Mechanistic mathematical representation of CD8+ T cell mediated drug-induced liver injury (DILI) Part 2: translation from experimental antigen, ovalbumin (OVA), to drug, amodiaquine (AQ) response

Abstract

Abstract Idiosyncratic DILI (iDILI) is poorly understood and costly to patients and drug developers. Some iDILI events appear immune-mediated. This work builds on the DILIsym representation of T cell cytotoxicity against OVA-expressing hepatocytes1, to translate the OVA representation to AQ-induced hepatotoxicity. AQ-related changes include a physiologically-based pharmacokinetic (PBPK) model for mouse AQ exposure, AQ metabolism to reactive metabolites (RMs), RM-mediated ER stress leading to inflammation, fewer endogenous AQ responsive T cells of reduced affinity and avidity for AQ antigen. Simulations show no CD8+ T cell mediated ALT elevations in simulated wild-type mice treated with AQ, consistent with data2 and provide a mechanistic basis for the result. With low levels of AQ antigen, low T cell numbers and lower affinity and avidity interactions were insufficient for a cytotoxic T lymphocyte (CTL) response. With high levels of AQ antigen, T cell expansion and differentiation occurred but regulatory pathways, i.e., T cell exhaustion, inhibited an effective CTL response. In PD1−/− mice treated with anti-CTLA4, CD8+ T cell mediated AQ DILI was apparent (ALT >100 U/L)3,4. In DILIsym, blocking coinhibitory activity on proliferation and differentiation was permissive for AQ DILI (ALT >100 U/L) and could be further exacerbated by blocking differentiation to an exhausted phenotype (ALT >200 U/L). The results provide proof-of-concept for translation of OVA hepatotoxicity to AQ DILI and set the stage for exploration of human AQ DILI5.