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Current science and translational opportunities in the prediction and prevention of immunologically-mediated adverse drug reactions

Phillips, E. (2015) Current science and translational opportunities in the prediction and prevention of immunologically-mediated adverse drug reactions. In: 54th Annual Meeting Society of Toxicology (SOT) and ToxExpo, 22 - 26 March 2015, San Diego, CA.


Many severe immunologically-mediated adverse drug reactions (ADRs) have been recently shown to be specifically HLA Class I restricted. Abacavir hypersensitivity reaction (ABC HSR) has been strongly associated with HLA-B*57:01, and level 1a evidence now supports the routine use of HLA-B*57:01 testing as a screening strategy to predict and prevent ABC HSR. Other examples of severe HLA-mediated drug hypersensitivity include the association of HLA-B*15:02 and carbamazepine- associated Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), HLA-B*58:01 and allopurinol associated HSR and SJS/TEN and HLA-B*13:01 in association with dapsone HSR. Although clinical, epidemiological and in vitro scientific studies have defined the specificity of the relevant HLA class I alleles for these ADRs they do not explain the low positive predictive value for the HLA allele in question for clinical disease. For instance only 55% of HLA-B*57:01 positive patients experience ABC HSR and only 3% of HLA-B*15:02 positive and HLA-B*58:01 positive individuals develop carbamazepine SJS/TEN and allopurinol SJS/TEN/HSR respectively. To explain this. we propose a heterologous immune model in which chronic prevalent viruses such as human herpes viruses sensitize and maintain a T-cell response that has the potential to cross-react with cells presenting the neo-antigen following drug ingestion. T-cell receptor repertoire usage may be restricted and oligoclonal as for carbamazepine induced SJS/TEN. For ABC, the heterologous immune model is supported by the rapidity of onset of the clinical syndrome (<5 days in 25% of patients) and the observation that ABC reactive memory CD8+ T-cells can be detected, without ABC driven expansion, in healthy HLA-B*57:01+ donors. In reference to this model, the potential immunopathogenetic basis and translational opportunities of different HLA-restricted drug HSR will be discussed.

Item Type: Conference Item
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
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