Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset. (21st July 2014)

• Record Type: Journal Article
• Authors: Metushi, Imir G.; Cai, Ping; Dervovic, Dzana; Liu, Feng; Lobach, Alexandra; Nakagawa, Tetsuya; Uetrecht, Jack
• Is Part Of: Journal of immunotoxicology. Volume 12:Number 3(2015)
• Page Start: 247
• Page End: 260
• Publication Date: 2014-07-21
• Subjects: Covalent binding -- drug-induced liver injury -- immune-mediated -- immune tolerance -- reactive metabolite; Immunotoxicology -- Periodicals; Poisons -- Immunology -- Periodicals; Environmental health -- Periodicals; 616.97
• DOI: 10.3109/1547691X.2014.934977
• Languages: English
• ISSNs: 1547-691X

Abstract

Abstract: Amodiaquine (AQ) treatment is associated with a high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. Evidence suggests that AQ-induced IDILI is immune mediated. A significant impediment to mechanistic studies of IDILI is the lack of valid animal models. This study reports the first animal model of IDILI with characteristics similar to mild IDILI in humans. Treatment of female C57BL/6 mice with AQ led to liver injury with delayed onset, which resolved despite continued treatment. Covalent binding of AQ was detected in the liver, which was greater in female than in male mice, and higher in the liver than in other organs. Covalent binding in the liver was maximal by Day 3, which did not explain the delayed onset of alanine aminotransferase (ALT) elevation. However, coincident with the elevated serum ALT, infiltration of liver and splenic mononuclear cells and activation of CD8 T-cells within the liver were identified. By Week 7, when ALT levels had returned close to normal, down-regulation of several inflammatory cytokines and up-regulation of PD-1 on T-cells suggested induction of immune tolerance. Treatment of Rag1 −/− mice with AQ resulted in higher ALT activities than C57BL/6 mice, which suggested that the adaptive immune response was responsible for immune tolerance. In contrast, depletion of NK cells significantly attenuated the increase in ALT, which implied a role for NK cells in mild AQ-induced IDILI. This is the first example of a delayed-onset animal model of IDILI that appears to be immune-mediated.