Anticonvulsant-induced toxic epidermal necrolysis: Monitoring the immunologic response

Leyva, Laura; Torres, Marı́a José; Posadas, S; Blanca, Miguel; Besso, Guillermo; O’Valle, Francisco; Moral, Raimundo García del; Santamaría, L.F.; Juárez, C.

doi:10.1016/s0091-6749(00)90191-x

Cited by 92 publications

(69 citation statements)

References 29 publications

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“…Thus, splenocytes from rats administered with nitroso sulphamethoxazole, but not sulphamethoxazole hydroxylamine or the parent drug, responded to nitroso sulphamethoxazole on restimulation ex vivo ( Figure 5) (Xu et al, 1996;Singh et al, 1999), the responding T-cells secreted IFN-g, but not IL-4, indicating a Th 1 /Tc 1 response. Consistent with our results, IFN-g production has been demonstrated in PBMC from patients with anticonvulsant-induced toxic epidermal necrolysis (Leyva et al, 2000;Koga et al, 2000).…”

Section: British Journal Of Pharmacology Vol 133 (2)supporting

confidence: 92%

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism‐dependent haptenation and T‐cell proliferation in vivo

Naisbitt

Gordon

Pirmohamed

et al. 2001

British J Pharmacology

123

116

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1 Sulphamethoxazole has been associated with the occurrence of hypersensitivity reactions. There is controversy as to whether the immune response is metabolism-dependent or -independent. We have therefore investigated the site of antigen formation and the nature of the drug signal presented to the immune system in vivo. 2 Male Wistar rats were dosed with sulphamethoxazole, sulphamethoxazole hydroxylamine or nitroso sulphamethoxazole. Antigen formation on cell surfaces was determined by¯ow cytometry using a speci®c anti-sulphamethoxazole antibody. Immunogenicity was determined by assessment of ex vivo T-cell proliferation. 3 Administration of nitroso sulphamethoxazole, but not sulphamethoxazole or sulphamethoxazole hydroxylamine, resulted in antigen formation on the surface of lymphocytes, splenocytes and epidermal keratinocytes, and a strong proliferative response of splenocytes on re-stimulation with nitroso sulphamethoxazole. Rats dosed with sulphamethoxazole or sulphamethoxazole hydroxylamine did not respond to any of the test compounds. 4 CD4 + or CD8 + depleted cells responded equally to nitroso sulphamethoxazole. The proliferative response to nitroso sulphamethoxazole was seen even after pulsing for only 5 min, and was not inhibited by glutathione. Responding cells produced IFN-g, but not IL-4. 5 Haptenation of cells by sulphamethoxazole hydroxylamine was seen after depletion of glutathione by pre-treating the rats with diethyl maleate. Splenocytes from the glutathione-depleted sulphamethoxazole hydroxylamine-treated rats responded weakly to nitroso sulphamethoxazole, but not to sulphamethoxazole or sulphamethoxazole hydroxylamine. 6 Dosing of rats with sulphamethoxazole produced a cellular response to nitroso sulphamethoxazole (but not to sulphamethoxazole or its hydroxylamine) when the animals were primed with complete Freund's adjuvant. 7 These studies demonstrate the antigenicity of nitroso sulphamethoxazole in vivo and provide evidence for the role of drug metabolism and cell surface haptenation in the induction of a cellular immune response in the rat.

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Section: British Journal Of Pharmacology Vol 133 (2)supporting

confidence: 92%

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism‐dependent haptenation and T‐cell proliferation in vivo

Naisbitt

Gordon

Pirmohamed

et al. 2001

British J Pharmacology

123

116

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“…T cells from the patients sensitized with anticonvulsants are activated in vivo and in vitro (4,5). By immunohistochemistry, both CD4 ϩ and CD8 ϩ T cells infiltrate in the lesional skin (2,6,7). These data indicate that pathogenic T cells reactive with phenobarbital may induce the various aspects of clinical manifestations.…”

mentioning

confidence: 78%

“…A nticonvulsants such as phenobarbital have a high risk in eliciting adverse hypersensitivity reactions characterized by not only cutaneous but also by extracutaneous involvements (1,2). Toxic epidermal necrolysis (TEN) 2 and Stevens-Johnson syndrome (SJS) are the most severe and acute life-threatening conditions with a high mortality rate.…”

mentioning

confidence: 99%

“…Toxic epidermal necrolysis (TEN) 2 and Stevens-Johnson syndrome (SJS) are the most severe and acute life-threatening conditions with a high mortality rate. The patients with these conditions have severe malaise, high fever, and liver and renal dysfunction in addition to extensive epidermal bullae and epithelial detachment in cutaneous and mucous membranes (1,3).…”

mentioning

confidence: 99%

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Characterization of Drug-Specific T Cells in Phenobarbital- Induced Eruption

Hashizume

Takigawa

Tokura

2002

The Journal of Immunology

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Phenobarbital has a high potential to elicit adverse reactions including severe skin eruptions and systemic involvements among the worldwide-prescribed drugs. Although phenobarbital hypersensitivity is thought to be mediated by T cells specific to the drug, its precise mechanism remains not fully elucidated. To characterize T cells reactive with phenobarbital, we generated drug-specific T cell clones and lines from PBMCs of patients with phenobarbital hypersensitivity showing various degrees of cutaneous and extracutaneous involvements. Although the TCR Vβ repertoire and phenotype in the T cell clones/T cell lines were heterogeneous among the patients, Vβ13.1+ and Vβ5.1+ clones or lines were raised from the individuals examined who possessed different HLA haplotypes. Histopathological examination suggested that Vβ5.1+CD8+ T cells and Vβ13.1+ T cells played a role in cutaneous and extracutaneous involvements, respectively. A Vβ13.1+CD4+ clone was found to proliferate in response to the Ag with processing-impaired, fixed APCs. Most of the clones and lines belonged to the Th2 phenotype, producing IL-4 and IL-5 but not IFN-γ upon phenobarbital stimulation. Clones/lines with Th1 or Th0 phenotypes also constituted minor populations. These observations clearly indicate the heterogeneity and a marked individual deviation of reactive T cell subsets among the patients in terms of CD4/8 phenotype, Vβ repertoire, Ag recognition pattern, and cytokine production; and thus provide evidence whereby each pathogenic T cell subset contributes to special elements of clinical presentation.

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“…T cells infiltrating skin express high levels of cutaneous lymphocyte-associated antigen (CLA) and the chemokine receptors CCR4 and CCR10, and drug-specific T cells from patients with cutaneous drug hypersensitivity reactions express high levels of these receptors. 52,[60][61][62] Although the expression of chemokine receptors on liver homing T cells is less defined, CXCR3, CCR5, CCR9, and CXCR6 have been found on T cells isolated from patients with various forms of liver disease. 63 Lymphocytes from a patient with trimethoprim-induced liver injury express high levels of CXCR3 and CCR9, but only low levels of skin-homing receptors.…”

Section: Drug Immunogenicitymentioning

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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Anticonvulsant-induced toxic epidermal necrolysis: Monitoring the immunologic response

Cited by 92 publications

References 29 publications

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism‐dependent haptenation and T‐cell proliferation in vivo

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism‐dependent haptenation and T‐cell proliferation in vivo

Characterization of Drug-Specific T Cells in Phenobarbital- Induced Eruption

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

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