Genetics – improving the mechanistic understanding of drug hypersensitivity

Published Online: August 2015

Hypersensitivity or immune-mediated reactions can occur with almost any drug. They are collectively common, causing a great deal of morbidity and clinical concern. In addition, they can affect any bodily system. Lack of understanding of the mechanisms of these reactions, and therefore the development of diagnostic, predictive, and preventive strategies remains an unmet medical need.

In a review article recently published in The Journal of Allergy and Clinical Immunology (JACI), Pirmohamed and colleagues highlight how the advances in genomic technologies in this century have led to the identification of at least 24 new HLA associations with a number of drugs causing a variety of hypersensitivity reactions, most commonly affecting the skin and liver. These genetic associations provide mechanistic insights, the most important of which is the role of the immune system in the hypersensitivity reactions seen with many different structurally and therapeutically distinct drugs, and the need for HLA-restriction in the development of such reactions. Although there are several different hypotheses of how drugs (and their metabolites) can stimulate the immune system to cause hypersensitivity reactions (hapten hypothesis, p-I hypothesis, altered peptide hypothesis), it is likely that these mechanisms are complementary, and more than one mechanism, together with HLA-restriction, may be operating at the same time, leading to the heterogeneity in clinical manifestations seen in different patients, even with the same drug.

Better understanding of the mechanisms of drug hypersensitivity is required to develop superior evidence-based methods for predicting and preventing these serious reactions. The HLA associations in particular provide exciting opportunities for developing interventions including multiple HLA biomarker panels for prospective screening prior to drug use, the development of novel in vitro assays that could be used in drug development, and diagnostic assays to help in the clinical decision making process. Importantly, the novel insights being generated from an understanding of how drugs interact with both the HLA molecules and T-cell receptors will also provide lessons for autoimmune diseases that are so prevalent in the human population.

The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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