title: Transfection of drug-specific T-cell receptors into hybridoma cells: tools to monitor drug interaction with T-cell receptors and evaluate cross-reactivity to related compounds.
abstract: In the context of drug hypersensitivity, our group has recently proposed a new model based on the structural features of drugs (pharmacological interaction with immune receptors; p-i concept) to explain their recognition by T cells. According to this concept, even chemically inert drugs can stimulate T cells because certain drugs interact in a direct way with T-cell receptors (TCR) and possibly major histocompatibility complex molecules without the need for metabolism and covalent binding to a carrier. In this study, we investigated whether mouse T-cell hybridomas transfected with drug-specific human TCR can be used as an alternative to drug-specific T-cell clones (TCC). Indeed, they behaved like TCC and, in accordance with the p-i concept, the TCR recognize their specific drugs in a direct, processing-independent, and dose-dependent way. The presence of antigen-presenting cells was a prerequisite for interleukin-2 production by the TCR-transfected cells. The analysis of cross-reactivity confirmed the fine specificity of the TCR and also showed that TCR transfectants might provide a tool to evaluate the potential of new drugs to cause hypersensitivity due to cross-reactivity. Recombining the alpha- and beta-chains of sulfanilamide- and quinolone-specific TCR abrogated drug reactivity, suggesting that both original alpha- and beta-chains were involved in drug binding. The TCR-transfected hybridoma system showed that the recognition of two important classes of drugs (sulfanilamides and quinolones) by TCR occurred according to the p-i concept and provides an interesting tool to study drug-TCR interactions and their biological consequences and to evaluate the cross-reactivity potential of new drugs of the same class.
authors.affiliation: MD/Division of Allergology, Inselspital, University of Bern, 3010 Bern, Switzerland. werner.pichler@insel.ch.
authors.forename: Daphné Anne
authors.initials: DA
authors.lastname: Schmid
authors.forename: Jan Paul Heribert
authors.initials: JP
authors.lastname: Depta
authors.forename: Michael
authors.initials: M
authors.lastname: Lüthi
authors.forename: Werner Joseph
authors.initials: WJ
authors.lastname: Pichler
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002939:Ciprofloxacin / Q000494:pharmacology; D003429:Cross Reactions; D004347:Drug Interactions; D005434:Flow Cytometry; D006801:Humans; D006825:Hybridomas; D007376:Interleukin-2 / Q000096:biosynthesis*; D051379:Mice; D009643:Norfloxacin / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013419:Sulfamethizole / Q000494:pharmacology; D013420:Sulfamethoxazole / Q000494:pharmacology; D013424:Sulfanilamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D007376:Interleukin-2; D015363:Quinolones; D011948:Receptors, Antigen, T-Cell; D013424:Sulfanilamides; D013419:Sulfamethizole; D002939:Ciprofloxacin; D013420:Sulfamethoxazole; D009643:Norfloxacin