E. Sayeh et Jp. Uetrecht, Factors that modify penicillamine-induced autoimmunity in Brown Norway rats: failure of the Th1/Th2 paradigm, TOXICOLOGY, 163(2-3), 2001, pp. 195-211
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.