Pathology of T-cell-mediated drug hypersensitivity reactions and impact of tolerance mechanisms on patient susceptibility

Abstract

Purpose of reviewT-cell-mediated drug hypersensitivity is responsible for significant morbidity and mortality, and represents a substantial clinical concern. The purpose of this article is to focus on T-cell reactions and discuss recent advances in disease pathogenesis by exploring the impact of tolerance mechanisms in determining susceptibility in genetically predisposed patients. Recent findingsCertain drugs preferentially activate pathogenic T cells that have defined pathways of effector function. Thus, a critical question is what extenuating factors influence the direction of immune activation. A large effort has been given towards identifying phenotypic (e.g., infection) or genotypic (e.g., human leukocyte antigen) associations which predispose individuals to drug hypersensitivity. However, many individuals expressing known risk factors safely tolerate drug administration. Thus, mechanistic insight is needed to determine what confers this tolerance. Herein, we discuss recent clinical/mechanistic findings which indicate that the direction in which the immune system is driven relies upon a complex interplay between co-stimulatory/co-regulatory pathways which themselves depend upon environmental inputs from the innate immune system.

The Meat of the Matter: Understanding and Managing Alpha-Gal Syndrome

“… 19 While a cell-mediated delayed type hypersensitivity response is an intriguing alternative explanation for the delayed symptoms in alpha-gal syndrome, the nature of the clinical signs and symptoms of AGS are more consistent with an IgE-driven hypersensitivity response than cytotoxic T-cell or macrophage-driven, cell-mediated responses which are associated more frequently with mucocutaneous lesions and tissue damage. 39 To date, there are no experimental models linking cytotoxic T cells and macrophages to symptom onset or progression in AGS.…”

Comparison of the Liverpool Causality Assessment Tool vs. the Naranjo Scale for predicting the likelihood of an adverse drug reaction: A retrospective cohort study

“…The 2 published assessment tools: the older Naranjo Scale and newly developed tool by the Liverpool group were correlated with wellstudied diagnostic tests such as the allergy skin test, lymphocyte toxicity assay, in vitro platelet toxicity assay, radioallergosorbent test and oral challenge. [22][23][24][25] Both assessment tools have a high sensitivity in predicting ADR cases but poor specificity. Liverpool Causality Assessment Tool (97.2 ± 2.4%) proved to be the more sensitive tool compared with its predecessor, Naranjo Scale (81.2 ± 5.69%).…”

“…This study was conducted to examine the value of screening suspected ADR cases prior to any investigations using history and clinical presentation alone in an ambulatory care setting and to compare the Naranjo Scale to the Liverpool Causality Assessment. The 2 published assessment tools: the older Naranjo Scale and newly developed tool by the Liverpool group were correlated with well‐studied diagnostic tests such as the allergy skin test, lymphocyte toxicity assay, in vitro platelet toxicity assay, radioallergosorbent test and oral challenge 22–25 …”

Drug hypersensitivity reactions: review of the state of the science for prediction and diagnosis

“…For example, regulatory T cells may be insufficiently activated in some patients, making them more susceptible to allergic reactions ( Pichler et al , 2010 ). Additionally, the inhibitory role for dual signals from molecules PDL-1 and CTLA-4 during the in vitro priming of drug-specific T cells have been reported ( Gibson et al , 2014 , 2017a ; Hammond et al , 2022 ; Line et al , 2022 ; Naisbitt et al , 2020 ). In this respect, the breakdown of immune tolerance due to loss or blockade of PD-1 and CTLA-4 signaling unmasked isoniazid-, amodiaquine-, and nevirapine-induced modeled idiosyncratic liver injury in mice ( Mak and Uetrecht, 2015a , b ).…”