HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes.

Zanni, M; Greyerz, Salome von; Schnyder, Benno; Brander, Karl A.; Frutig, Karin; Hari, Yvonne; Valitutti, Salvatore; Pichler, Werner J.

doi:10.1172/jci3544

Cited by 223 publications

(199 citation statements)

References 30 publications

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“…The ability of reversible binding of SMX and antigen presenting cells to activate drug-specific T-cells from patients with a history of hypersensitivity to the drug in an MHCdependent fashion suggests that elicitation of an immune response in sensitized individuals may not require bioactivation of the drug to reactive species (Zanni et al, 1998). It has also been suggested that non-reactive drug may stimulate the production of drug-specific T-cells in non-sensitized individuals (Engler et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

Bhaiya

Roychowdhury

Vyas

et al. 2006

Toxicology and Applied Pharmacology

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Cutaneous drug reactions (CDRs) associated with sulfonamides are believed to be mediated through the formation of reactive metabolites that result in cellular toxicity and protein haptenation. We evaluated the bioactivation and toxicity of sulfamethoxazole (SMX) and dapsone (DDS) in normal human dermal fibroblasts (NHDF). Incubation of cells with DDS or its metabolite (D-NOH) resulted in protein haptenation readily detected by confocal microscopy and ELISA. While the metabolite of SMX (S-NOH) haptenated intracellular proteins, adducts were not evident in incubations with SMX. Cells expressed abundant N-acetyltransferase-1 (NAT1) mRNA and activity, but little NAT2 mRNA or activity. Neither NAT1 nor NAT2 protein were detectable. Incubation of NHDF with S-NOH or D-NOH increased reactive oxygen species formation and reduced glutathione content. NHDF were less susceptible to the cytotoxic effect of S-NOH and D-NOH than are keratinocytes. Our studies provide the novel observation that NHDF are able to acetylate both arylamine compounds and bioactivate the sulfone, DDS, giving rise to haptenated proteins. The reactive metabolites of SMX and DDS also provoke oxidative stress in these cells in a time-and concentration-dependent fashion. Further work is needed to determine the role of the observed toxicity in mediating CDRs observed with these agents.

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Section: Discussionmentioning

confidence: 99%

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

Bhaiya

Roychowdhury

Vyas

et al. 2006

Toxicology and Applied Pharmacology

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“…Although drug metabolism is thought to be essential for immune recognition, recent studies have demonstrated an alternative (or additive) mechanism that occurs in the absence of protein conjugation and antigen processing (MauriHellweg et al, 1995;Schnyder et al, 1997;Zanni et al, 1998;Von Greyerz et al, 1999). It has been termed the HLArestricted, processing-and metabolism-independent pathway of immune recognition by drugs (Figure 1) (Zanni et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…It has been termed the HLArestricted, processing-and metabolism-independent pathway of immune recognition by drugs (Figure 1) (Zanni et al, 1998). In these experiments, the large majority of T-cell clones, generated from two sulphamethoxazole-hypersensitive patients, proliferated in response to sulphamethoxazole, but not sulphamethoxazole hydroxylamine or nitroso sulphamethoxazole (Schnyder et al, 2000;Burkhart et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…T-cells proliferate and in the presence of the appropriate co-stimulatory signals may cause hypersensitivity. Pathway 2, proposed by Pichler et al (Mauri-Hellweg et al, 1995;Schnyder et al, 1997;Zanni et al, 1998;von Greyerz et al, 1999), suggests that sulphamethoxazole stimulates T-cell proliferation, in the absence of drug metabolism and antigen processing, via a direct, reversible interaction between the parent drug and an antigenic peptide embedded within the MHC binding groove of antigen presenting cells.…”

Section: Introductionmentioning

confidence: 99%

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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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“…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.

133

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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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HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes.

Cited by 223 publications

References 30 publications

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

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

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

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