T Cell–Mediated Hypersensitivity Reactions to Drugs

Pavlos, Rebecca; Mallal, S.; Ostrov, David A.; Buus, Søren; Metushi, Imir G.; Peters, Bjoern; Phillips, Elizabeth

doi:10.1146/annurev-med-050913-022745

Cited by 112 publications

(127 citation statements)

References 79 publications

(85 reference statements)

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…It can be easily extended to consider p-i-mediated reactions as well. Clues for a possible p-i reaction would be (a) the type of the reaction, namely severe forms like SJS/TEN/DRESS, as these are mainly p-i mediated; (b) the property of the drug and history of prior DHR; an exanthema, for example, which is triggered by a known SJS/TEN/DRESS-eliciting drug like allopurinol should be judged differently than an exanthem due to a β-lactam; and (c) a known HLA association which is usually linked to p-i [25] (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…In p-i stimulations , the pharmacological activity of the drug on immune receptors is often linked to the presence of a certain immune receptor in the individual: HLA associations of certain DHR are described for a growing number of drugs [25], some of them with an almost exclusive association to a certain HLA allele, providing a negative predictive value close to 100%, while other drugs were associated with various alleles. On the other hand, the positive predictive value was mostly low (<3%), with the notable exception of abacavir, where about 50% of HLA-B*57:01 carriers developed a hypersensitivity reaction upon drug exposure [57].…”

Section: Relation Of Allergic-immune P-i and Pseudo-allergic Reactimentioning

confidence: 99%

“…• Many severe DHR were linked to the presence of a certain HLA allele due to direct drug binding to a critical region of the HLA protein and thus represent a typical “p-i HLA”-type reaction [25,27,28,29,32,33,34,35,36]. …”

Section: Sjs/ten and Dress Are P-i Reactionsmentioning

confidence: 99%

See 2 more Smart Citations

Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms

Pichler

Hausmann²

2016

Int Arch Allergy Immunol

130

125

View full text Add to dashboard Cite

Drug hypersensitivity reactions (DHR) are clinically and functionally heterogeneous. Different subclassifications based on timing of symptom appearance or type of immune mechanism have been proposed. Here, we show that the mode of action of drugs leading to immune/inflammatory cell stimulation is a further decisive factor in understanding and managing DHR. Three mechanisms can be delineated: (a) some drugs have or gain the ability to bind covalently to proteins, form new antigens, and thus elicit immune reactions to hapten-carrier complexes (allergic/immune reaction); (b) a substantial part of immune-mediated DHR is due to a typical off-target activity of drugs on immune receptors like HLA and TCR (pharmacological interaction with immune receptors, p-i reactions); such p-i reactions are linked to severe DHR; and (c) symptoms of DHR can also appear if the drug stimulates or inhibits receptors or enzymes of inflammatory cells (pseudo-allergy). These three distinct ways of stimulations of immune or inflammatory cells differ substantially in clinical manifestations, time of appearance, dose dependence, predictability, and cross-reactivity, and thus need to be differentiated.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Relation Of Allergic-immune P-i and Pseudo-allergic Reactimentioning

confidence: 99%

See 1 more Smart Citation

Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms

Pichler

Hausmann²

2016

Int Arch Allergy Immunol

130

125

View full text Add to dashboard Cite

show abstract

“…These associations have been described for a growing number of drugs [reviewed in [21]]. Some of these have almost exclusive associations with certain HLA alleles, providing negative predictive values approximating 100%, while the positive predictive values tend to be low (<3%).…”

Section: P-i Hla and P-i Tcrmentioning

confidence: 99%

Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors

Pichler

Adam

Watkins

et al. 2015

Int Arch Allergy Immunol

157

View full text Add to dashboard Cite

Small chemicals like drugs tend to bind to proteins via noncovalent bonds, e.g. hydrogen bonds, salt bridges or electrostatic interactions. Some chemicals interact with other molecules than the actual target ligand, representing so-called ‘off-target' activities of drugs. Such interactions are a main cause of adverse side effects to drugs and are normally classified as predictable type A reactions. Detailed analysis of drug-induced immune reactions revealed that off-target activities also affect immune receptors, such as highly polymorphic human leukocyte antigens (HLA) or T cell receptors (TCR). Such drug interactions with immune receptors may lead to T cell stimulation, resulting in clinical symptoms of delayed-type hypersensitivity. They are assigned the ‘pharmacological interaction with immune receptors' (p-i) concept. Analysis of p-i has revealed that drugs bind preferentially or exclusively to distinct HLA molecules (p-i HLA) or to distinct TCR (p-i TCR). P-i reactions differ from ‘conventional' off-target drug reactions as the outcome is not due to the effect on the drug-modified cells themselves, but is the consequence of reactive T cells. Hence, the complex and diverse clinical manifestations of delayed-type hypersensitivity are caused by the functional heterogeneity of T cells. In the abacavir model of p-i HLA, the drug binding to HLA may result in alteration of the presenting peptides. More importantly, the drug binding to HLA generates a drug-modified HLA, which stimulates T cells directly, like an allo-HLA. In the sulfamethoxazole model of p-i TCR, responsive T cells likely require costimulation for full T cell activation. These findings may explain the similarity of delayed-type hypersensitivity reactions to graft-versus-host disease, and how systemic viral infections increase the risk of delayed-type hypersensitivity reactions.

show abstract

“…Allelic variation in the genes that encode the major histocompatibility complex (MHC) family of proteins is often associated with risk of T-cell mediated DHR in certain populations (Table 1). 12 This review focuses on the purely T-cell mediated drug hypersensitivity reactions, although the same principles and models likely apply to B-cell mediated reactions as well. [12][13][14] Here, we provide an overview of the data supporting current models of T-cell mediated DHR, propose a new model of drug hypersensitivity that expands upon the existing models to include the role of microbial pathogen exposure in the generation of drug-specific T-cell responses, and discuss the implications for clinical practice and drug safety, design and development..…”

Section: Introductionmentioning

confidence: 99%

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

2015

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Immune-mediated adverse drug reactions (IM-ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B-cell mediated and primary T-cell mediated IM-ADRs. In this review, we summarize the role of host genetics, microbes and drugs in the development of IM-ADRs, expand upon the existing models of IM-ADR pathogenesis to address multiple unexplained observations, discuss the implications of this work in clinical practice today, and describe future applications for pre-clinical drug toxicity screening, drug design, and development.

show abstract

T Cell–Mediated Hypersensitivity Reactions to Drugs

Cited by 112 publications

References 79 publications

Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms

Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms

Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

Contact Info

Product

Resources

About