Towards the development of mechanism-based biomarkers to diagnose drug hypersensitivity

Abstract

T-cells are activated by different mechanisms in the presence of drugs, metabolites or haptens, and they release several molecules that can be used in the diagnosis of drug hypersensitivity.

Up-Regulation of T-Cell Activation MicroRNAs in Drug-Specific CD4+ T-Cells from Hypersensitive Patients

“…The presence of drug-specific T-cells in the peripheral blood and inflamed tissue of hypersensitivity patients has been widely documented. − Several factors including genetic background, co-morbidities at the time of the reaction, metabolism and reactivity of the drug, individually or together, contribute to the generation of the drug-specific T-cell response. Despite the complexity of the major histocompatibility complex (MHC), drugs −T-cell receptor (TCR) interaction, it has been possible to elucidate three basic mechanisms of drug-specific T-cell activation through in vitro experiments using PBMCs from hypersensitive patients: (1) the hapten/pro-hapten pathway; (2) the pharmacological interaction or P–I theory; and (3) the altered self-repertoire pathway. , Furthermore, the ability of drug-specific T-cells to damage target tissue such as liver and skin has been described. , Despite this, little is known about the role of post-transcriptional regulators, particularly miRNAs, in the pathogenesis of drug hypersensitivity. MiRNAs are single-stranded 22 nucleotides RNAs that regulate gene expression by binding to the 3′ untranslated region (UTR) of their target promoting translational repression or the direct degradation of the mRNA.…”

“…Despite the complexity of the major histocompatibility complex (MHC), drugs −T-cell receptor (TCR) interaction, it has been possible to elucidate three basic mechanisms of drug-specific T-cell activation through in vitro experiments using PBMCs from hypersensitive patients: (1) the hapten/pro-hapten pathway; (2) the pharmacological interaction or P−I theory; and (3) the altered self-repertoire pathway. 7,8 Furthermore, the ability of drugspecific T-cells to damage target tissue such as liver and skin has been described. 9,10 Despite this, little is known about the role of post-transcriptional regulators, particularly miRNAs, in the pathogenesis of drug hypersensitivity.…”

Advances in Our Understanding of the Interaction of Drugs with T-cells: Implications for the Discovery of Biomarkers in Severe Cutaneous Drug Reactions

“…Then, the second signal known as a costimulatory signal is the result of cell-to-cell interactions between a mature dendritic cell, on which costimulatory receptors are overexpressed, and the nai ̈ve T-cells. Thus, mechanistic research behind drug-specific T-cell activation is mostly devoted to explaining the nature of signal one, the antigen-specific signal, resulting in the formulation of three models named: the hapten and pro-hapten theory, the pharmacological interaction (P−I) hypothesis, and more recently the altered peptide presentation 60 (Figure 1a). In the first two mechanisms, drugs interact with the TCR either by covalently binding with a peptide or by a labile weak interaction within the immune receptors, while in the third mechanism a drug interacts intracellularly with a specific HLA and changes the peptidome presented to T-cells.…”

Specific and non-specific perioperative drug reactions

“…Современная классификация механизмов РГЛС во многом расширена за счет новых представлений об иммунопатогенезе аллергии и гиперчувствительности (табл. 1) [9,10,11].…”