title: Steatosis and intrahepatic lymphocyte recruitment in hepatitis C virus transgenic mice.
abstract: 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.
authors.affiliation: Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
authors.forename: Tonino
authors.initials: T
authors.lastname: Alonzi
authors.affiliation: Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Agrati
authors.affiliation: Fondazione 'Istituto Pasteur Cenci-Bolognetti', Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Costabile
authors.affiliation: Fondazione 'Istituto Pasteur Cenci-Bolognetti', Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Cicchini
authors.affiliation: Fondazione 'Istituto Pasteur Cenci-Bolognetti', Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Amicone
authors.affiliation: Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cavallari
authors.affiliation: Medicina Sperimentale, Sezione Anatomia Patologica, Università La Sapienza, Rome, Italy.
authors.forename: Carlo Della
authors.initials: CD
authors.lastname: Rocca
authors.affiliation: IRBM, P. Angeletti, Pomezia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Folgori
authors.affiliation: IRBM, P. Angeletti, Pomezia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fipaldini
authors.affiliation: Istituto Nazionale Malattie Infettive 'L. Spallanzani' IRCCS, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Poccia
authors.affiliation: IRBM, P. Angeletti, Pomezia, Italy.
authors.forename: Nicola La
authors.initials: N
authors.lastname: Monica
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Tripodi
mesh_terms: 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
chemical_list: D016207:Cytokines; D000515:alpha 1-Antitrypsin