Worldwide, nearly 200 million people have hepatitis C virus (HCV), the great majority of which have chronic hepatitis, nearly 2% in the U.S. are infected with HCV, a major public health challenge with ~9,000 U.S. deaths / yr. currently. Chronic hepatitis frequently leads to cirrhosis, which in turn is the major risk factor for hepatocellular carcinoma (HCC). Although roles of specific immunity in acute and chronic hepatitis C (CHC) are emerging, little is known about key liver immune subset changes with progression. Adaptive HCV-specific T cells are concentrated in liver with innate-like natural killer (NK) and NKT, which represent to ~50% of normal and diseased liver leukocytes. Hepatic NKT are implicated in protection against acute viral infection, but maybe subverted by HCV. Regulation of activation of hepatic NKT cells is poorly understood. This proposal is to determine mechanisms by which the major and heterogeneous population of human hepatic NKT, that we first functionally defined, are regulated by CD1d+ liver cells in hepatitis C. Based on our findings, we hypothesize that in chronic hepatitis C, this large heterogeneous population of liver NKT, instead of being protective, promote inflammation and fibrosis, believed to be prerequisites for development of HCC. We propose that hepatic CD1d can present novel lipid ligands to liver NKT cells. We have evidence for ligand(s) for hepatic NKT and we have isolated fractions from CD1d+ cells that stimulate iNKT selectively. These data provide proof-of-principle that we can obtain fractions with ligand-like activity for NKT. This proposal will exploit our unique expertise with human hepatic and control NKT, physiological CD1d+ presenting liver cells, and reagents we and collaborators have developed to identify hepatic NKT- activating fractions and potential ligands from lipid libraries, to provide target(s) for preclinical development of potential novel therapeutic interventions in CHC and HCC. Given deleterious effects of chronic NKT stimulation we have uncovered, this will enable us to potentially manipulate hepatic NKT through novel molecule(s) toward novel therapeutics to help delay progression to cirrhosis and HCC in hepatitis C.
Aim 1. Establish a representative panel of human hepatic CD1d-reactive NKT cells and test candidate small molecules for specific activation or inhibition of hepatic NKT cells vs. blood invariant NKT cells. 1a. Prepare and functionally characterize enriched hepatic NKT panels for use alongside our iNKT. 1b. Determine which iNKT ligands from a selective library also activate hepatic NKT and which inhibit.
Aim 2. Determine specificity of human hepatic NKT for hepatic vs. other CD1d+ target cells, and define hepatic CD1d+ cell fractions that specifically activate or inhibit hepatic NKT. 2a. Determine whether enriched hepatic NKT cells have distinct fine specificity for hepatic vs. other CD1d+ target cells relative to iNKT cells. 2b. Identify fractions of eluted liver CD1d ligands that specifically activate hepatic NKT and/or iNKT.

Public Health Relevance

Worldwide nearly 200 million people have hepatitis C and many of these will progress to develop complications of the infection, including cirrhosis and hepatocellular carcinoma. This proposal is to study and manipulate a major immune population in the human liver, 'NKT'cells, which while protective in acute infections appear to contribute to inflammatory and fibrotic damage leading to liver disease progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA143748-02
Application #
8100457
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2010-06-28
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$183,549
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Li, Shaoyong; Vriend, Lianne E M; Nasser, Imad A et al. (2012) Hepatitis C virus-specific T-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis. Hepatology 56:2094-105
Exley, Mark A; Lynch, Lydia; Varghese, Bindu et al. (2011) Developing understanding of the roles of CD1d-restricted T cell subsets in cancer: reversing tumor-induced defects. Clin Immunol 140:184-95

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