Molecular aspects of drug recognition by specific T cells.
Adverse reactions to drugs are a major problem in pharmacotherapy. About 1/6 of all side-effects are thought to be drug-induced immune-mediated reactions. It is well established that T and B cells recognize a drug if it is bound as hapten to carrier molecules. However, the model does not explain many T cell-mediated reactions with chemically inert compounds. This review will first discuss the hapten-carrier concept of drug-presentation to T cells and the currently used methods to predict an allergenic potential of a drug. It then introduces our new model of drug-uptake- and processing-free HLA class II-restricted T-cell response termed "direct metabolism-independent T-cell stimulation". This led us to an other new concept: the pharmacological interaction of drugs with immunological receptors, namely the MHC and T-cell receptors. Additionally, we focus on certain conditions of non-covalent drug presentation by antigen presenting cells and on the molecular recognition of MHC/peptide/drug complexes by specific T-cell receptors. Finally, we discuss the clinical relevance of drug-specific T cells, namely that T cells seem to exert a certain pathology (e.g. drug-induced exanthema or pustular eruptions) depending on their function. These findings, which are based on the analysis of clinical drug allergy, have major implications for our understanding of T-cell biology and on the concept how to test and predict the allergenic potential of a drug.
Britschgi
Markus
M
Division of Allergology, Clinic of Rheumatology and Clinical Immunology/Allergology, PKT2 D572, Inselspital, CH-3010 Bern, Switzerland.
von Greyerz
Salome
S
Burkhart
Christoph
C
Pichler
Werner J
WJ
D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D006241:Haptens / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008285:Major Histocompatibility Complex / Q000276:immunology; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D002352:Carrier Proteins; D006241:Haptens; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D004364:Pharmaceutical Preparations; D011971:Receptors, Immunologic