title: Effects of immunization and checkpoint inhibition on amodiaquine-induced liver injury.
abstract: If idiosyncratic drug-induced liver injury (IDILI) is immune-mediated, it is possible that an individual's prior exposure to antigens may affect their susceptibility to IDILI. An individual's repertoire of memory immune cells is shaped by every past exposure to antigens. Subsequent drug-induced adverse drug reactions may therefore involve an immune cell's cross reactivity between a prior antigen and resulting drug-modified proteins. Therefore in this experiment, mice were immunized with amodiaquine (AQ)-modified hepatic proteins to mimic a previous exposure; treated with a RIBI adjuvant and anti-CD40 antibodies to stimulate an immune response; and, treated with anti-PD1 and anti-CTLA-4 antibodies prior to AQ treatment in order to overcome immune tolerance. This treatment led to greater liver injury than treatment with AQ alone. However, the mice did not develop serious liver injury. PD1-/-mice were then immunized and treated with AQ and anti-CTLA-4 antibodies so that immune tolerance would be impaired, both during immunization and also during AQ treatment. However, even this did not result in liver failure, and the liver injury was not significantly increased relative to un-immunized PD1-/-mice treated with anti-CTLA-4 and AQ. From these results we conclude that, although previous antigen exposure may affect the risk of IDILI, it appears that a very strong stimulus is required, and impairing immune tolerance remains the most effective method for producing an animal model of IDILI.
authors.affiliation: a Department of Pharmaceutical Sciences, Faculty of Pharmacy , University of Toronto , Toronto , Ontario , Canada.
authors.forename: Alastair
authors.initials: A
authors.lastname: Mak
authors.affiliation: a Department of Pharmaceutical Sciences, Faculty of Pharmacy , University of Toronto , Toronto , Ontario , Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Johnston
authors.affiliation: a Department of Pharmaceutical Sciences, Faculty of Pharmacy , University of Toronto , Toronto , Ontario , Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Uetrecht
mesh_terms: D000655:Amodiaquine / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D019013:CD40 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000628:therapy*; D003429:Cross Reactions; D063926:Drug Hypersensitivity Syndrome / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000655:Amodiaquine
keywords: Idiosyncratic drug-induced liver injury; amodiaquine; animal model; immune tolerance; immunization