The mechanisms of idiosyncratic drug reactions (IDRs) are unknown; however, most appear to be immune-mediated. Their idiosyncratic nature and the paucity of animal models make mechanistic studies very difficult. One of the few animal models is penicillamine-induced autoimmunity in Brown Norway rats. The major focus of this thesis was the use of this model to study the interaction between penicillamine and macrophages, the involvement of Th17 cells, and extension of this model to idiosyncratic drug-induced liver injury.
One of the costimulatory signals leading to T cell activation appears to be reversible Schiff-base formation between an amine on T cells and an aldehyde on macrophages. We hypothesized that penicillamine binds to these aldehydes leading to macrophage activation and autoimmunity. By using biotinylated aldehyde-reactive agents such as ARP, we demonstrated the existence of aldehydes on the surface of macrophages. We synthesized biotinylated-penicillamine and it also binds to macrophages. Several proteins to which ARP binds were identified providing clues to the signal transduction pathways leading to macrophage activation. Biological consequences of this binding were investigated with a microarray study. ARP binding was also observed in the macrophage cell line, RAW264.7, and incubation with penicillamine stimulated the production of TNF-α, IL-6, and IL-23. Hydralazine and isoniazid, which are known to cause a lupus-like syndrome in humans and irreversibly bind to aldehyde groups, were also found to activate RAW264.7 cells.
Th17 cells are prominent in autoimmune syndromes and Th17-associated cytokines such as IL-17 were elevated in the penicillamine-treated animals that developed autoimmunity. We have hypothesized that some drug-induced liver injury has an autoimmune component. A pilot study quantified serum concentrations of 26 cytokines/chemokines in patients with various forms of acute liver failure (ALF): idiosyncratic drug-induced ALF, acetaminophen-induced ALF, and viral hepatitis. IL-17 was elevated in 60% of patients with idiosyncratic drug-induced ALF, which supports an autoimmune component in these patients; however, it was also elevated in many cases of acetaminophen-induced ALF, presumably released by the innate immune system.
These studies provide important insights into the mechanism of penicillamine-, hydralazine-, and isoniazid-induced autoimmunity and also provide clues to other IDRs that may have an autoimmune component.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/19282 |
| Date | 03 March 2010 |
| Creators | Li, Jinze |
| Contributors | Uetrecht, Jack |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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