Stimulation of human T cells with sulfonamides and sulfonamide metabolites

Castrejón-Flores, José Luis; Berry, Neil G.; El-Ghaiesh, Sabah; Gerber, Basil O.; Pichler, Werner J.; Park, B. Kevin; Naisbitt, Dean J.

doi:10.1016/j.jaci.2009.10.031

Cited by 113 publications

(133 citation statements)

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“…T he presence of Ag-specific T cells in blood and target organs of drug-hypersensitive patients provides a robust case for their involvement in the pathogenesis of a reaction (1)(2)(3)(4)(5)(6). It is thought that drugs activate T cells by covalent modification of protein generating novel antigenic determinants (2,3,(7)(8)(9).…”

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confidence: 99%

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Mass Spectrometric Characterization of Circulating and Functional Antigens Derived from Piperacillin in Patients with Cystic Fibrosis

Whitaker

Meng

Lavergne

et al. 2011

The Journal of Immunology

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142

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A mechanistic understanding of the relationship between the chemistry of drug antigen formation and immune function is lacking. Thus, mass spectrometric methods were employed to detect and fully characterize circulating antigens derived from piperacillin in patients undergoing therapy and the nature of the drug derived-epitopes on protein which can function as an antigen to stimulate T-cells. Albumin modification with piperacillin in vitro resulted in the formation of two distinct haptens, one formed directly from piperacillin and a second in which the dioxopiperazine ring had undergone hydrolysis. Modification was time- and concentration-dependent, with selective modification of Lys541 observed at low concentrations, whereas at higher concentrations up to 13/59 lysine residues were modified, four of which (Lys190, 195, 432 and 541) were detected in patients’ plasma. Piperacillin-specific T-lymphocyte responses (proliferation, cytokines and granzyme-B release) were detected ex vivo with cells from hypersensitive patients, and analysis of incubation medium showed that modification of the same lysine residues in albumin occurred in situ. The antigenicity of piperacillin-modified albumin was confirmed by stimulation of T-cells with characterized synthetic conjugates. Analysis of minimally-modified T-cell stimulatory albumin conjugates revealed peptide sequences incorporating Lys190, 432 and 541 as principal functional epitopes for T-cells. This study has characterized the multiple haptenic structures on albumin in patients, and showed that they constitute functional antigenic determinants for T-cells.

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confidence: 99%

“…It is thought that drugs activate T cells by covalent modification of protein generating novel antigenic determinants (2,3,(7)(8)(9). However, the paucity of studies that define the chemistry of drug-protein binding in patients has severely restricted mechanistic studies that relate the chemistry of Ag formation to immune function.…”

mentioning

confidence: 99%

Mass Spectrometric Characterization of Circulating and Functional Antigens Derived from Piperacillin in Patients with Cystic Fibrosis

Whitaker

Meng

Lavergne

et al. 2011

The Journal of Immunology

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142

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“…Drugs have also been shown to be associated directly with peptides embedded in the MHC to stimulate a T-cell response. [30][31][32][33][34][35][36][37] Despite this, very few studies have attempted to define drug-protein antigens in patients and hence relate the chemistry of antigen formation to the immune response.…”

Section: Predisposition To Immunological Drug Reactionsmentioning

confidence: 99%

“…This concept, referred to as the "pharmacological interaction of drugs with immune receptors (p-i concept), " states that drugs by themselves act as antigens interacting in a reversible fashion with immunological receptors. 49 By characterizing T-cell clones from patients with immunological drug reactions, the pharmacophore of several drugs, including sulfamethoxazole, 30,34,50 carbamazepine, 51,52 abacavir, 53 and penicillin, 54 have been shown to interact with MHC molecules directly and provide a sufficiently strong signal to stimulate T cells.…”

Section: Drug Antigenicitymentioning

confidence: 99%

Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

Kim

Naisbitt

2016

Allergy Asthma Immunol Res

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug-induced liver injury (DILI) is a major concern for public health, as well as for drug development in the pharmaceutical industry, since it can cause liver failure and lead to drug withdrawal from the market and black box warnings. Thus, it is important to identify biomarkers for early prediction to increase our understanding of mechanisms underlying DILI that will ultimately aid in the exploration of novel therapeutic strategies to prevent or manage DILI. DILI can be subdivided into 'intrinsic' and 'idiosyncratic' categories, although the validity of this classification remains controversial. Idiosyncratic DILI occurs in a minority of susceptible individuals with a prolonged latency, while intrinsic DILI results from drug-induced direct hepatotoxicity over the course of a few days. The rare occurrence of idiosyncratic DILI requires multicenter collaborative investigations and phenotype standardization. Recent progress in research on idiosyncratic DILI is based on key developments in 3 areas: (1) newly developed highthroughput genotyping across the whole genome allowing for the identification of genetic susceptibility markers, (2) new mechanistic concepts on the pathogenesis of DILI revealing a key role of drug-responsive T lymphocytes in the immunological response, and (3) broad multidisciplinary approaches using different platform "-omics" technologies that have identified novel biomarkers for the prediction of DILI. An association of a specific human leukocyte antigen (HLA) allele with DILI has been reported for several drugs. HLA-restricted T-cell immune responses have also been investigated using lymphocytes and T-cell clones isolated from patients. A microRNA, miR-122, has been discovered as a promising biomarker for the early prediction of DILI. In this review, we summarize recent advances in research on idiosyncratic DILI with an understanding of the key role of adaptive immune systems.

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“…Furthermore, some organic chemicals may be recognized especially by effector and memory T cells without covalent binding to carrier peptides on MHC as formulated in the p-i concept (Fig. 1) [35][36][37][38][39].…”

Section: Replacement Of Animal Testing: T Cells As Tools In Immunotoxmentioning

confidence: 99%

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Martin

Esser

Schmucker

et al. 2010

Cell. Mol. Life Sci.

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130

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Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an This article is dedicated to the memory of our colleague and friend Reinhard Wanner, died 2 April 2010. Cellular and Molecular Life Sciences overview of the development of the field over the last two decades.

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Stimulation of human T cells with sulfonamides and sulfonamide metabolites

Cited by 113 publications

References 41 publications

Mass Spectrometric Characterization of Circulating and Functional Antigens Derived from Piperacillin in Patients with Cystic Fibrosis

Mass Spectrometric Characterization of Circulating and Functional Antigens Derived from Piperacillin in Patients with Cystic Fibrosis

Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

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