Investigation of the Mechanism of Idiosyncratic Drug-Induced Liver Injury by Immune System Modulation

Idiosyncratic drug-induced liver injury (IDILI) continues to be an important issue. There is increasing clinical evidence that most IDILI is immune mediated. Extensive mechanistic studies are needed to better understand these reactions; however, it is impossible to do controlled experiments in humans, and previous animal models did not properly model IDILI. If IDILI is immune mediated, and the major factor preventing liver injury in patients is immune tolerance, then a plausible method to develop an animal model of IDILI would be to impair immune tolerance. Therefore, the objectives of my research were to develop a valid animal model of IDILI, use this model to test mechanistic hypotheses, and to develop better ways to predict risk. In my first two papers I show that immunization of mice with drug-modified hepatic proteins prior to drug exposure paradoxically decreased liver injury unless immune tolerance was impaired during the immunization. In my third paper, I show that PD1-/- mice treated with anti- CTLA-4 and amodiaquine can lead to significant liver injury and liver dysfunction, which is mediated by CD8 T cells. In my fourth paper, I show that this impaired immune tolerance model is able to unlock the potential of isoniazid and nevirapine to cause increased liver injury. Finally, in my fifth paper, I show that this impaired immune tolerance model is also able to distinguish the potential for liver injury of chemically similar drugs, where one drug causes IDILI in humans and the other does not (troglitazone/pioglitazone and tolcapone/entacapone). Overall, I have shown that risk of developing IDILI may be influenced by previous exposures, and I have further developed a model of IDILI, showing its potential for other drugs and as a tool for drug screening. Further characterization and validation of these models is required; however, it is likely that they will make it possible to perform mechanistic studies that have been impossible in the past.Ph.D