The Danger Hypothesis Applied to Idiosyncratic Drug Reactions

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Abstract

The danger hypothesis has had a profound effect on the way immunologists view the immune response. This hypothesis proposes that the major determinant of whether an immune response is mounted against some agent is determined by whether that agent causes some type of cell damage. Assuming that most idiosyncratic drug reactions (IDRs) are immune-mediated, this hypothesis also has the potential to explain many aspects of the mechanism of these adverse drug reactions. For example, most IDRs appear to be caused by chemical metabolites rather than the parent drug, but not all drugs that form reactive metabolites are associated with a significant incidence of IDRs. Therefore, using the danger hypothesis, one feature of a drug candidate that may predict whether it causes an IDR is whether the drug, or more likely its reactive metabolites, cause cell damage. Although the range of molecules that can act as danger signals is unknown, the most attractive candidates are high mobility group box 1 protein (HMGB1), heat shock proteins, and S100 proteins. These molecules act through the same receptors (toll-like receptors) as pathogen-associated molecules that stimulate the immune system. Therefore, other environmental factors such as infections or trauma might determine which patients would be at increased risk for IDRs. Although there are examples where this appears to be the case, in most cases there are no obvious environmental factors that determine IDR risk. In addition, in animal models of immune-mediated reactions, stimulation of toll-like receptors often does not increase the immune response, and depending on the timing, it can actually be protective. Therefore, there may be additional unknown control mechanisms that are involved. A better understanding of these fundamental immune mechanisms has the potential to have a significant impact on many areas of medicine.