Induction of hepatic injury by hepatitis C virus-specific CD8+ murine cytotoxic T lymphocytes in transgenic mice expressing the viral structural genes.
In the present study, we generated killer cells specific for hepatitis C virus (HCV) structural protein by re-stimulation of immune spleen cells from H-2(d) haplotype transgenic (Tg) mice, expressing the core, E1, E2, and NS2 genes of HCV regulated by the Cre/loxP switching system. The generated killer cells were conventional CD8(+)L(d) class-I MHC molecule-restricted cytotoxic T lymphocytes (CTLs) and specific for the HCV E1 structural protein. Because the CTLs could also kill hepatocytes from the Tg mice expressing HCV structural proteins in vitro, we attempted to transfer those CTLs intravenously into interferon regulatory factor-1 (IRF-1) negative, CD8-deficient Tg mice representing the HCV structural genes on hepatocytes to examine whether the inoculated CD8(+) CTLs can eliminate hepatocytes expressing the HCV genes in vivo. We observed an elevation of serum ALT level as well as damage of the liver tissue histologically. To our knowledge, this is the first demonstration to show that HCV-specific CD8(+) CTLs specifically attack hepatocytes expressing the HCV structural proteins both in vitro and in vivo.
Takaku
Shun
S
Department of Microbiology and Immunology, Nippon Medical, School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Nakagawa
Yohko
Y
Shimizu
Masumi
M
Norose
Yoshihiko
Y
Maruyama
Isao
I
Wakita
Takaji
T
Takano
Teruo
T
Kohara
Michinori
M
Takahashi
Hidemi
H
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005260:Female; D005814:Genes, Viral; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019076:Transgenes; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015678:Viral Structural Proteins / Q000235:genetics*
D014764:Viral Proteins; D015678:Viral Structural Proteins; C045073:Cre recombinase; D019426:Integrases