Role of animal models in the study of drug-induced hypersensitivity reactions.

Drug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very difficult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basic hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only approximately 0.25%, and large-breed dogs are difficult to use as an animal model. Two more practical models are penicillamine-induced autoimmunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquine-induced agranulocytosis/hepatotoxicity and halothane-induced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This finding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also significantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow.