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.)

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Our data demonstrate activation and drug specificity of T cells in drug-induced skin eruptions. A predominant CD8(+) T cell activation leads to more severe (bullous) skin symptoms or liver involvement, while predominant activation of CD4(+) cells elicits mainly maculo-papular reactions.

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T cells recognize peptide and non-peptide antigens. Drugs represent typical examples of non-peptide antigens. The majority of drug-specific T cells are alphabeta+ TCR T cells and are MHC class I or II restricted. Here we show the existence of drug (lidocaine)-specific T cell clones which proliferate in the presence of antigen-presenting cells (APC) with different HLA alleles. Two clones (SFT24 and E20) were analyzed in detail. They show a narrow dose-dependent proliferation to lidocaine, but not to procaine. With the use of a panel of HLA-typed allogeneic APC, we observed that certain allogeneic APC plus lidocaine lead to a similar, others to partial and some to no proliferation of the lidocaine-specific T cell clones. An APC-independent proliferation could be excluded since both clones proliferated only marginally without APC and increasing the number of APC resulted in a higher proliferation. Blocking experiments with anti-DP, -DQ and -DR antibodies showed that lidocaine is presented in a HLA-DR-restricted way both with autologous or allogeneic APC. Mouse fibroblasts transfected with an allogeneic HLA-DRB1*01 but not HLA-DR-negative mouse fibroblasts could serve as presenting cells. Fixation of APC did not hamper drug presentation, but pulsing of APC with the drug was not possible, indicating that processing is not required and that lidocaine binds in an unstable way to the MHC-peptide complex. This degenerate drug recognition has certain features of superantigen recognition, such as the ability of drugs to bind from the outside to multiple HLA-DR alleles. Such features of drug recognition may open new therapeutic possibilities to intervene with TCR-MHC interactions in a selective way.