Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones.

Abstract

T cells can recognize small molecular compounds like drugs. It is thought that covalent binding to MHC bound peptides is required for such a hapten stimulation. Sulfamethoxazole, like most drugs, is not chemically reactive per se, but is thought to gain the ability to covalently bind to proteins after intracellular drug metabolism. The purpose of this study was to investigate how sulfamethoxazole is presented in an immunogenic form to sulfamethoxazole-specific T cell clones. The stimulation of four CD4 ϩ and two CD8 ϩ sulfamethoxazole-specific T cell clones by different antigen-presenting cells (APC) was measured both by proliferation and cytolytic assays. The MHC restriction was evaluated, first, by inhibition using anti-class I and anti-class II mAb, and second, by the degree of sulfamethoxazole-induced stimulation by partially matched APC. Fixation of APC was performed with glutaraldehyde 0.05%. The clones were specific for sulfamethoxazole without cross-reaction to other sulfonamides. The continuous presence of sulfamethoxazole was required during the assay period since pulsing of the APC was not sufficient to induce proliferation or cytotoxicity. Stimulation of clones required the addition of MHC compatible APC. The APC could be fixed without impairing their ability to present sulfamethoxazole. Sulfamethoxazole can be presented in an unstable, but MHC-restricted fashion, which is independent of processing. These features are best explained by a direct, noncovalent binding of sulfamethoxazole to the MHC-peptide complex. ( J. Clin. Invest. 1997. 100:136-141.)

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

“…Furthermore, some organic chemicals may be recognized especially by effector and memory T cells without covalent binding to carrier peptides on MHC as formulated in the p-i concept (Fig. 1) [35][36][37][38][39].…”

Reações alérgicas a medicamentos

“…20 The participation of T cells in allergic reactions to chemically inert drug structures has been shown in the last few years. 10,31 A new model of interaction between drug, MHC molecule and T cells, known as pharmacological interaction with immune receptors (p-i concept), has been proposed. 31 According to this hypothesis, the structure of the drug would bind to the peptide-MHC complex on one side and to the T cell receptor on the other side.…”

“…[7][8][9][10] In HIV-positive patients, ARs are at least ten times more frequent than in HIV-negative patients. 8,10 For instance, sulfonamide therapy in HIV-patients is associated with high incidence of adverse reactions (greater than 40%).…”

“…[7][8][9][10] In HIV-positive patients, ARs are at least ten times more frequent than in HIV-negative patients. 8,10 For instance, sulfonamide therapy in HIV-patients is associated with high incidence of adverse reactions (greater than 40%). 10 The incidence of skin reactions due to the oral administration of ampicillin or amoxicillin during an acute episode caused by the Epstein-Barr virus (infectious mononucleosis) is elevated among children and young adults.…”

“…8,10 For instance, sulfonamide therapy in HIV-patients is associated with high incidence of adverse reactions (greater than 40%). 10 The incidence of skin reactions due to the oral administration of ampicillin or amoxicillin during an acute episode caused by the Epstein-Barr virus (infectious mononucleosis) is elevated among children and young adults. 9 Familial susceptibility to AR also has been reported, 11 and may be related to different metabolic pathways of the drug, and to the antigenic process.…”