Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement

Correia, Osvaldo

doi:10.1001/archderm.129.4.466

Cited by 107 publications

(93 citation statements)

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“…Cutaneous manifestations vary in the type of clinical presentation; co-trimoxazole and allergenic drugs in general cause both mild urticarial rashes and severe reactions such as toxic epidermal necrolysis (Barranco & Lopez-Serrano, 1998;Becker, 1998). Immunohistochemical analyses of skin at the time of a reaction have revealed a dermal and epidermal in®ltrate of CD4 + and CD8 + cells, respectively (Miyauchi et al, 1991;Correia et al, 1993). The incidence of cutaneous adverse reactions in HIV-infected patients is much higher than in the general population; greater than 30% develop allergic symptoms (Coopman et al, 1993;Koopmans et al, 1995).structure necessary for the maintenance of cell integrity leading to apoptosis or necrosis (Rieder et al, 1988;Hess et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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

124

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: Introductionmentioning

confidence: 99%

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

124

116

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“…Immunohistochemical analyses revealed infiltrates of CD4 ϩ and CD8 ϩ T cells in the skin of patients afflicted with SMX-induced cutaneous reactions (Miyauchi et al, 1991;Correia et al, 1993). Furthermore, it has been demonstrated that CD4 ϩ T cells isolated from SMX-hypersensitive patients proliferated in response to in vitro restimulation with both SMX and its reactive metabolite, 4-(nitroso)-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide (SMX-NO; chemical structure shown in Fig.…”

mentioning

confidence: 99%

Covalent Binding of the Nitroso Metabolite of Sulfamethoxazole Is Important in Induction of Drug-Specific T-Cell Responses in Vivo

et al. 2008

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Immune-mediated drug hypersensitivity reactions (IDHRs) represent a significant problem due to their unpredictable and severe nature, as well as the lack of understanding of the pathogenesis. Sulfamethoxazole (SMX), a widely used antibiotic, has been used as a model compound to investigate the underlying mechanism of IDHRs because it has been associated with a relatively high incidence of hypersensitivity. Previous studies by others showed that administration of 4-(nitroso)-N- (5-methyl-1,2-oxazol-3-yl)benzenesulfonamide (SMX-NO), the reactive metabolite of SMX, to rats resulted in the generation of SMX-specific antibodies and ex vivo splenocyte proliferative responses, as well as haptenation of skin keratinocytes, circulating peripheral blood mononuclear cells, and splenocytes. The objective of the present study was to further investigate SMX-NO-protein binding in relationship to its immunogenicity. In female DBA/1 mice treated with SMX-NO, varying degrees of SMX-NO-dependent T-cell responses and SMX-NO-protein adduct formation were observed in the spleen and in inguinal, brachial, and axillary lymph nodes. The data suggested a tissue-specific threshold of SMX-NO dosage that triggers the detection of adducts and immune response. Furthermore, serum albumin and immunoglobulin were identified as protein targets for SMX-NO modification. It seemed that these adducts were formed in the blood, circulated to lymphoid tissues, and initiated SMX-NO-dependent immune responses. Collectively, these data revealed a causal link between the deposition of SMX-NO-protein adducts in a lymphoid tissue and the induction of immune response in that tissue. Our findings also suggest that the immunogenicity of SMX-NO is determined by the immunogenic nature of the hapten, rather than special characteristics of the adducted protein.

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“…The time-course of the hypersensitivity syndrome development, the presence of T-cells in affected skin, and the reactivity of patients' T-cells upon re-stimulation with SMX or SMX-NO (Miyauchi et al, 1991;Correia et al 1993;Schnyder et al 2000;Burkhart et al 2001), each strongly suggested the involvement of the adaptive immune system in SMX hypersensitivity. Consistent with the clinical observations, our data identify SMX to have the strongest immunogenicity among all five test compounds.…”

Section: Discussionmentioning

confidence: 99%

Development of a screening assay to evaluate the potential of drugs to cause immune-mediated hypersensitivity reactions

Qin

Cheng

et al. 2013

Journal of Immunotoxicology

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Evidence suggests that bio-activation of drugs to generate chemically reactive metabolites (RM) that act as haptens to form immunogenic protein conjugates may be an important cause of immune-mediated drug hypersensitivity reactions (IDHR). Although many drugs that form RMs raise concerns about producing IDHR, standard non-clinical testing methods are rarely able to identify compounds with the potential to produce IDHR in humans. The objective of this study was to develop a predictive assay for IDHR that involves: (1) the use of an in vitro drugmetabolizing system to generate the RM that is captured by GSH, (2) conjugating the RM-GSH conjugate to mouse serum albumin (MSA) by using a chemical cross-linker, (3) immunization of mice with RM-GSH-MSA adducts, and (4) ex vivo challenge with RM-GSH-MSA adduct and measurement of lymphocyte proliferation to determine if the RM is immunogenic. The predictivity of the assay was evaluated by using drugs that produce RM and have been strongly, weakly, or not associated with IDHRs in the clinic. While this method requires additional validation with more drugs, the results demonstrate the feasibility of identifying drugs strongly associated with IDHR and the utility of the assay for rank ordering drugs with respect to their potential to cause IDHR. KeywordsDrug-protein adducts, drug-specific immune T-cell response, immune-mediated adverse drug reactions, reactive metabolite History

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Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement

Cited by 107 publications

References 0 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

Covalent Binding of the Nitroso Metabolite of Sulfamethoxazole Is Important in Induction of Drug-Specific T-Cell Responses in Vivo

Development of a screening assay to evaluate the potential of drugs to cause immune-mediated hypersensitivity reactions

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