The high failure rates associated with the use of IFNalpha clearly show the need for novel therapeutic strategies for chronic hepatitis C. IFNalpha probably directly inhibits hepatitis C virus (HCV) production or release. IFNalpha also has potent immunoregulatory activities, however, that likely play an important role in the overall response to its use in HCV infection. Interleukin 12 (IL-12) is an immunoregulatory cytokine which is central to the development of cell-mediated immune responses. Production of IL-12 by monocyte/macrophages and other antigen presenting cells is critical for immunity to a wide variety of viral and other pathogens. The immunology of chronic HCV infection, and the immunology of HCV therapy, strongly suggests that endogenous IL-12 plays an important role in successful viral clearance in this infection. We have shown that IFNalpha is a potent inhibitor of IL-12 production by monocyte/macrophages in vitro. IL-12 production is also reported to be suppressed in patients with HCV during IFNalpha therapy. Furthermore, successful therapeutic clearance of HCV with IFNalpha appears to be associated with maintained IL-12 responses, although this has not yet been definitively addressed. The central hypothesis underlying these studies is that therapeutic use of IFNalpha in chronic hepatitis C is compromised by suppression of the production of the critical immunoregulatory cytokine IL-12. The ultimate goal of this research is to use knowledge of the molecular mechanisms underlying IFNalpha- mediated alterations in IL-12 responses to devise novel therapeutic strategies for this disease. The studies in this proposal aim to further characterize the effects of therapeutic IFNalpha on in vivo and ex vivo IL-12 production, and to characterize, in vitro, the molecular mechanism(s) responsible for IFNalpha-mediated suppression of IL-12 production.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK056415-02
Application #
6177705
Study Section
Special Emphasis Panel (ZDK1-GRB-5 (M1))
Program Officer
Doo, Edward
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$189,140
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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