Steatosis and intrahepatic lymphocyte recruitment in hepatitis C virus transgenic mice.
To assess the effects of constitutive hepatitis C virus (HCV) gene expression on liver, transgenic mice carrying the entire HCV open reading frame inserted in the alpha1 antitrypsin (A1AT) gene were generated. Expression of A1AT/HCV mRNA was found to be mainly limited to perivascular areas of the liver as indicated by in situ hybridization analysis. HCV core protein was detected in Western blots of liver extracts, whereas the expression of E2, NS3 and NS5 proteins was revealed by immunostaining of liver samples using HCV-specific antisera. Histological analysis of HCV transgenic mice showed that these animals develop extensive steatosis, but very little necrosis of liver tissue. Moreover, a consistent T cell infiltrate and a slight hepatocyte proliferation were observed. Phenotypic analysis of cells infiltrating the liver indicated that recruitment and/or expansion of residing CD8(+), NK, NKT and gammadelta T cells occurred in transgenic animals. Among these cells, a large fraction of CD8(+) T lymphocytes released mainly IL-10 and, to a lesser extent, IFN-gamma upon mitogenic stimulation in vitro. Furthermore, both intrahepatic lymphocytes and splenocytes did not produce cytokines in response to HCV antigens. Thus, these data indicate that constitutive expression of HCV proteins may be responsible for intrahepatic lymphocyte recruitment in absence of viral antigen recognition. This response is likely to be driven by virus-induced cellular factors and may play a significant role in the immunopathology of chronic HCV infection and liver disease.
Alonzi
Tonino
T
Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
Agrati
Chiara
C
Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
Costabile
Barbara
B
Fondazione 'Istituto Pasteur Cenci-Bolognetti', Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.
Cicchini
Carla
C
Fondazione 'Istituto Pasteur Cenci-Bolognetti', Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.
Amicone
Laura
L
Fondazione 'Istituto Pasteur Cenci-Bolognetti', Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.
Cavallari
Claudio
C
Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
Rocca
Carlo Della
CD
Medicina Sperimentale, Sezione Anatomia Patologica, Università La Sapienza, Rome, Italy.
Folgori
Antonella
A
IRBM, P. Angeletti, Pomezia, Italy.
Fipaldini
Cristina
C
IRBM, P. Angeletti, Pomezia, Italy.
Poccia
Fabrizio
F
Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
Monica
Nicola La
N
IRBM, P. Angeletti, Pomezia, Italy.
Tripodi
Marco
M
Fondazione 'Istituto Pasteur Cenci-Bolognetti', Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.|Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
D000818:Animals; D002465:Cell Movement; D016207:Cytokines / Q000096:biosynthesis; D005234:Fatty Liver / Q000209:etiology*; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000150:complications / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000515:alpha 1-Antitrypsin / Q000235:genetics
D016207:Cytokines; D000515:alpha 1-Antitrypsin