Mechanistic studies of adaptive immune-mediated drug-induced liver injury (DILI) using drug-specific T-cells in patients

Abstract

Many pharmaceutical companies take the strategy to screen out compounds that form highly reactive metabolites to avoid drug-induced liver injury (DILI). Reactive metabolites could bind to carrier proteins and show immunogenicity as haptens. Idiosyncratic DILI is not detectable in conventional animal studies of drug development and does not occur in most patients indicating the species- and interindividual-differences in DILI onset. Retrospective Genome Wide Association Study (GWAS) have identified human leukocyte antigens (HLAs) as a human specific genetic risk marker. HLA is necessary for antigen presentation system so the clinical associations provide persuasive evidence to hypothesize that the reactions involve the drug-specific activation of the adaptive immune system. Mechanistic studies using T-cells from skin-hypersensitivity patients who express risk HLA provide direct evidence to support this adaptive immune system and the hapten-mediated reaction. With regard to DILI, I will show mechanistic study results using isoniazid specific T-cell from patients with anti-tuberculosis drug-related liver injury or skin reaction and the challenges for DILI mechanism/prediction will be discussed.