T-cell-mediated drug hypersensitivity: immune mechanisms and their clinical relevance

Abstract

T-cell-mediated drug hypersensitivity represents a significant proportion of immune mediated drug hypersensitivity reactions. In the recent years, there has been an increase in understanding the immune mechanisms behind T-cell-mediated drug hypersensitivity. According to hapten mechanism, drug specific T-cell response is stimulated by drug-protein conjugate presented on major histocompatibility complex (MHC) as it is presented as a new antigenic determinant. On the other hand, p-i concept suggests that a drug can stimulate T cells via noncovalent direct interaction with T-cell receptor and/or peptide-MHC. The drug binding site is quite variable and this leads to several different mechanisms within p-i concept. Altered peptide repertoire can be regarded as an 'atypical' subset of p-i concept since the mode of the drug binding and the binding site are essentially identical to p-i concept. However, the intracellular binding of abacavir to HLA-B*57:01 additionally results in alteration in peptide repertoire. Furthermore the T-cell response to altered peptide repertoire model is only shown for abacavir and HLA-B*57:01 and therefore it may not be generalised to other drug hypersensitivity. Danger hypothesis has been postulated to play an important role in drug hypersensitivity by providing signal 2 but its experimental data is lacking at this point in time. Furthermore, the recently described allo-immune response suggests that danger signal may be unnecessary. Finally, in view of these new understanding, the classification and the definition of type B adverse drug reaction should be revised.

Etiology and Immunopathogenesis of Sarcoidosis: Novel Insights

“…122 Haptens are molecules not immunogenic themselves but only when bound to a carrier protein. 123 Another mechanism has been recently identified upon detailed analysis of T-cell proliferation process mediated by beryllium. The T-cell receptor does not interact with beryllium directly.…”

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

“…Because drugs are usually too small to potentially induce an immunogenic response, several mechanistic hypotheses including the hapten/prohapten, pharmacological interaction with immune receptors (p–i), and altered repertoire models have been proposed to explain how small compounds are recognized by T cells in an HLA-dependent manner [10,11]. In brief, the hapten/prohapten model delineates that the drug or its metabolite (hapten/prohapten) reacts with a self-protein through covalent binding to produce a haptenated, de novo product [12,13], while the p–i model involves a noncovalent, labile interaction of the drug, with the HLA receptor at the cell surface independent of antigen processing or cellular metabolism [14].…”

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

“…The role of HLA in these adverse drug reactions has been hypothesised in three main ways: the Hapten model, the Pharmacological Interaction model and the Altered Peptide Repertoire model. The Hapten model predicts the drug binds covalently to a self-protein and is processed via HLA molecules; this drug-protein combination is presented and recognised as being non-self, initiating an immune response (5). The Pharmacological Interaction (PI) model predicts the drugs bind directly to the TCR or via the formation of HLA-drug complexes which activate T cells and thus initiate an immune response without the need for a specific peptide ligand (6).…”

“…Except where noted below, the results presented here work under the assumption that the drugs we are investigating here will follow the Altered Peptide Repertoire model, with the drug interacting non-covalently with the HLA molecule directly within the antigen presentation site. This leads to a difference in the self-peptide set that is presented to the T-cell receptors and thus, initiating an immune response (7). Currently, the most widely investigated HLA-ADR association is that of abacavir with B*57:01.…”