Idiosyncratic drug-induced liver injury (iDILI), which is typically rare and often severe, has led to black box warnings or drug withdrawals from the market, with adverse effects on patients and drug development ¹. T cell- mediated immune responses have been implicated for many iDILI drugs¹. Previous work has expanded an existing quantitative systems toxicology (QST) model (DILIsym®) to include mouse CD8+ T cell responses to hepatocyte-expressed OVA² and mouse CD8+ T cell responses to hepatocyte-expressed amodiaquine (AQ) antigen³. This work aims to reproduce human CD8+ T cell responses to hepatocyte-expressed AQ antigen and explore putative mechanisms underlying cross-species differences.
Simulating human responses involved human AQ dosing protocols and species differences in the represented biology, including numbers of human naïve antigen-specific CD8+ T cells⁴,⁵. The simulated mouse was treated with 250mg/kg/day AQ⁶. The simulated human was treated with 600mg AQ per week⁷.
AQ exposure in a simulated mouse resulted in delayed, mild hepatotoxicity, illustrated by alanine aminotransferase (ALT) elevations >100U/L after roughly two weeks of treatment. There was no progression to severe liver injury on continued drug treatment through 10 weeks, consistent with published data⁶. In a simulated human, AQ exposure resulted in delayed hepatotoxicity, illustrated by ALT elevations 120U/L after roughly m4.5 weeks of simulated AQ treatment. With continuing AQ treatment, the simulated human progressed to severe liver injury, evidenced by ALT >1000U/L and TB >2mg/dL, consistent with AQ DILI⁷. Relative expansion of CD8+ T cells was similar between species, as was their cytotoxic potential. A surprising variable that differentiated the severity of injury was the relative recovery potential of mouse vs. human hepatocytes. Simulations include hepatocyte proliferation with subsequent liver regeneration. Hepatocyte proliferation rates were previously optimized to available acetaminophen recovery data⁸,⁹ and were unaltered for these simulations. The parameterization is permissive for balanced injury and recovery in the simulated mouse but generates progressive injury with insufficient recovery in the simulated human. These abstract results have been previously presented in part at Immunology2020, Honolulu, HI, 5/2020 and published in the conference proceedings as abstract 2352.
The results provide proof-of-concept that leveraging data from mouse studies of CD8+ T cell responses in the liver can translate to a human representation consistent with published data. The results illuminate a potential mechanism for cross-species differences in
susceptibility to T cell- mediated injury. Further simulations and experimental follow-up will beconducted to confirm or refute the model findings.
Presented at ACoP 11 Virtual Conference, Nov. 9-13, 2020
By Zackary R. Kenz, Christina Battista, Lisl K.M. Shoda