Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States, and is a significant cause of morbidity and mortality. The T cell response directed at HCV derived antigens is thought to be important in the pathogenesis of HCV mediated disease, participating in favorable clinical outcome as well as in organ damage. Effector dysfunction of HCV reactive T cells has been proposed to contribute to the common persistence of HCV infection. In fact, HCV infection has been proposed to result in ARC dysfunction, abnormal APC-T cell interactions, and for the presence of dysfunctional virus specific T cells. Peripherally circulating immature dendritic cell (DC) subpopulations (MDC and PDC or myeloid and plasmacytoid DC) have emerged as key APC in shaping T cell immunity. Dysfunction in expanded MDC has been shown in HCV infection. An improved understanding of MDC and PDC function, and T cell responsiveness, during HCV infection may reveal important insight into host defense mechanisms, and lay the foundation for appropriate design of therapeutics in HCV infection. We will investigate the hypothesis that HCV infection results in altered DC ability to undergo maturation, manifesting in an impaired ability to process and present antigen, and a deficit in secretion of immune regulatory cytokines, and impaired activation of naive and effector memory T cell immunity that in turn prevents control of the infection. In addition HCV infection may affect T-cell responsiveness to normal functioning DC. To test this hypothesis we will determine the impact of HCV infection on DC phenotype and function, the impact of HCV on T cells by characterizing T cell responsiveness in HCV infected and healthy control subjects, and the effects of HCV core protein as a direct inhibitor DC function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068361-05
Application #
7795750
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Doo, Edward
Project Start
2006-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$242,562
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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