In vivo approaches for immune-mediated drug hypersensitivity research

Abstract

Drug allergies, immune-mediated drug hypersensitivity reactions (IDHRs) or drug induced liver injury (DILI) are important causes of black box warnings and drug withdrawals, and thus a major problem in the development of drugs. Also drug induced liver injury Despite the high demand for preclinical screening tools, no validated in vitro or in vivo models are available. At the moment, current methods (e.g. standard toxicity testing) are not sufficient to preclinically) predict the hazard or risk of IDHR by new pharmaceuticals. The aim of the work presented in this thesis was to identify (new) approaches that may help to predict IDHR and was performed in the framework of two large consortia within Top Institute Pharma and the Innovative Medicines Initiative. The experimental models that we used include innovative approaches to detect adjuvant activity, T-cell involvement (DTH, TNP-Ficoll response and T-cell differentiation following drug exposure) and drug-adduct/hapten formation. Together, these read outs were matched to the prevailing hypotheses linked to IDHR. We did so by using drugs known to cause IDHRs in human, namely, paracetamol, diclofenac, ofloxacin and carbamazepine. In this thesis, we have shown, by a series of experiments, that drugs display the capacity to activate both the innate as well as the adaptive immune system. For this, we used oral exposure protocols in mice. We set out to further evaluate in more detail which components of the innate and adaptive immune system were involved in the responses by different drugs. We saw that multiple immune parameters were altered upon exposure to the drugs, but that there were also clear differences between the drugs. However, despite these differences, the notion that both innate and adaptive components are involved will help to generate common predictive models. In all, the current work describes several experimental approaches that can be used to predict the potential hazard of new drug entities to induce IDHR. In addition, the developed in vivo approaches can be used to explore several different mechanisms and working hypotheses involved in the induction of IDHR. The research presented may therefore add substantially to a better understanding of IDHR and contribute to better predictive strategies in the future.