Chimeric Mice With Humanized Livers Demonstrate Human-Specific Hepatotoxicity Caused by a Therapeutic Antibody Against TRAIL-Receptor 2/Death Receptor 5.
Toxicol Sci
; 167(1): 190-201, 2019 01 01.
Article
em En
| MEDLINE
| ID: mdl-30202993
ABSTRACT
The activation of tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2)/death receptor 5 (DR5) induces apoptosis in various tumor cells but not in normal human cells. Because some therapeutic antibodies targeting TRAIL-R2 have demonstrated severe hepatotoxicity in clinical applications, novel in vivo models reflecting clinical hepatotoxicity are now required. In this study, we investigated the hepatotoxicity caused by KMTR2, an anti-human TRAIL-R2 monoclonal antibody, in chimeric mice with humanized livers (PXB-mice). PXB-mice were exposed to KMTR2 by single or repeated (weekly for 4 weeks) intravenous administrations, and the analyses of blood chemistry, liver histopathology, hepatic gene expression, and toxicokinetics were performed. Treatment with 1 or 10 mg/kg of KMTR2 increased alanine transaminase (ALT) activity and human ALT1 levels in blood. Histopathological analysis revealed that cell death and degeneration with the infiltration of inflammatory cells in human but not mouse hepatocytes were increased in a time-dependent manner after KMTR2 administration. Furthermore, increases in TdT-mediated dUTP nick end labeling (TUNEL)-positive human hepatocytes and serum concentration of cleaved cytokeratin 18, a human-specific apoptosis marker, were observed. RNA sequence analysis showed that the gene expression profile changed in different manners between human and mouse hepatocytes and the up-regulation of TRAIL-R2-related genes was observed only in human hepatocytes. Taken together, these results indicate that KMTR2-mediated TRAIL-R2 activation induces apoptosis of human hepatocytes and hepatotoxicity in PXB-mice and suggest that chimeric mice with humanized liver can be novel tools for the evaluation of in vivo human-specific hepatotoxicity induced by therapeutic antibodies in pre-clinical studies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores do Ligante Indutor de Apoptose Relacionado a TNF
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Doença Hepática Induzida por Substâncias e Drogas
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Fígado
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Anticorpos Monoclonais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Toxicol Sci
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Japão