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Practical Implementation of Genetics: New Concepts in Immunogenomics to Predict, Prevent, and Diagnose Drug Hypersensitivity

Deshpande, P., Li, Y., Thorne, M., Palubinsky, A.M., Phillips, E.J. and Gibson, A. (2022) Practical Implementation of Genetics: New Concepts in Immunogenomics to Predict, Prevent, and Diagnose Drug Hypersensitivity. The Journal of Allergy and Clinical Immunology: In Practice .

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Delayed drug hypersensitivities are CD8+ T-cell mediated reactions associated with up to 50% mortality. Human leukocyte antigen (HLA) alleles are known to predispose disease, specific to drug, reaction, and patient ethnicity, with pre-treatment screening recommended for a handful of the strongest associations to identify and prevent drug use in high-risk patients. However, an incomplete predictive value implicates other HLA-imposed risk factors, and low carriage of many identified HLA-risk alleles combined with the high cost of sequence-based typing has limited economic viability for similar recommendation of screening across drugs and healthcare systems. To mitigate, an expanding armoury of low-cost polymerase chain reaction-based screens is being developed, and HLA-imposed risk factors are being discovered. These include (i) polymorphic variants of metabolic and endoplasmic reticulum aminopeptidase enzymes, towards multi-allelic screening with increased predictivity, (ii) regulation by immune checkpoint inhibitors, enabling de-tolerised animal models of human disease, and (iii) immunodominant T-cell receptors (TCR) on clonally-expanded CD8+ T-cells. For the latter, HLA-risk restricted TCR provides immunogenomic strategies and samples from a single patient to identify (i) novel HLA-risk associations in underserved minority populations, (ii) tissue-relevant effector biomarkers towards earlier diagnosis and treatment, and (iii) HLA-TCR-presented immunogenic structures to aid future drug development.

Item Type: Journal Article
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: Elsevier
Copyright: © 2022 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
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