Treatment of PD‐1−/− mice with amodiaquine and anti‐CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients

Abstract

We report here the first animal model of IDILI that is similar to the IDILI that occurs in humans, and it was accomplished by inhibiting immune tolerance.

The chemical, genetic and immunological basis of idiosyncratic drug–induced liver injury

“…However, much more extensive studies with other drugs are needed. 84,85 A variety of different genetic polymorphisms associated with iDILI suggests the involvement of a wide variety of toxicological mechanisms. However, the number of the HLA associations discovered and the recent data on T-cells implies that immunological mechanisms play a critical role in the aetiology of iDILI.…”

Idiosyncratic drug‐induced liver injury: A short review

“…Metushi et al42 recently reported the treatment of PD‐1 –/– mice with amodiaqine and anticytotoxic T lymphocyte antigen 4 led to liver injury similar to human iDILI. This model suggested that immune tolerance would have an important role in the development of iDILI 43.…”

Novel circulating- and imaging-based biomarkers to enhance the mechanistic understanding of human drug-induced liver injury

“…However, most pre-clinical and clinical models mentioned throughout this review involve acute toxicity with high doses of a drug, therefore omitting idiosyncratic DILI (IDILI) which accounts for up to 13 % of all acute liver failure (ALF) and represents a burden for drug development as it is ever difficult to predict IDILI [17,59]. IDILI has been widely described as an immune-mediated adverse drug reaction associated with human leukocyte antigen (HLA) and the principal reason that it is poorly understood is because preclinical animal models are lacking [60,61]. The mouse model currently used is known to develop immune tolerance and therefore subjects do not develop serious liver injury, as is the case for some patients that develop ALF in IDILI situations.…”

“…The mouse model currently used is known to develop immune tolerance and therefore subjects do not develop serious liver injury, as is the case for some patients that develop ALF in IDILI situations. Metushi et al suggested that developing a model that has its immune tolerance inhibited could allow us to better understand this phenomena in human [61]. Nowadays, the prevention of IDILI is based on high-throughput genotyping and collaborative databases to evaluate the predisposition of each individual patient [62].…”