title: Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+ T-cells.
abstract: 1. Hypersensitivity to the drug sulfamethoxazole (SMX) is thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX-NHOH) and further oxidation to the ultimate reactive metabolite, nitroso-sulfamethoxazole (SMX-NO). SMX-NO covalently modifies self proteins which in turn might be recognized as neo-antigens by T-cells. The antioxidant glutathione (GSH) is known to protect cells from reactive metabolites by conjugation and subsequent dissociation to SMX-NHOH and/or SMX. 2. To study the reactivity of T-cells to SMX metabolites and their respective role in the generation of drug-specific T-cells, we analysed the effect of GSH on the response of PBMC to SMX and its metabolites SMX-NHOH and SMX-NO. Furthermore, we monitored the proliferative response of drug-specific T-cell clones in the presence or absence of GSH. 3. We found that addition of GSH to peripheral blood mononuclear cells had no effect on the SMX-specific response but enhanced the proliferation to SMX-metabolites. The response of SMX-NO-specific T-cell clones was abrogated when GSH was present during the covalent haptenation of antigen presenting cells (APC). Conversely, SMX-specific T-cell clones gained reactivity through the conversion of SMX-NO to the parent drug by GSH. While GSH had no effect on the initial activation of T-cell clones, it prevented covalent binding to APCs, reduced toxicity and thereby led to proliferation of drug-specific T-cells to non-reactive drug metabolites. 4. Our data support the concept that in allergic individuals T-cells recognize the non-covalently bound parent drug rather than APC covalently modified by SMX-NO.
authors.affiliation: Clinic of Rheumatology and Clinical Immunology/Allergology, Inselspital, 3010 Bern, Switzerland. christoph.burkhart@insel.ch
authors.forename: C
authors.initials: C
authors.lastname: Burkhart
authors.forename: S
authors.initials: S
authors.lastname: von Greyerz
authors.forename: J P
authors.initials: JP
authors.lastname: Depta
authors.forename: D J
authors.initials: DJ
authors.lastname: Naisbitt
authors.forename: M
authors.initials: M
authors.lastname: Britschgi
authors.forename: K B
authors.initials: KB
authors.lastname: Park
authors.forename: W J
authors.initials: WJ
authors.lastname: Pichler
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004342:Drug Hypersensitivity; D004347:Drug Interactions; D005260:Female; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects*; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000378:metabolism; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D011948:Receptors, Antigen, T-Cell; C059873:sulfamethoxazole hydroxylamine; C072956:4-nitrososulfamethoxazole; D005978:Glutathione; D013420:Sulfamethoxazole