Pathology of drug hypersensitivity reactions and mechanisms of immune tolerance

Immune-mediated type IV adverse drug reactions are idiosyncratic in nature, generally not related to the primary or secondary pharmacology of the drug. Due to their complex nature and rarity, these iatrogenic reactions are seldom predicted or encountered during preclinical/early clinical development stages, and often precipitate upon exposure to wider populations (i.e. phase III onwards). They confer a burden on the healthcare sector in both a clinical and financial sense presenting a severe impediment to the drug discovery and development process. Research over the past 50 years has improved our understanding of these reactions markedly as both in vitro and in vivo studies have placed the role of the immune system, in particular; drug-responsive T cells, firmly in the spotlight as the mediators of these reactions. Indeed, the role of different populations of T cells in adverse events and the interaction of drug molecules with HLA proteins expressed on the surface of antigen-presenting cells is of considerable interest. Herein, this review examines the pathways of immune-mediated adverse events including the various T cell subtypes implicated and the mechanisms of T cell activation. Additionally, we address the enigma of immunological tolerance and explore the role tolerance plays in determination of susceptibility to such adverse events even in individuals carrying immunogenic liabilities.