Human In-vitro Inflammatory Liver Model Recapitulates Immune-Associated Drug Efects with High Predictivity

Immune-mediated drug-induced liver injury is often undermined or not well-studied due to lack of appropriate in vitro models comprised of immune cells and suitable endpoints. Current advances in co-cultures deploying primary human Kupffer cells (PHKCs) or alternative cells such as THP-1 macrophages are limited by their inability of recapitulating drug-induced cytokine responses which are important immune-mediated drug effects. Since human iPSC-derived Kupffer cells (iKCs, PMID: 30497023) functionally resemble PHKCs, we investigated the use of iKCs to mimic drug-specific cytokine responses in vitro. iKCs were co-cultured with hiPSC-derived hepatocytes, which were then subjected to treatment of drugs with known immune-mediated effects. Out of the cytokine measurements including interleukin-6 and tumor necrosis factor α obtained from 19 compounds, 17 showed good in vitro-in vivo correlation (89.5%). Furthermore, co-cultures using THP-1 macrophages instead of iKCs could not recapitulate IL-6 responses upon treatment with paradigm compounds. RNA-Seq was used to explore the interaction between cytokines and drug-induced hepatotoxicity in greater detail for one pair of drugs - trovafloxacin and its non-hepatotoxic analogue, levofloxacin. Our study demonstrates for the first time, the use of iKCs in a physiologically relevant model that captures cytokine responses upon treatment with a wide range of immune-mediated drugs and hence can be very useful in warranting further investigation of new drugs that elicit drug-induced cytokine imbalance.