Purpose of reviewT-cell-mediated drug hypersensitivity is responsible for significant morbidity and mortality, and represents a substantial clinical concern. The purpose of this article is to focus on T-cell reactions and discuss recent advances in disease pathogenesis by exploring the impact of tolerance mechanisms in determining susceptibility in genetically predisposed patients.
Recent findingsCertain drugs preferentially activate pathogenic T cells that have defined pathways of effector function. Thus, a critical question is what extenuating factors influence the direction of immune activation. A large effort has been given towards identifying phenotypic (e.g., infection) or genotypic (e.g., human leukocyte antigen) associations which predispose individuals to drug hypersensitivity. However, many individuals expressing known risk factors safely tolerate drug administration. Thus, mechanistic insight is needed to determine what confers this tolerance. Herein, we discuss recent clinical/mechanistic findings which indicate that the direction in which the immune system is driven relies upon a complex interplay between co-stimulatory/co-regulatory pathways which themselves depend upon environmental inputs from the innate immune system.
Drugs
can activate different cells of the immune system and initiate
an immune response that can lead to life-threatening diseases collectively
known as severe cutaneous adverse reactions (SCARs). Antibiotics,
anticonvulsants, and antiretrovirals are involved in the development
of SCARs by the activation of αβ naïve T-cells.
However, other subsets of lymphocytes known as nonconventional T-cells
with a limited T-cell receptor repertoire and innate and adaptative
functions also recognize drugs and drug-like molecules, but their
role in the pathogenesis of SCARs has only just begun to be explored.
Despite 30 years of advances in our understanding of the mechanisms
in which drugs interact with T-cells and the pathways for tissue injury
seen during T-cell activation, at present, the development of useful
clinical biomarkers for SCARs or predictive preclinical in
vitro assays that could identify immunogenic moieties during
drug discovery is an unmet goal. Therefore, the present review focuses
on (i) advances in the understanding of the pathogenesis of SCARs
reactions, (ii) a description of the interaction of drugs with conventional
and nonconventional T-cells, and (iii) the current state of soluble
blood circulating biomarker candidates for SCARs.
Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of the antigenic determinants that interact with HLA and whether T cell stimulatory peptides contain the bound drug metabolite has not been defined. Because susceptibility to dapsone hypersensitivity is associated with the expression of HLA-B*13:01, we have designed and synthesized nitroso dapsone–modified, HLA-B*13:01 binding peptides and explored their immunogenicity using T cells from hypersensitive human patients. Cysteine-containing 9-mer peptides with high binding affinity to HLA-B*13:01 were designed (AQDCEAAAL [Pep1], AQDACEAAL [Pep2], and AQDAEACAL [Pep3]), and the cysteine residue was modified with nitroso dapsone. CD8+ T cell clones were generated and characterized in terms of phenotype, function, and cross-reactivity. Autologous APCs and C1R cells expressing HLA-B*13:01 were used to determine HLA restriction. Mass spectrometry confirmed that nitroso dapsone–peptides were modified at the appropriate site and were free of soluble dapsone and nitroso dapsone. APC HLA-B*13:01–restricted nitroso dapsone–modified Pep1- (n = 124) and Pep3-responsive (n = 48) CD8+ clones were generated. Clones proliferated and secreted effector molecules with graded concentrations of nitroso dapsone–modified Pep1 or Pep3. They also displayed reactivity against soluble nitroso dapsone, which forms adducts in situ, but not with the unmodified peptide or dapsone. Cross-reactivity was observed between nitroso dapsone–modified peptides with cysteine residues in different positions in the peptide sequence. These data characterize a drug metabolite hapten CD8+ T cell response in an HLA risk allele–restricted form of drug hypersensitivity and provide a framework for structural analysis of hapten HLA binding interactions.
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