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 admissions 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 reactions. Our understanding of the way in which the immune system recognises drugs is based on the hapten hypothesis; the onset of hypersensitivity involves drug bioactivation, covalent binding to proteins, followed by uptake, antigen processing and T cell proliferation. Central to this hypothesis is the critical role of drug metabolism, with the balance between metabolic bioactivation and detoxification being one important component of individual susceptibility. The purpose of this review is to classify drug hypersensitivity reactions in terms of their clinical presentation, and also to consider recent advances in our understanding of the chemical, biochemical and, in particular, cellular immunological mechanisms of hypersensitivity. The following topics are reviewed: (i) drug disposition and cellular metabolism; (ii) mechanisms of antigen processing and presentation: (iii) the role of cytokines and co-stimulatory molecules in the induction and maintenance of a polarised immune response; and (iv) the application of the hapten hypothesis, danger hypothesis and serial triggering model to drug hypersensitivity. A greater understanding of the mechanism(s) of hypersensitivity may identify novel therapeutic strategies and help to combat one of the more severe forms of adverse reactions to drugs.