title: The Combination of Anti-CTLA-4 and PD1-/- Mice Unmasks the Potential of Isoniazid and Nevirapine To Cause Liver Injury.
abstract: Our laboratory recently reported what we believe is the first valid animal model of idiosyncratic drug-induced liver injury (IDILI) by treating PD1-/- mice with an anti-CTLA-4 antibody and amodiaquine (AQ). PD1 and CTLA-4 are important immune checkpoint receptors that are involved in inducing immune tolerance. This model was able to produce significant liver injury that looks very similar to the liver injury seen in humans. Although this model was shown to work with AQ, the question becomes whether blocking immune tolerance would unmask the potential of other drugs to cause IDILI. In this study, we tested isoniazid and nevirapine, both drugs with significant histories of causing IDILI in humans even though they do not cause significant injury in animals with doses that result in therapeutic blood levels. Both drugs in combination with these immune checkpoint inhibitors caused mild but significant delayed onset liver injury, which is similar to the mild injury that they can cause in humans. INH-induced liver injury in this model was associated with an increase in NK cells, while NVP-induced liver injury was associated with a greater increase in CD8 T cells. Although the liver injury caused by these drugs in this model was mild, these results suggest that impairing immune tolerance may be a general method for unmasking the potential of drugs to cause IDILI and therefore provide a screening tool for drug development.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
authors.forename: Alastair
authors.initials: A
authors.lastname: Mak
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D053804:Granzymes; D006801:Humans; D007538:Isoniazid / Q000633:toxicity*; D008099:Liver / Q000187:drug effects; D051379:Mice; D019829:Nevirapine / Q000633:toxicity*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D019829:Nevirapine; D053804:Granzymes; C509214:Gzmb protein, mouse; D007538:Isoniazid