Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4(+) T cells from allergic individuals

The recognition of the antibiotic sulfamethoxazole (SMX) by T cells is usua lly explained with the hapten-carrier model. However, recent investigations have revealed a MHC-restricted but processing- and metabolism-independent pathway of drug presentation. This suggested a labile, low-affinity binding of SMX to MHC-peptide complexes on APC, To study the role of covalent vs n oncovalent drug presentation in SMX allergy, we analyzed the proliferative response of PBMC and T cell clones from patients with SMX allergy to SMX an d its reactive oxidative metabolites SMX-hydroxylamine and nitroso-SMX. Alt hough the great majority of T cell clones were specific for noncovalently b ound SMX, PBMC and a small fraction of clones responded to nitroso-SMX-modi fied cells or were cross-reactive. Rapid down-regulation of TCR expression in T cell clones upon stimulation indicated a processing-independent activa tion irrespective of specificity for covalently or noncovalently presented Ag, In conclusion, our data show that recognition of SMX presented in coval ent and noncovalent bound form is possible by the same TCR but that the For mer is the exception rather than the rule. The scarcity of cross-reactivity between covalently and noncovalently bound SMX suggests that the primary s timulation may be directed to the noncovalently bound SMX.