Journal Article

Involvement of T Helper 17 Cells in <span class="smallCaps">D</span>-Penicillamine–Induced Autoimmune Disease in Brown Norway Rats

Xu Zhu, Jinze Li, Feng Liu and Jack P. Uetrecht

in Toxicological Sciences

Volume 120, issue 2, pages 331-338
Published in print April 2011 | ISSN: 1096-6080
Published online January 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq392
Involvement of T Helper 17 Cells in D-Penicillamine–Induced Autoimmune Disease in Brown Norway Rats

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Idiosyncratic drug reactions (IDRs) are poorly understood, but their clinical characteristics suggest that they are immune mediated. Penicillamine-induced autoimmunity in Brown Norway rats has been utilized as an animal model for mechanistic studies of one type of IDR because it closely mimics the autoimmune syndromes that it causes in humans. Our previous work suggested that it is T-cell mediated. It has been shown that T helper 17 (Th17) cells play a central role in many types of autoimmune diseases. This study was designed to test whether Th17 cells are involved in the pathogenesis of penicillamine-induced autoimmunity and to establish an overall serum cytokine/chemokine profile for this IDR. In total, 24 serum cytokines/chemokines were determined and revealed a dynamic process. In sick animals, interleukin (IL) 6 and transforming growth factor-β1, known to be driving forces of Th17 differentiation, were consistently increased at both early and late stages of penicillamine treatment; however, no significant changes in these cytokines were observed in animals that did not develop autoimmunity. IL-17, a characteristic cytokine produced by Th17 cells, was increased in sick animals at both the messenger RNA and serum protein level. In addition, serum concentrations of IL-22, another characteristic cytokine produced by Th17 cells, were found to be elevated. Furthermore, the percentage of IL-17–producing CD4 T cells was significantly increased but only in sick animals. These data strongly suggest that Th17 cells are involved in penicillamine-induced autoimmunity. Such data provide important mechanistic clues that may help to predict which drug candidates will cause a relatively high incidence of such autoimmune IDRs.

Keywords: idiosyncratic drug reactions; penicillamine; Th17; autoimmune; animal models

Journal Article.  3572 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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