an important public health problem, affecting millions of individuals worldwide who have chronic liver disease. We will study how specific immune cells, named dendritic cells, accelerate fibrosis resolution and recovery following liver injury. This application will open a new avenue for modifying the natural history of fibrosis regression, possibly leading to the testing of dendritic cell therapy to reduce fibrosis in patients with liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK088954-02
Application #
8300830
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2011-07-15
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$149,958
Indirect Cost
$11,108
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Jiao, Jingjing; Dragomir, Ana-Cristina; Kocabayoglu, Peri et al. (2014) Central role of conventional dendritic cells in regulation of bone marrow release and survival of neutrophils. J Immunol 192:3374-82
Bonito, Anthony J; Aloman, Costica; Fiel, M Isabel et al. (2013) Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J Clin Invest 123:3510-24
Pradere, Jean-Philippe; Kluwe, Johannes; De Minicis, Samuele et al. (2013) Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58:1461-73
Rahman, Adeeb H; Aloman, Costica (2013) Dendritic cells and liver fibrosis. Biochim Biophys Acta 1832:998-1004