Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+T-cells

1 Hypersensitivity to the drug sulfamethoxazole (SMX) is thought to be a co nsequence of bioactivation to the hydroxylamine metabolite (SMX-NHOH) and f urther oxidation to the ultimate reactive metabolite, nitroso-sulfamethoxaz ole (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 sub sequent dissociation to SMX-NHOH and/or SMX. 2 To study the reactivity of T-cells to SMX metabolites and their respectiv e role in the generation of drug-specific T-cells, we analysed the effect o f GSH on the response of PBMC to SMX and its metabolites SMX-NHOH and SMX-N O. 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 n o effect on the SMX-specific response but enhanced the proliferation to SMX -metabolites. The response of SMX-NO-specific T-cell clones was abrogated w hen GSH was present during the covalent haptenation of antigen presenting c ells (APC). Conversely, SMX-specific T-cell clones gained reactivity throug h the conversion of SMX-NO to the parent drug by GSH. While GSH had no effe ct on the initial activation of T-cell clones, it prevented covalent bindin g to APCs, reduced toxicity and thereby led to proliferation of drug-specif ic T-cells to non-reactive drug metabolites. 4 Our data support the concept that in allergic individuals T-cells recogni ze the non-covalently bound parent drug rather than APC covalently modified by SMX-NO.