Journal
GASTROENTEROLOGY
Volume 140, Issue 4, Pages 1334-1344Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2011.01.001
Keywords
Animal Model of Hepatitis; Human Immunology; Fibrosis; Virology
Categories
Funding
- UNC UCRF
- NIH [AI076142, AA018009, AI077454, AA018372, T32 AI007273]
- UNC Lineberger Comprehensive Cancer Center
- LCRF
- UNC University
- Ministry of Science and Technology [2009CB522507, 2006CB910901, KSCX20YW-R-150]
- Ministry of Health [2009ZX10604, 2008ZX10002-011]
- Greenberg Medical Research Institute
- Ellison Medical Foundation
- Starr Foundation
- Ronald A. Shellow Memorial Fund
- Richard Salomon Family Foundation
- Foundation NIH
- Center for Clinical and Translational Research [RR024143]
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BACKGROUND & AIMS: Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C virus pathogenesis and treatment. METHODS: To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2(-/-) gamma C-null mice. Cotransplantation of human CD34(+) human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leukocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases. RESULTS: AFC8-hu HSC/Hep mice supported HCV infection in the liver and generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes. CONCLUSIONS: AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection.
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