Risk Assessment in Drug Hypersensitivity: Detecting Small Molecules Which Outsmart the Immune System

Abstract

Drug hypersensitivity (DH) reactions are clinically unusual because the underlying immune stimulations are not antigen-driven, but due to non-covalent drug-protein binding. The drugs may bind to immune receptors like HLA or TCR which elicits a strong T cell reaction (p-i concept), the binding may enhance the affinity of antibodies (enhanced affinity model), or drug binding may occur on soluble proteins which imitate a true antigen (fake antigen model). These novel models of DH could have a major impact on how to perform risk assessments in drug development. Herein, we discuss the difficulties of detecting such non-covalent, labile and reversible, but immunologically relevant drug-protein interactions early on in drug development. The enormous diversity of the immune system, varying interactions, and heterogeneous functional consequences make it to a challenging task. We propose that a realistic approach to detect clinically relevant non-covalent drug interactions for a new drug could be based on a combination of in vitro cell culture assays (using a panel of HLA typed donor cells) and functional analyses, supplemented by structural analysis (computational data) of the reactive cells/molecules. When drug-reactive cells/molecules with functional impact are detected in these risk assessments, a close clinical monitoring of the drug may reveal the true incidence of DH, as suppressing but also enhancing factors occurring in vivo can influence the clinical manifestation of a DH.

Risk factors and drugs that trigger the onset of Stevens–Johnson syndrome and toxic epidermal necrolysis: A population-based cohort study using the Shizuoka Kokuho database

“… 42 , 43 , 44 Additionally, in-silico biomolecular studies of the distinctive combinations between human leukocyte antigen alleles and drugs have shown exquisite molecular interactions, 45 , 46 , 47 , 48 which are caused by the enhancement of cytotoxic T-cell reactions, such as allorecognition via the “pharmacological-interaction” concept. 47 , 49 Therefore, the diseases that were risk factors in our study might be associated with genetic factors, such as human leukocyte antigen alleles, predisposing to SJS/TEN. However, in the general population of this study, the probability that individuals had such genetic information is rare.…”

Development of mouse models with restricted HLA-B∗57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury

“…Early cytotoxicity in vitro may occur by TCR activation by noncovalently bound drug to HLA or TCR, which is labile and reversible and thus likely less stable than drug-haptenated peptides. 11 , 45 Suboptimal TCR stimulation in the absence of costimulation or/and proinflammatory cytokines may lead to T-cell tolerance or anergy. 46 , 47 Unlike Tg/KO, Tg/DKO had higher bystander liver inflammation associated with lack of PD-1 expression, 41 , 48 which was enhanced by the depletion of CD4 + T cells.…”

Drug-Induced Enterocolitis Syndrome in Children

“…However, the tolerance towards phenoxymethylpenicillin in some reported cases [2,6,8] suggested that the side chain of AMX and not the b-lactam ring side is responsible for allergy to penicillins [1]. However, studies evaluating other type of drug hypersensitivity highlighted that the immune reactivity could be triggered by the nature of carrier molecules, suggesting other pathogenic mechanisms [57,58].…”