Immunological principles of adverse drug reactions - The initiation and propagation of immune responses elicited by drug treatment

Adverse drug reactions account for between 2 to 5% of all hospital admissio ns and can prevent the administration of an otherwise effective therapeutic agent. Hypersensitivity or immune-mediated reactions, although less common , tend to be proportionately more serious. There is convincing evidence to implicate the immune system in the pathogenesis of hypersensitivity reactio ns. Our understanding of the way in which the immune system recognises drug s is based on the hapten hypothesis; the onset of hypersensitivity involves drug bioactivation, covalent binding to proteins, followed by uptake, anti gen processing and T cell proliferation. Central to this hypothesis is the critical role of drug metabolism, with the balance between metabolic bioact ivation and detoxification being one important component of individual susc eptibility. The purpose of this review is to classify drug hypersensitivity reactions i n terms of their clinical presentation, and also to consider recent advance s in our understanding of the chemical, biochemical and, in particular, cel lular immunological mechanisms of hypersensitivity. The following topics ar e reviewed: (i) drug disposition and cellular metabolism; (ii) mechanisms o f antigen processing and presentation: (iii) the role of cytokines and co-s timulatory molecules in the induction and maintenance of a polarised immune response; and (iv) the application of the hapten hypothesis, danger hypoth esis and serial triggering model to drug hypersensitivity. A greater unders tanding of the mechanism(s) of hypersensitivity may identify novel therapeu tic strategies and help to combat one of the more severe forms of adverse r eactions to drugs.