Precision-Cut Human Liver Slices as a New Methodological Approach

Immune-mediated mechanisms in drug-induced liver injury (immune-related Drug-Induced Liver Injury, irDILI) remain insufficiently understood in the preclinical setting. A well-known example is sitaxsentan, an endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension, which was withdrawn from the market due to severe hepatotoxicity. Clinical observations, particularly the beneficial effects of anti-inflammatory corticosteroids, suggest the involvement of immune-mediated processes.

A New Approach Methodology (NAM) is being implemented at Fraunhofer ITEM to specifically investigate such mechanisms, namely the use of living human Precision-cut Liver Slices (PCLiS) as an immune-competent ex-vivo model system. Preservation of the complex cellular architecture and immune cell populations of the human liver in viable functional active PCLiS enables a differentiated analysis of early, time-resolved immune responses to potentially hepatotoxic compounds.

Using the well-characterized reference compound acetaminophen (APAP) for intrinsic, dose-dependent drug-induced liver injury as a benchmark, immunomodulatory cytokine and transcriptomic profiles induced by compounds such as sitaxsentan can be interpreted.

The PCLiS model thus provides critical mechanistic insights into immune-mediated hepatotoxicity, strengthens the human relevance of preclinical safety assessments, reduces the need for animal testing, and supports a mechanistically informed prediction of drug-induced liver injury.