The Danger Hypothesis

An alternative theory to the hapten hypothesis that goes some way to explain why not all drugs that form reactive intermediates are associated with idiosyncratic reactions 

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Pirmohamed, M. et al., The danger hypothesis—potential role in idiosyncratic drug reactions, Toxicology, 181, 55-63, 202. 

Seguin, B., and Uetrecht, J., The danger hypothesis applied to idiosyncratic drug reactions, Curr. Opin. Allergy Clin. Immunol., 3, 235, 2003. 

The Thl/Th2 paradigm and the danger hypothesis have been useful to some extent... 

It may be that several mechanisms operate depending on exposure and host factors. A further twist is the suggestion that the reason so few individuals suffer the immune response is a result of tolerance. Clearly, from the "danger hypothesis," absence of the second signal, i.e., direct cytotoxicity from the free radical metabolite, because of better protective measures or lack of anaerobic conditions, then means that the immune response would not occur. 

Limited information exists on the possible role of the danger hypothesis in chemical-induced autoimmune-like derangements. Interestingly, poly I C has been shown to increase the incidence and severity of D-penicillamine-induced autoimmunity in Brown Norway rats (Sayeh Uetrecht, 2001). 

Based on recent concepts that immune responses are triggered in response to dangerous insults instead of to nonself-infectious agents (Matzinger, 1994,2002), the danger hypothesis has been brought forward for chemical allergens as well... 

Uetrecht, J. P. 1999. New concepts in immunology relevant to idiosyncratic drug reactions The danger hypothesis and innate immune system. Chemical Research in Toxicology 12 387-395. 

Seguin B, Uetrecht J (2003) The danger hypothesis applied to idiosyncratic drag reactions. Curr Opin Allergy Clin Immunol 3(4) 235-242... 

The Danger Hypothesis Applied to Idiosyncratic Drug Reactions... 

An important question is, if the danger hypothesis is correct, how closely tied to the dmg does a danger signal have to be in order to increase the risk of an IDR In other words, does the danger signal have to originate from the drug or can... 

Data Consistent with the Danger Hypothesis of IDRs Tienilic Acid-Induced Hepatotoxicity... 

The idiosyncratic nature of IDRs limits our ability to study them and presents a major challenge to elucidating the mechanisms involved. In vitro studies of IDRs cannot possibly mimic all the complex interactions that occur in vivo. Therefore, developing animal models with the potential to provide insight into the mechanisms of IDRs is essential to test mechanistic hypotheses and to study the sequence of events involved. Nevertheless, consistent with low incidence in humans, IDRs are also generally idiosyncratic in animals (Shenton et al. 2004). One explanation of why IDRs only occur in a minority of treated individuals is that in most cases the immune response is tolerance. If the danger hypothesis is correct, it should be... 

The danger hypothesis has had a revolutionary effect on the way that immunologists view what initiates an immune response. Assuming that most IDRs are immune-mediated, this hypothesis has very important implications for the... 

Pacitto SR, Uetrecht JP, Boutros PC, Popovic M (2007) Changes in gene expression induced by tienilic Acid and sulfamethoxazole testing the danger hypothesis. J Immunotoxicol 4 253-266... 

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