Investigating the mechanism of idiosyncratic drug reactions
Subtitle: role of covalent binding and danger in D-penicillamine induced autoimmunity in the brown Norway rat.
Published: 2005
Language: eng
Number of pages: 221
Description: Finally, we examined the role of immunological tolerance in D-penicillamine-induced autoimmunity and assessed the presence of regulatory T cells in the spleen of tolerant animals. We co-transferred T cells or splenocytes-depleted of T cells from tolerant BN rats into syngeneic recipients. We found that both tolerant splenocyte subpopulations partially prevented clinical signs of autoimmunity. These results demonstrate that APCs and T cells may contribute to immune tolerance to D-penicillamine.Idiosyncratic drug reactions (IDRs) are unpredictable and their mechanisms are largely unknown. They are associated with a high rate of morbidity and mortality. In this study, we used D-penicillamine-induced autoimmunity in the Brown Norway (BN) rat as an animal model of IDRs to test two hypotheses that may explain their mechanism: the "Hapten Hypothesis" and "Danger Hypothesis".We identified factors which might be danger signals using microarrays to compare animals 6 hr after receiving either D-penicillamine or vehicle. We found that drug-treated animals clustered into two distinctive groups: putative danger signals were identified in 50% of treated animals. Hierarchical clustering using a set of the putative danger signals, gck, pcscl, sgk and kid-1 showed that three of the resistant animals clustered tightly together, for a disease classification success rate of 75%.We produced an antibody that recognizes D-penicillamine-disulfide adducts and found that D-penicillamine covalently binds in the skin and spleen of drug-treated BN rats even if they did not develop drug-induced autoimmunity. Moreover, D-penicillamine bound to collagen-like fibres but not to cells, such as macrophages. We conclude that this antibody may not recognize the important antigenic epitopes that are formed in vivo, such as thiazolidine adducts between D-penicillamine and aldehydes.We also performed studies that demonstrated that the incidence of D-penicillamine-induced autoimmunity can be manipulated by the prostaglandin analog, misoprostol, and by NSAIDs. In sensitized rats, prevention of disease on drug re-challenge was partial: 5/13 animals pretreated with misoprostol became ill (p = 0.002). A single dose of the nonselective COX inhibitor, ketoprofen, decreased the time to onset of D-penicillamine-induced autoimmunity and continuous treatment significantly increased the incidence (p = 0.024). One dose of the selective inhibitor, rofecoxib, lowered the incidence of D-penicillamine-induced autoimmunity (p = 0.001).
Notes: Advisor: Uetrecht, Jack

Thesis (Ph.D.)--University of Toronto, 2005.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3082.