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  • 1
    Keywords: CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; SURVIVAL ; tumor ; carcinoma ; Germany ; MODEL ; SYSTEM ; HEPATOCELLULAR-CARCINOMA ; liver ; TUMORS ; MICE ; RESPONSES ; TRANSPLANTATION ; INDUCTION ; ANTIGEN ; DENDRITIC CELLS ; TOLERANCE ; BONE-MARROW ; MOUSE ; hepatocellular carcinoma ; PROMOTER ; PEPTIDES ; ONCOGENE ; NETHERLANDS ; IMMUNOTHERAPY ; MOUSE MODEL ; MELANOMA PATIENTS ; FAILURE ; albumin ; IMMUNIZATION ; T-CELL TOLERANCE ; IMMUNE-SYSTEM ; therapeutic ; Nodules ; Inducible hepatoma model ; LYMPHOCYTE RESPONSES ; Tumor tolerance
    Abstract: Tumors often induce tolerance in the immune system, which may contribute to the limited success of clinical vaccination against tumors. In order to develop strategies for overcoming tumor tolerance we have developed an inducible mouse model of autochthonus hepatocellular carcinoma growth, which relates more closely to the clinical situation than transplantation tumors. These so-called AST mice harbour a construct consisting of the hepatocyte-specific albumin promoter, a loxP flanked stop-cassette, and the oncogene SV40 large T antigen (Tag). By intravenous application of an adenovirus encoding Cre recombinase the stop cassette was excised, thereby inducing Tag expression and formation of hepatoma nodules in a dose-dependent fashion in about 3 months. Non-induced AST mice showed tumor tolerance, as demonstrated by the failure to reject Tag-positive transplantation tumors and the inability to mount CTL following Tag immunization. Dendritic cell-based immunization with an agonist Tag peptide was able to overcome tolerance and resulted in marked CTL activity against naturally occurring Tag epitopes. importantly, vaccination with the agonist peptide prevented growth of the autochthonous liver tumors and significantly prolonged survival of the animals. Our findings demonstrate that agonist peptides can be used in immunization protocols for breaking of tolerance and induction of CTL that mediate effective anti-tumor responses. In addition, the inducible hepatoma model described here can be used for the design of therapeutic strategies against hepatocellular carcinoma. (C) 2009 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19428549
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  • 2
    Keywords: APOPTOSIS ; CELLS ; IN-VITRO ; AGENTS ; human ; MODEL ; DEATH ; DISEASE ; liver ; SAMPLES ; TISSUE ; TIME ; INFECTION ; SERA ; primary ; INDUCTION ; hepatocytes ; culture ; virus ; VECTORS ; hepatitis B virus ; isolation ; HUMAN-LIVER ; FAS-MEDIATED APOPTOSIS ; ANTICANCER DRUGS ; ADULT HUMAN HEPATOCYTES ; LONG-TERM CULTURE ; X-PROTEIN
    Abstract: Background/Aims: Apoptosis is a key event in the pathophysiology of many liver diseases. Primary human hepatocytes (PHH) provide a useful model to study physiological and pathophysiological processes in the liver. Our aim was to optimize PHH cultures to allow studies on induction of apoptosis and of hepatitis B virus (HBV) infection. Methods: PHH were isolated from human liver tissue by two-step collagenase perfusion. PHH and hepatoma cells were treated with different apoptosis-inducing agents in parallel. PHH cultures were infected with wild type HBV and transduced with HBV genomes using adenoviral vectors. Results: PHH were successfully isolated from 40 different tissue samples with high viability and purity. Perfusion time and seeding density turned out to be critical parameters for optimal cell yield and culture conditions, respectively. Serum addition to the medium reduced viability of PHH. PHH allowed reproducible studies of CD95-dependent and-independent apoptosis. Sensitivity towards CD95-mediated apoptosis was markedly higher than in hepatoma cells. PHH could efficiently be infected with HBV, but infection did neither induce apoptosis nor prevent CD95-induced cell death. Conclusions: Our data show that PHH provide an excellent tool for the investigation of apoptosis induced by agents like death receptor-ligands and hepatotropic viruses. (C) 2003 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12763365
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