Asia Pac Allergy.  2016 Apr;6(2):77-89. 10.5415/apallergy.2016.6.2.77.

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

• Yun J
• Cai F
• Lee FJ
• Pichler WJ

• KMID: 2396975
• DOI: http://doi.org/10.5415/apallergy.2016.6.2.77

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.

Keyword

Drug hypersensitivity; Receptors, antigen, T-Cell; Haptens; HLA antigens

MeSH Terms

Binding Sites
Classification
Drug Hypersensitivity*
Drug-Related Side Effects and Adverse Reactions
Hand
Haptens
HLA Antigens
Major Histocompatibility Complex
Receptors, Antigen, T-Cell
T-Lymphocytes
HLA Antigens
Haptens
Receptors, Antigen, T-Cell

Figure

• 

  Fig. 1 The mechanisms of drug binding to TCR and/HLA. (A) A drug is covalently bound to a peptide. The covalent bond is represented by the black line joining the drug to the peptide. (B) A drug binds preferentially to TCR at the site of TCR-pMHC interaction. (C) A drug binds to TCR at a position that is distant to the site of TCR-pMHC interaction. This binding results in altered conformation of TCR resulting in increased TCR binding affinity. (D) Another nonstimulating drug binds to TCR at the binding site of a stimulatory drug (see B), functioning as a competitive antagonist. (E) A drug binds to the peptide binding groove of pMHC complex. The peptide itself has not changed but the conformation of peptide-drug-MHC complex is different to the initial pMHC complex. This new conformation is similar to another allogeneic pMHC complex as outlined in H. (F) A drug binds to both pMHC complex and TCR simultaneously with increased affinity for both molecules. (G) A drug binds to the peptide binding groove of empty HLA in endoplasmic reticulum resulting in alteration of self peptide repertoire (represented by red peptide). (H) Allogeneic pMHC complex stimulates alloreactivity T-cell response. p-i, pharmacological interaction with immune receptors; TCR, T-cell receptors; HLA, human leukocyte antigens; pMHC, peptide-major histocompatibility.

• 

  Fig. 2 The p-i HLA model. (A) Stable self-pMHC complex do not elicit T-cell response. The drug binding site is hidden underneath peptide and is inaccessible. (B) Due to flexibility of pMHC complexes, transient partial peptide detachment can occur, exposing the drug binding site. (C) Soluble drug binds to the peptide binding groove but this intermediate peptide-drug-HLA complex is intrinsically unstable and my revert to (A). Alternatively the entire complexes may be dissociated. (D) If the new drug-HLA complex is accommodating, the peptide may reattach, resulting in a new conformation and stable peptide-drug-HLA complexes. This new conformation may elicit a T-cell response. p-i, pharmacological interaction with immune receptors; HLA, human leukocyte antigens; pMHC, peptide-major histocompatibility; TCR, T-cell receptors. Adapted from Yun et al. J Immunol 2014;192:2984-93 [27].

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