title: Factors that modify penicillamine-induced autoimmunity in Brown Norway rats: failure of the Th1/Th2 paradigm.
abstract: Idiosyncratic drug reactions appear to be immune-mediated. Immune responses are driven by helper T cells (Th); Th1 responses promote cell-mediated immunity, whereas Th2 responses drive antibody-mediated reactions. Th1 cytokines inhibit Th2 responses and Th2 cytokines inhibit Th1 responses; therefore, it may be possible to prevent idiosyncratic drug reactions by changing the Th1/Th2 cytokine balance. We tested this hypothesis in an animal model in which penicillamine causes an autoimmune syndrome in Brown Norway rats. This syndrome has the hallmarks of a Th2-mediated response and we tried to inhibit 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 onset of penicillamine treatment, significantly increased both the incidence (100 vs. 60%) and accelerated the onset (30+/-4 vs. 39+/-5 days) of penicillamine-induced autoimmunity when compared with controls. To rule out other effects of poly I:C that might overshadow the induction of Th1 cytokines, we directly tested the effects of the prototypic Th1 cytokine, interferon-gamma. Although not as dramatic, interferon-gamma-pretreatment also appeared to make the syndrome worse. Conversely, when we used misoprostol, a prostaglandin-E analog that inhibits Th1 cytokines, it completely protected the animals. Just one dose of misoprostol prior to initiation of penicillamine treatment was sufficient to provide this protection. The syndrome was also completely inhibited by aminoguanidine, an inhibitor of iNOS. These results, although dramatic, suggest that the effects of these agents were not mediated by their effects on Th1/Th2 balance, but rather by some other mechanism.
authors.affiliation: Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Canada M5S 2S2.
authors.forename: E
authors.initials: E
authors.lastname: Sayeh
authors.forename: J P
authors.initials: JP
authors.lastname: Uetrecht
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity; D003875:Drug Eruptions / Q000097:blood / Q000209:etiology / Q000652:urine; D007073:Immunoglobulin E / Q000097:blood; D007369:Interferon Inducers / Q000008:administration & dosage; D007371:Interferon-gamma / Q000096:biosynthesis / Q000627:therapeutic use; D015847:Interleukin-4 / Q000096:biosynthesis; D016595:Misoprostol / Q000008:administration & dosage; D023421:Models, Animal; D009573:Nitrites / Q000652:urine; D010396:Penicillamine / Q000009:adverse effects / Q000633:toxicity*; D011070:Poly I-C / Q000008:administration & dosage; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013577:Syndrome; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D007369:Interferon Inducers; D009573:Nitrites; D016595:Misoprostol; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010396:Penicillamine; D011070:Poly I-C