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- W4313374715 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." @default.
- W4313374715 created "2023-01-06" @default.
- W4313374715 creator A5044816452 @default.
- W4313374715 creator A5048881280 @default.
- W4313374715 creator A5070399190 @default.
- W4313374715 date "2020-05-01" @default.
- W4313374715 modified "2023-09-27" @default.
- W4313374715 title "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" @default.
- W4313374715 cites W2098159917 @default.
- W4313374715 cites W2205608260 @default.
- W4313374715 doi "https://doi.org/10.4049/jimmunol.204.supp.72.8" @default.
- W4313374715 hasPublicationYear "2020" @default.
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