Factors that modify penicillamine-induced autoimmunity in Brown Norway rats: failure of the Th1/Th2 paradigm

Idiosyncratic drug reactions: appear to be immune-mediated. Immune response s are driven by helper T cells (Th), Th1 responses promote cell-mediated im munity, whereas Th2 responses drive antibody-mediated reactions. Th1 cytoki nes inhibit Th2 responses and Th? cytokines inhibit Th1 responses: therefor e, it may be possible to prevent idiosyncratic drug reactions by changing t he Th1/Th2 cytokine balance. We tested this hypothesis in an animal model i n which penicillamine causes an autoimmune syndrome in Brown Norway rats. T his syndrome has the hallmarks of a Th2-mediated response and we tried to i nhibit it with a polymer of inosine and cytosine (poly I:C), a Th1 cytokine -inducer. However. we found that a single dose of poly I:C, given at the on set of penicillamine treatment, significantly increased both the incidence (100 vs. 60%) and accelerated the onset (30 +/- 4 vs. 39 +/- 5 days) of pen icillamine-induced autoimmunity when compared with controls. To rule out ot her effects of poly I:C that might overshadow the induction of Th1 cytokine s, we directly tested the effects of the prototypic Th1 cytokine, interfero n-gamma. Although not as dramatic, interferon-gamma -pretreatment also appe ared to make the syndrome worse. Conversely. when we used misoprostol, a pr ostaglandin-E analog that inhibits Th1 cytokines it completely protected th e animals. Just one dose of misoprostol prior to initiation of penicillamin e treatment was sufficient to provide this protection. The syndrome was als o completely inhibited by aminoguanidine. an inhibitor of iNOS. These resul ts, although dramatic. suggest that the: effects of these agents were not m ediated by their effects on Th1/Th2 balance, but rather by some other mecha nism. (C) 2001 Elsevier Science ireland Ltd. All rights reserved.