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

Abstract

A BSTRACTDrug-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 diffi cult, 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 ~0.25%, and large-breed dogs are diffi cult 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 amodiaquineinduced agranulocytosis/hepatotoxicity and halothaneinduced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This fi nding 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 signifi cantly 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. K EYWORDS: animal models , hypersensitivity reactions , idiosyncratic drug reactions , penicillamine , nevirapine , popliteal lymph node assay INTRODUCTIONTo an immunologist, the term hypersensitivity implies an immune-mediated reaction. The term drug-induced hypersensitivity reaction (DHR) is used to describe a syndrome consisting of fever, rash, and involvement of various organs associated with drugs such as phenytoin, carbamazepine, abacavir, sulfonamides, and allopurinol; however, it is also frequently used to describe any idiosyncratic drug reaction. For many of the adverse reactions to be discussed in this review, it has not been conclusively demonstrated that they are immune mediated, and the term hypersensitivity reaction will be used broadly to refer to any idiosyncratic drug reaction that has features that suggest it is immune mediated. Another working hypothesis for this review, which is supported by a large amount of circumstantial evidence, 1 but in virtually no case proven, is that most DHRs are caused by reactive metabolites. Therefore, a major role of animal models is to test whether reactive metabolites are responsible for hypersensitivity reactions and further to determine how reactive metabolites provoke an immune response.A major characteristic of DHRs is their unpredictable or idiosyncratic nature. This means that at the present time it is impossible to predict which drug candidates will...

Erythroderma and Epidermal Necrosis Induced by a Type of Proton Pump Inhibitor in Beagle Dogs

“…Severe sulfonamide-associated skin eruptions, including TEN, erythema multiforme and pemphigus folliacious, and acute hepatopathy have been reported in dogs and are considered to be a useful animal model for sulfonamideinduced hypersensitivity reactions 12,13 . The epidermal changes in this study were unpredictable when considering the pharmacological effects of the compound.…”

Bone marrow-derived mesenchymal stem cells (MSCs) stimulate neurite outgrowth from differentiating adult hippocampal progenitor cells

“…This property would be a benefit to meet the needs of generating a large number of cells for scientific research and preclinical applications. Unexpectedly, a low a commonly used strain for biomedical research [20,23,24,37,38]. MSCs were successfully isolated from the bone marrow and were cultured for 20 passages displaying stable and consistent growth rates.…”

“…However, MSCs from the bone marrow of Brown Norway rats (Rattus norvegicus), have not been studied systematically. Brown Norway rats are a relatively common animal model CrossMark ← Click for updates doi: 10.7243/2054-717X-3-3 used for biomedical research [19][20][21][22][23][24]. They are well-defined genetically, physiologically, and behaviorally [19,[25][26][27][28][29].…”

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