The effect of haptens on protein‐carrier immunogenicity

Gefen, Tal; Vaya, Jacob; Khatib, Soliman; Rapoport, Irena; Lupo, Meital; Barnea, Eilon; Admon, Arie; Heller, E. D.; Aizenshtein, É. M.; Pitcovski, Jacob

doi:10.1111/imm.12356

Cited by 47 publications

(34 citation statements)

References 27 publications

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“…to a novel drug‐modified protein, to which no intrinsic tolerance exists and which may thus act as a new antigen (antigenicity). A broad adaptive immune response can be induced with the involvement of T and B cells, which react specifically with the whole or processed hapten‐protein or hapten‐peptide complexes . Of note, the initial binding of the drug to a fitting site in the larger protein is fast and involves electrostatic interactions, hydrogen bonds, van der Waals forces.…”

Section: The Mode Of Action Of Drugs As Basis For Sub‐classifying Dhrmentioning

confidence: 99%

Immune pathomechanism and classification of drug hypersensitivity

Pichler

2019

Allergy

170

179

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Drug hypersensitivity reactions (DHR) are based on distinct mechanisms and are clinically heterogeneous. Taking into account that also off-target activities of drugs may lead to stimulations of immune or inflammatory cells, three forms of DHR were discriminated: the allergic-immune mechanism relies on the covalent binding of drugs/ chemicals to proteins, which thereby form new antigens, to which a humoural and/or cellular immune response can develop. In IgE-mediated drug allergies, a possible tolerance mechanism to the drug during sensitization and the need of a covalent hapten-carrier link for initiation, but not for elicitation of IgE-mediated reactions is discussed. The p-i ("pharmacological interaction with immune receptor") concept represents an off-target activity of drugs with immune receptors (HLA or TCR), which can result in unorthodox, alloimmune-like stimulations of T cells. Some of these p-i stimulations occur only in carriers of certain HLA alleles and can result in clinically severe reactions. The third form of DHR ("pseudo-allergy") is represented by drug interactions with receptors or enzymes of inflammatory cells, which may lead to their direct activation or enhanced levels of inflammatory products. Specific IgE or T cells are not involved. This classification is based on the action of drugs and is clinically useful, as it can explain differences in sensitizations, unusual clinical symptoms, dependence on drug concentrations, predictability and immunological and pharmacological cross-reactivities in DHR. K E Y W O R D Sallergic/immune hypersensitivity, classification, drug hypersensitivity, p-i concept, pseudoallergic drug reactions

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Section: The Mode Of Action Of Drugs As Basis For Sub‐classifying Dhrmentioning

confidence: 99%

Immune pathomechanism and classification of drug hypersensitivity

Pichler

2019

Allergy

170

179

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“…albumin, transferrin) or cell-bound protein (e.g. integrins, selectins) to a novel drug-modified protein, which acts as a new antigen [16,20,21] to which no intrinsic tolerance exists. The adaptive immune response reacts via specific receptors (TCR for antigen on T cells and immunoglobulin receptor on B cells) with these newly formed antigens [16,20].…”

Section: Three Distinct Mechanisms Leading To Dhrmentioning

confidence: 99%

“…Hapten-modified peptides are finally presented on HLA molecules to TCR [16,21]. In most instances, haptens bind to a specific amino acid (e.g.…”

Section: Three Distinct Mechanisms Leading To Dhrmentioning

confidence: 99%

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

Pichler

Hausmann²

2016

Int Arch Allergy Immunol

130

125

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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.

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“…Spontaneous protein modification by the reactive form of the drug is an important process in adverse drug reactions . In this process, drugs or haptens bind covalently to protein to form a complex of a sufficient size to trigger an immune response (haptenation) . This structure can later be processed by antigen presenting cells, such as dendritic cells (DCs), and the resulting haptenated peptides exposed through major histocompatibility complex (MHC) class I or class II‐dependent pathways are presented to T‐cell receptors (TCRs).…”

Section: Introductionmentioning

confidence: 99%