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Vol. 62, Issue 3, 628-637, September 2002
Department of Pharmacology and Therapeutics, The University of
Liverpool, Liverpool, United Kingdom (D.J.N., J.F., S.F.G., J.L.M.,
M.P., B.K.P.); and Clinic of Rheumatology and Clinical
Immunology/Allergology, Inselspital, University Bern, Bern, Switzerland
(C.B., W.J.P.)
Treatment with sulfamethoxazole (SMX) can lead to hypersensitivity
reactions. T cells from hypersensitive patients recognize either the
parent drug and/or the reactive nitroso (SMX-NO) metabolite. In this
study, using a novel in vitro rat splenocyte assay, we have
investigated the toxicological and immunological consequences of cell
surface haptenation by SMX-NO. SMX-NO was found to be unstable in
solution; spontaneous transformation yielded appreciable amounts of
SMX-hydroxylamine, nitro-SMX, and the previously unknown azoxy and azo
dimers within 15 min. Irreversible binding of SMX-NO to cellular
protein was demonstrated by flow cytometry, with haptenation being
greater on the surface of antigen-presenting cells than on T cells. The
consequences of irreversible binding of SMX-NO were examined in two
ways. First, haptenation above a threshold level led to a proportionate
increase in cell death (both apoptosis and necrosis). Indeed, the cells
that became haptenated were the same as those that underwent necrotic
cell death. Second, sensitized splenocytes proliferated in the presence
of major histocompatibility complex (MHC)-restricted antigen
derived from both viable and dead cells haptenated with low and high
levels of SMX-NO, respectively. However, direct modification of MHC by
SMX-NO was not the mechanism of antigen presentation. The antigenic
threshold of SMX-NO for T-cell proliferation and toxicity was estimated
to be between 0.5 and 1 µM and 5 to 10 µM, respectively. The
potential of SMX-NO to generate a potent antigen and cause cytotoxicity
may in combination provide the signals necessary to induce a
hypersensitivity reaction to SMX.
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