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- W4313374486 abstract "Abstract Idiosyncratic DILI (iDILI), rare liver injury not dependent on drug dose, is poorly understood and costly to patients and drug developers. Some iDILI events appear immune-mediated. This work builds on the established hepatocyte life cycle and intrinsic injury models in DILIsym, utilizing quantitative systems toxicology methods to incorporate direct activation of liver CD8+ T cells by OVA-expressing hepatocytes. Simulated hepatocyte OVA expression leads to activation of naïve OVA-specific CD8+ T cells. Activated T cells differentiate to effector, memory, or exhausted T cells. T cell cytotoxicity induces apoptosis in antigen-presenting hepatocytes, with resultant ALT release. By design, the model reproduces a differential CD8+ T cell response to low vs. high levels of hepatocyte OVA expression consistent with data 1,2. Mechanistically, the differential response is driven by effector T cell mediated clearance of low antigen vs. persistent high antigen and differentiation of exhausted T cells3. Reducing T cell functional avidity by 70x, as described for OVA altered peptide ligands4, reduced IFN-γ production and T cell cytotoxicity consistent with data5. By reproducing these results, DILIsym establishes proof-of-concept in the quantitative relationships among antigen-expressing hepatocytes, antigen-specific T cell number, cytotoxicity, and ALT release. These quantitative relationships set the stage for translation to drug-mediated CD8+ T cell cytotoxicity6." @default.
- W4313374486 created "2023-01-06" @default.
- W4313374486 creator A5044816452 @default.
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- W4313374486 date "2020-05-01" @default.
- W4313374486 modified "2023-09-27" @default.
- W4313374486 title "Mechanistic mathematical representation of CD8+ T cell mediated drug-induced liver injury (DILI) Part 1: initial development using experimental antigen, ovalbumin (OVA)" @default.
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- W4313374486 doi "https://doi.org/10.4049/jimmunol.204.supp.72.7" @default.
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