Plasma Cysteine Deficiency and Decreased Reduction of Nitrososulfamethoxazole with HIV Infection

Naisbitt, Dean J.; Vilar, F. Javier; Stalford, A C; Wilkins, E.G.L.; Pirmohamed, Munir; Park, B. Kevin

doi:10.1089/088922200750054657

Cited by 62 publications

(46 citation statements)

References 58 publications

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“…In the surrogate system, an IgG2 was incubated in a PBS solution (pH 7.2) containing the redox reagents levels of 250 M cystine and 15 M cysteine, near those found in human serum (23)(24)(25). Analysis in the PBS system was simpler than in whole blood, because the material could be analyzed directly by RP-HPLC without prior time consuming affinity purification.…”

Section: Structural Heterogeneity Of Human Igg2 and Homogeneity Of Igmentioning

confidence: 99%

Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass

Dillon

Ricci

Vezina

et al. 2008

Journal of Biological Chemistry

259

327

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we have identified that the human IgG2 subclass exists as an ensemble of distinct isoforms, designated IgG2-A, -B, and -A/B, which differ by the disulfide connectivity at the hinge region. In this report, we studied the structural and functional properties of the IgG2 disulfide isoforms and compared them to IgG1. Human monoclonal IgG1 and IgG2 antibodies were designed with identical antigen binding regions, specific to interleukin-1 cell surface receptor type 1. In vitro biological activity measurements showed an increased activity of the IgG1 relative to the IgG2 in blocking interleukin-1␤ ligand from binding to the receptor, suggesting that some of the IgG2 isoforms had lower activity. Under reduction-oxidation conditions, the IgG2 disulfide isoforms converted to IgG2-A when 1 M guanidine was used, whereas IgG2-B was enriched in the absence of guanidine. The relative potency of the antibodies in cell-based assays was: IgG1 > IgG2-A > IgG2 Ͼ Ͼ IgG2-B. This difference correlated with an increased hydrodynamic radius of IgG2-A relative to IgG2-B, as shown by biophysical characterization. The enrichment of disulfide isoforms and activity studies were extended to additional IgG2 monoclonal antibodies with various antigen targets. All IgG2 antibodies displayed the same disulfide conversion, but only a subset showed activity differences between IgG2-A and IgG2-B. Additionally, the distribution of isoforms was influenced by the light chain type, with IgG2 composed mostly of IgG2-A. Based on crystal structure analysis, we propose that IgG2 disulfide exchange is caused by the close proximity of several cysteine residues at the hinge and the reactivity of tandem cysteines within the hinge. Furthermore, the IgG2 isoforms were shown to interconvert in whole blood or a "bloodlike" environment, thereby suggesting that the in vivo activity of human IgG2 may be dependent on the distribution of isoforms.

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Section: Structural Heterogeneity Of Human Igg2 and Homogeneity Of Igmentioning

confidence: 99%

Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass

Dillon

Ricci

Vezina

et al. 2008

Journal of Biological Chemistry

259

327

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“…This is probably the reason why administration of sulphamethoxazole hydroxylamine did not result in either haptenation or a cellular response, unless glutathione was depleted, i.e. the balance was changed in favour of bioactivation.There is a clinical parallel for this since HIV positive patients have a relative de®ciency of circulating thiols (Eck et al, 1989;Walmsley et al, 1997;Naisbitt et al, 2000). Taken together with the fact that sulphamethoxazole hydroxylamine readily circulates in peripheral blood , this may be a major factor accounting for the high prevalence of sulphamethoxazole hypersensitivity reactions in HIV-positive patients.…”

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

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

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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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“…It is interesting to note, therefore, that lymphocytes from hypersensitive patients are more susceptible to cell death in response to reactive drug metabolites than control cells (35)(36)(37)(38). Furthermore, patients with HIV infection have a decreased capacity to detoxify SMX-NO (39,40) and lymphocytes from these patients are more susceptible to SMX metabolite-induced cell death (41).…”

mentioning

confidence: 99%

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

Sanderson

Naisbitt

Farrell

et al. 2007

The Journal of Immunology

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117

107

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Different signals in addition to the antigenic signal are required to initiate an immunological reaction. In the context of sulfamethoxazole allergy, the Ag is thought to be derived from its toxic nitroso metabolite, but little is known about the costimulatory signals, including those associated with dendritic cell maturation. In this study, we demonstrate increased CD40 expression, but not CD80, CD83, or CD86, with dendritic cell surfaces exposed to sulfamethoxazole (250–500 μM) and the protein-reactive metabolite nitroso sulfamethoxazole (1–10 μM). Increased CD40 expression was not associated with apoptosis or necrosis, or glutathione depletion. Covalently modified intracellular proteins were detected when sulfamethoxazole was incubated with dendritic cells. Importantly, the enzyme inhibitor 1-aminobenzotriazole prevented the increase in CD40 expression with sulfamethoxazole, but not with nitroso sulfamethoxazole or LPS. The enzymes CYP2C9, CYP2C8, and myeloperoxidase catalyzed the conversion of sulfamethoxazole to sulfamethoxazole hydroxylamine. Myeloperoxidase was expressed at high levels in dendritic cells. Nitroso sulfamethoxazole immunogenicity was inhibited in mice with a blocking anti-CD40L Ab. In addition, when a primary nitroso sulfamethoxazole-specific T cell response using drug-naive human cells was generated, the magnitude of the response was enhanced when cultures were exposed to a stimulatory anti-CD40 Ab. Finally, increased CD40 expression was 5-fold higher on nitroso sulfamethoxazole-treated dendritic cells from an HIV-positive allergic patient compared with volunteers. These data provide evidence of a link between localized metabolism, dendritic cell activation, and drug immunogenicity.

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Plasma Cysteine Deficiency and Decreased Reduction of Nitrososulfamethoxazole with HIV Infection

Cited by 62 publications

References 58 publications

Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass

Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass

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

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

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