Activation of T cells by carbamazepine and carbamazepine metabolites

Wu, Ying; Sanderson, Joseph P.; Farrell, John; Drummond, Nicola S.; Hanson, Anita; Bowkett, Elizabeth R.; Berry, Neil G.; Stachulski, Andrew V.; Clarke, Stephen E.; Pichler, Werner J.; Pirmohamed, Munir; Park, B. Kevin; Naisbitt, Dean J.

doi:10.1016/j.jaci.2006.03.005

Cited by 123 publications

(102 citation statements)

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“…The presence of drug-specific cytotoxic T cells in the peripheral circulation and target organs of hypersensitive patients, but not in drugexposed controls, provides a robust case for their involvement in the pathogenesis of the reaction (1)(2)(3)(4). To initiate an immune response, the drug Ag must be presented in the context of specific MHC molecules expressed on dendritic cells (DCs) to specific TCRs in a microenvironment rich in costimulatory signaling and cytokines, which are necessary for sustained T cell expansion (5,6).…”

mentioning

confidence: 99%

Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism

Elsheikh

Lavergne

Castrejón-Flores

et al. 2010

The Journal of Immunology

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Recognition of drugs by immune cells is usually explained by the hapten model, which states that endogenous metabolites bind irreversibly to protein to stimulate immune cells. Synthetic metabolites interact directly with protein generating antigenic determinants for T-cells; however, experimental evidence relating intracellular metabolism in immune cells and the generation of physiologically relevant antigens to functional immune responses is lacking. The aim of this study was to develop an integrated approach using both animal and human experimental systems to characterize sulfamethoxazole (SMX) metabolism-derived antigenic protein adduct formation in immune cells and define the relationship between adduct formation, cell death, co-stimulatory signalling and stimulation of a T-cell response. Formation of SMX-derived adducts in antigen presenting cells was dose- and time-dependent, detectable at non-toxic concentrations and dependent on drug metabolizing enzyme activity. Adduct formation above a threshold induced necrotic cell death, dendritic cell co-stimulatory molecule expression and cytokine secretion. Antigen presenting cells cultured with SMX for 16h, the time needed for drug metabolism, stimulated T-cells from sensitized mice and lymphocytes and T-cell clones from allergic patients. Enzyme inhibition decreased SMX-derived protein adduct formation and the T-cell response. Dendritic cells cultured with SMX and adoptively transferred to recipient mice initiated an immune response; however, T-cells were stimulated with adducts derived from SMX metabolism in antigen presenting cells, not the parent drug. This study shows that antigen presenting cells metabolize SMX; subsequent protein binding generates a functional T-cell antigen. Adduct formation above a threshold stimulates cell death, which provides a maturation signal for dendritic cells.

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mentioning

confidence: 99%

Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism

Elsheikh

Lavergne

Castrejón-Flores

et al. 2010

The Journal of Immunology

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“…İİHS'de olayı başlatanın T hücreleri uyaran alerjik reaksiyon olduğu düşünülmektedir. T hücre uyarımı, T hücrelerde muhafaza edilen herpes virüs viral genomunun reaktivasyonuna yol açar 22,23 . İİHS'li hastalarda görülen immünglobulin düşüklüğünün de HHV reaktivasyonuna katkıda bulunduğu düşünülmektedir 21 .…”

Section: Discussionunclassified

Sulfasalazin İle Tetiklenen İlaçla İlişkili Hipersensitivite Sendromu

Saral¹,

Akay²,

Şanlı³

2013

Turkderm

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Türk derm-De ri Has ta lık la rı ve Fren gi Ar şi vi Der gi si, Ga le nos Ya yı ne vi ta ra f›n dan ba s›l m›fl t›r. Turk derm-Arc hi ves of the Tur kish Der ma to logy and Ve ne ro logy, pub lis hed by Ga le nos Pub lis hing. Özetİlaçla ilişkili hipersensitivite sendromu (İİHS), ilaç reaksiyonları arasında en tehlikelilerinden biridir. Sistemik organ tutulumları bu reaksiyonun mortalite ve morbiditesini arttırmaktadır. Lezyonlar en sık makülopapüler döküntü şeklinde ortaya çıkmakla birlikte, lezyon morfolojisi farklılık gösterebilir. Çoğunlukla aromatik antikonvulzanlarla ortaya çıkar. Ancak başka ilaçların da bu ilaç reaksiyonu patogenezinde rol oynayabileceği unutulmamalıdır. Erken tanı tedavide en önemli basamaktır. Burada sulfasalazin ile tetiklenen ve klinik olarak makülopapüler döküntüye eşlik eden püstüler lezyonlarla prezente olan bir İİHS olgusu sunmaktayız. Sum maryDrug-induced hypersensitivity syndrome (DIHS) is one of the most dangerous drug reactions. Mortality and morbidity is increased by consequent systemic organ involvement. Maculopapular eruptions are the most common lesions accompanying DIHS, however, the morphology of skin lesions may vary. The most common cause of DIHS is the use of aromatic anticonvulsant drugs. However, one must not forget that other drugs may also cause DIHS. Early recognition of the condition is the most important step in the treatment. Herein, we present a case of DIHS triggered by sulphasalazine and associated with pustular eruption and maculopapular eruption. (Turkderm 2013; 47: 123-5)

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“…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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Activation of T cells by carbamazepine and carbamazepine metabolites

Cited by 123 publications

References 28 publications

Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism

Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism

Sulfasalazin İle Tetiklenen İlaçla İlişkili Hipersensitivite Sendromu

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

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