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 I-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.