Innate immunity in idiosyncratic drug-induced liver injury: kinetics matters

Abstract

Drugs frequently affect the liver causing “drug-induced liver injury” (DILI). However, predicting which drugs will prove toxic to the liver is extremely difficult, and often problems are not detected until a drug is already on the market. In particular, idiosyncratic DILI (IDILI) is not clearly related to the dose and time of drug administration and is considered to be related to complex immune processes. The main aim of the project (https://www.imi.europa.eu/projects-results/project-factsheets/mip-dili), in which this thesis was embedded, was to develop a new predictive strategy for the identification of IDILI-causing compounds.We investigated mechanisms of IDILI using two different compounds: trovafloxacin and ximelagatran, both withdrawn from the market due to the high incidence of unpredicted DILI. Complex animal models have been developed that demonstrate clear liver damage. In both models we investigated if relevant immunological changes are induced by the above-mentioned drugs and how they mechanistically relate to the onset of liver damage.Results presented in this thesis confirms the requirement of an integrated approach based on a complementary and modulatory panel of tests to identify IDILI-causing compounds. We suggest that drugs should be at least tested for their effects on the kinetics of neutrophil and monocyte recruitment, the intracellular dynamic responses of NF-kB and MAPKs to TNF/LPS in macrophages/hepatocytes and the potency of the immune responses against viral infections. The integration of the results obtained by these assessments might represent an approach to estimate the risks of compounds to cause IDILI.