Recognition of Sulfamethoxazole and Its Reactive Metabolites by Drug-Specific CD4+ T Cells from Allergic Individuals

Abstract

The recognition of the antibiotic sulfamethoxazole (SMX) by T cells is usually 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 noncovalent drug presentation in SMX allergy, we analyzed the proliferative response of PBMC and T cell clones from patients with SMX allergy to SMX and its reactive oxidative metabolites SMX-hydroxylamine and nitroso-SMX. Although the great majority of T cell clones were specific for noncovalently bound SMX, PBMC and a small fraction of clones responded to nitroso-SMX-modified cells or were cross-reactive. Rapid down-regulation of TCR expression in T cell clones upon stimulation indicated a processing-independent activation irrespective of specificity for covalently or noncovalently presented Ag. In conclusion, our data show that recognition of SMX presented in covalent and noncovalent bound form is possible by the same TCR but that the former is the exception rather than the rule. The scarcity of cross-reactivity between covalently and noncovalently bound SMX suggests that the primary stimulation may be directed to the noncovalently bound SMX.

A marker for Stevens-Johnson syndrome …: ethnicity matters

“…In some cases there may be haptenization of self-peptides by a reactive metabolite, but it has been demonstrated that medications are often presented through noncovalent binding with MHC Class I molecules. 15 In this context, one may hypothesize that rare and severe reactions to drugs, such as SJS or TEN are dependent on infrequent HLA alleles, each being capable of binding to a 'specific' drug.…”

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

“…While much remains to be learned about the mechanisms of the varied reactions that can occur in the skin after systemic drug administration, many of these reactions are consistent with delayed-type hypersensitivity -implicating the involvement of the immune system in their provocation (Cribb et al, 1996a;Svensson et al, 2001;Pichler et al, 2002;Pichler, 2003). The observation that patients with a history of such reactions may possess drug-reactive T-cells suggests that these responses are T-cell mediated (Mauri-Hellweg et al, 1995;Schnyder et al, 2000;Nassif et al, 2002). As drugs noted to provoke these reactions are small molecules, it has been proposed that bioactivation of drugs to reactive metabolites is an essential prerequisite to the initiation of CDRs (Park and Kitteringham, 1990;Park et al, 1998;Park et al, 2000;Svensson, 2003).…”

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

“…RNeasy 96 total RNA extraction kit and RLT lysis buffer were obtained from Qiagen. Oligo(dT) [12][13][14][15][16][17][18] primer, 2Ј-deoxynucleoside 5Ј-triphosphate mix and the Superscript II reverse transcriptase kit were obtained from Invitrogen Life Technologies. Oligonucleotide fluorogenic probes and TaqMan Universal PCR Mastermix were obtained from Applied Biosystems.…”