12 Abstracts

required if progress is to be made in identifying NMEs with the potential to produce immune-mediated hypersensitivity.

Recognition of Drugs by the Immune System: Metabolic Activation and Epitope Formation

Kevin Park Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, L69 3GE, UK

Idiosyncratic drug toxicity is a major complication of drug therapy and drug development. Such adverse drug reactions include anaphylaxis, blood dyscrasias, hepatotoxicity and severe cutaneous reactions. They are usually serious and can be fatal. At present, prediction of idiosyncratic adverse drug reactions (ADRs) at the preclinical state of drug development is not possible because of a lack of suitable animal models and a lack of understanding of the basic mechanisms involved in the toxicity when it does occur in man. Many idiosyncratic reactions appear to have an immunological aetiology. For example, there is increasing direct evidence for the role of T lymphocytes in severe skin reactions. Nevertheless, the sequence of events by which a simple chemical can elicit severe tissue damage remains poorly understood and alternative novel mechanisms of toxicity must also be explored. The purpose of this presentation will be to review currently accepted mechanisms of drug allergy at the chemical and molecular level. In particular, the role of drug metabolism and drug bioactivation in drug epitope formation will be critically reviewed. The possibility of non-covalent drug binding in drug hypersensitivity will be considered.

The relevance of the Matzinger ‘danger theory’ to drug hypersensitivity will be discussed. In particular, we will consider how recent advances in cellular immunology and molecular biology can improve our understanding of both the chemical and clinical aspects of drug hypersensitivity. The clinically well characterised hypersensitivity reactions associated with the drugs carbamazepine and sulphamethoxazole will be used as examples to attempt to define the pathophysiological pathway from the initial bioactivation of the parent drug right through to the clinical manifestation of tissue damage. The roles of cytokines and T cells in determining the nature and severity of the toxicity will be discussed, as will recent advances in the role of both inter- and intra-cellular signalling in the regulation of the immune response to drugs and their metabolites. The possible role of secondary factors, such as inter-individual variation in drug metabolism, concomitant disease processes, in determining inter-individual variation in susceptibility to idiosyncratic reactions will also be explored. The long-term aim of such research is to provide test systems for the valuation of drug safety and patient susceptibility to idiosyncratic drug toxicity.

Park, B.K., Pirmohamed, M., Kitteringham, N.R., 1998. Chem. Res. Toxicol. 7637 Uetrecht, J.P., 1999. Chem. Res. Toxicol. 7638 Von Greyerz, S., Burkhart, C., Pichler, W.J., 1999. Int. Arch. Allergy Immunol. 199, 173-180. Zanni, M.P., von Greyerz, S., Schnyder, B., Brander, K.A., Frutig, K., Hari, Y., Valitutti, S., Pichler, W.J., 1998. J. Clin. Invest. 102, 1591-1598

Cellular Immune Responses in the Development of Drug Allergy

Werner J. Pichler and Christoph Burkhart Division Allergology, Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital, 3010 Bern, Switzerland

The pathogenesis of various drug induced allergic reactions is still enigmatic. Recent data suggested an involvement of drug specific T cells in various drug allergic reactions: to further investigate the role of T cells in drug induced exanthema, we generated T cell clones (TCC) specific for various drugs from drug allergic persons.