Exposure to sulfonamides is associated with a high incidence of hypersensitivity reactions. Antigen-specific T cells are involved in the pathogenesis; however, the nature of the antigen interacting with specific T-cell receptors is not fully defined.

We sought to explore the frequency of sulfamethoxazole (SMX)– and SMX metabolite–specific T cells in hypersensitive patients, delineate the specificity of clones, define mechanisms of presentation, and explore additional reactivity with structurally related sulfonamide metabolites.

SMX- and SMX metabolite–specific T-cell clones were generated from 3 patients. Antigen specificity, mechanisms of antigen presentation, and cross-reactivity of specific clones were then explored. Low-lying energy conformations of drugs (metabolites) were modeled, and the energies available for protein binding was estimated.

Lymphocytes proliferated with parent drugs (SMX, sulfadiazine, and sulfapyridine) and both hydroxylamine and nitroso metabolites. Three patterns of drug (metabolite) stimulation were seen: 44% were SMX metabolite specific, 43% were stimulated with SMX metabolites and SMX, and 14% were stimulated with SMX alone. Most metabolite-responsive T cells were stimulated with nitroso SMX–modified protein through a hapten mechanism involving processing. In contrast to SMX-responsive clones, which were highly specific, greater than 50% of nitroso SMX–specific clones were stimulated with nitroso metabolites of sulfapyridine and sulfadiazine but not nitrosobenzene. Pharmacophore modeling showed that the summation of available binding energies for protein interactions and the preferred spatial arrangement of atoms in each molecule determine a drug’s potential to stimulate specific T cells.

Nitroso sulfonamide metabolites form potent antigenic determinants for T cells from hypersensitive patients. T-cell responses against drugs (metabolites) bound directly to MHC or MHC/peptide complexes can occur through cross-reactivity with the haptenic immunogen.