Evaluating Immunotoxicity of CD137 Agonism on Liver-Chip

This technical report evaluates the immunotoxicity associated with CD137-induced agonism using the Emulate Human Liver-Chip. The study focuses on the immunotherapy Urelumab, which has shown efficacy in murine models but resulted in hepatotoxicity during clinical trials. The report outlines the development of a novel immuno-competent Quad-Culture Liver-Chip that incorporates primary human hepatocytes and non-parenchymal liver cells to model the hepatotoxic effects of Urelumab. The methodology includes the administration of Urelumab to the Liver-Chip in the presence or absence of stimulated peripheral blood mononuclear cells (PBMCs). The results indicate that Urelumab treatment leads to significant increases in inflammatory cytokines and liver injury markers only when CD3-stimulated PBMCs are present. The findings suggest that the Emulate Liver-Chip can predict immune-mediated drug-induced liver injury (DILI) and highlight the importance of optimizing PBMC density for future studies.