Murine models of drug hypersensitivity

Abstract

Drug hypersensitivity reactions are relatively rare but may result in severe morbidity and fatalities. Due to the idiosyncratic nature and multifactorial etiology of these reactions, development of a single animal model to study the immunosensitizing mechanisms of all drugs is impossible. This hampers the development of predictive screening models that are urgently needed to assess the immunostimulating capacity of newly developed drugs. The present review will focus on recent findings on mechanisms of drug hypersensitivity reactions obtained with murine models, and on the use of these models as potential screening tools to assess the immunostimulating capacity of drugs. Mechanisms of drug-induced sensitization versus tolerance appear dependent on generally accepted immunological paradigms. For instance, co-stimulatory signaling by antigen-presenting cells is decisive in drug-induced immunosensitization and both T cells and antigen-presenting cells are important for the induction of tolerance to orally administered drugs. From recent studies it has been hypothesized that expression of stress-associated transcription factors and the expression of costimulatory molecules or cytokine production within hours or days after the initial exposure may be representative of drug-induced hypersensitivity reactions and may thus be used as predictive parameters to screen for immunosensitizing drugs. The development of animal models to study mechanisms of drug hypersensitivity reactions is still in its infancy. Much effort has been made, however, to search for early indicators of immunostimulation in murine animal models that may eventually appear useful in a tiered strategy to assess drug-induced sensitization.