Mechanisms leading to T-cell activation in drug hypersensitivity

Purpose of review Delayed-type or nonimmediate drug hypersensitivity reactions often involve the activation of drug-specific T cells. As such, the molecular initiating event is an interaction between HLA proteins, HLA-binding peptides and the drug. For many years, the formation of covalently modified drug protein adducts was assumed to be a prerequisite for T-cell activation. The purpose of this article is to review recent studies using human PBMC, T-cell lines and clones, which show that drugs are in fact loaded onto HLA molecules in different forms to activate T cells. Recent findings We now know that protein-reactive drugs such as β-lactam antibiotics activate T cells via direct noncovalent interactions with HLA or HLA-binding peptides, direct covalent modification of HLA-binding peptides and covalent binding of non-HLA associated proteins. Adducts formed inside and outside of the cells undergo protein processing to generate HLA-binding peptides that are assumed to contain the drug modification. Studies using synthetic stable (e.g. oxypurinol) and reactive (e.g. nitroso sulfamethoxazole) metabolites show that metabolites activate T cells via the same pathways. A variety of drugs with different structural features have also been shown to activate T cells though a direct HLA-binding interaction. Of note, abacavir behaves in an unexpected way, binding deep in the peptide binding cleft of one HLA, selectively activating CD8+ T cells. Summary In-vitro studies have revealed that a number of drug HLA-binding interactions lead to the activation of T cells. These can be categorized according to two hypotheses, namely hapten and pharmacological interactions. As we move forward with the development of diagnostic and predictive T-cell assays, it is critical to reach a consensus that direct drug HLA binding and the formation of drug protein adducts are important events for T-cell activation. Correspondence to Dean J. Naisbitt, The University of Liverpool, Liverpool, United Kingdom. Tel: +44 151 7945346; E-mail: dnes@liverpool.ac.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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