Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis

Ayman Elsheikh; Luis Castrejon; Sidonie N. Lavergne; Paul Whitaker; Manal Monshi; Hayley Callan; Sabah El-Ghaiesh; John Farrell; Werner J. Pichler; Daniel Peckham; B. Kevin Park; Dean J. Naisbitt

doi:10.1016/j.jaci.2010.12.1119

Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis

Ayman Elsheikh, Luis Castrejon, Sidonie N. Lavergne, Paul Whitaker, Manal Monshi, Hayley Callan, Sabah El-Ghaiesh, John Farrell, Werner J. Pichler, Daniel Peckham, B. Kevin Park, Dean J. Naisbitt

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

Abstract

Background: Exposure of patients with cystic fibrosis to sulfonamides is associated with a high incidence of hypersensitivity reactions. Objective: To compare mechanisms of antigen presentation and characterize the phenotype and function of T cells from sulfamethoxazole-hypersensitive patients with and without cystic fibrosis. Methods: T cells were cloned from 6 patients and characterized in terms of phenotype and function. Antigen specificity and mechanisms of antigen presentation to specific clones were then explored. Antigen-presenting cell metabolism of sulfamethoxazole was quantified by ELISA. The involvement of metabolism in antigen presentation was evaluated by using enzyme inhibitors. Results: Enzyme inhibitable sulfamethoxazole-derived protein adducts were detected in antigen-presenting cells from patients with and without cystic fibrosis. A significantly higher quantity of adducts were detected with cells from patients with cystic fibrosis. Over 500 CD4⁺ or CD8 ⁺ T-cell clones were generated and shown to proliferate and kill target cells. Three patterns of MHC-restricted reactivity (sulfamethoxazole- responsive, sulfamethoxazole metabolite-responsive, and cross-reactive) were observed with clones from patients without cystic fibrosis. From patients with cystic fibrosis, sulfamethoxazole metabolite-responsive and cross-reactive, but not sulfamethoxazole-responsive, clones were observed. The response of the cross-reactive clones to sulfamethoxazole was dependent on adduct formation and was blocked by glutathione and enzyme inhibitors. Antigen-stimulated clones from patients with cystic fibrosis secreted higher levels of IFN-γ, IL-6, and IL-10, but lower levels of IL-17. Conclusion: Sulfamethoxazole metabolism and protein adduct formation is critical for the stimulation of T cells from patients with cystic fibrosis. T cells from patients with cystic fibrosis secrete high levels of IFN-γ, IL-6, and IL-10.

Original language	English
Pages (from-to)	1543-1551.e3
Journal	Journal of Allergy and Clinical Immunology
Volume	127
Issue number	6
DOIs	https://doi.org/10.1016/j.jaci.2010.12.1119
State	Published - Jun 2011
Externally published	Yes

Keywords

Human
T cells
cystic fibrosis
drug hypersensitivity
drug metabolism

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10.1016/j.jaci.2010.12.1119

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Elsheikh, A., Castrejon, L., Lavergne, S. N., Whitaker, P., Monshi, M., Callan, H., El-Ghaiesh, S., Farrell, J., Pichler, W. J., Peckham, D., Park, B. K., & Naisbitt, D. J. (2011). Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis. Journal of Allergy and Clinical Immunology, 127(6), 1543-1551.e3. https://doi.org/10.1016/j.jaci.2010.12.1119

@article{c9d53c99bf1840e0ad0f09df7c5ccd13,

title = "Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis",

abstract = "Background: Exposure of patients with cystic fibrosis to sulfonamides is associated with a high incidence of hypersensitivity reactions. Objective: To compare mechanisms of antigen presentation and characterize the phenotype and function of T cells from sulfamethoxazole-hypersensitive patients with and without cystic fibrosis. Methods: T cells were cloned from 6 patients and characterized in terms of phenotype and function. Antigen specificity and mechanisms of antigen presentation to specific clones were then explored. Antigen-presenting cell metabolism of sulfamethoxazole was quantified by ELISA. The involvement of metabolism in antigen presentation was evaluated by using enzyme inhibitors. Results: Enzyme inhibitable sulfamethoxazole-derived protein adducts were detected in antigen-presenting cells from patients with and without cystic fibrosis. A significantly higher quantity of adducts were detected with cells from patients with cystic fibrosis. Over 500 CD4+ or CD8 + T-cell clones were generated and shown to proliferate and kill target cells. Three patterns of MHC-restricted reactivity (sulfamethoxazole- responsive, sulfamethoxazole metabolite-responsive, and cross-reactive) were observed with clones from patients without cystic fibrosis. From patients with cystic fibrosis, sulfamethoxazole metabolite-responsive and cross-reactive, but not sulfamethoxazole-responsive, clones were observed. The response of the cross-reactive clones to sulfamethoxazole was dependent on adduct formation and was blocked by glutathione and enzyme inhibitors. Antigen-stimulated clones from patients with cystic fibrosis secreted higher levels of IFN-γ, IL-6, and IL-10, but lower levels of IL-17. Conclusion: Sulfamethoxazole metabolism and protein adduct formation is critical for the stimulation of T cells from patients with cystic fibrosis. T cells from patients with cystic fibrosis secrete high levels of IFN-γ, IL-6, and IL-10.",

keywords = "Human, T cells, cystic fibrosis, drug hypersensitivity, drug metabolism",

author = "Ayman Elsheikh and Luis Castrejon and Lavergne, {Sidonie N.} and Paul Whitaker and Manal Monshi and Hayley Callan and Sabah El-Ghaiesh and John Farrell and Pichler, {Werner J.} and Daniel Peckham and Park, {B. Kevin} and Naisbitt, {Dean J.}",

note = "Funding Information: A.E. and S.E.-G. are PhD students supported by the Egyptian government . L.C. is a PhD student supported by the Mexican National Council for Science and Technology . M.M. is a PhD student supported by the Saudi Arabian government . This work was supported by a grant from the Wellcome Trust ( 078598/Z/05/Z ) as part of the Centre for Drug Safety Science supported by the Medical Research Council ( G0700654 ). Funding Information: Disclosure of potential conflict of interest: S. N. Lavergne and D. J. Naisbitt have received research support from the Wellcome Trust . B. K. Park has received research support from the Medical Research Council . The rest of the authors have declared that they have no conflict of interest. ",

year = "2011",

month = jun,

doi = "10.1016/j.jaci.2010.12.1119",

language = "Ingl{\'e}s",

volume = "127",

pages = "1543--1551.e3",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

number = "6",

}

Elsheikh, A, Castrejon, L, Lavergne, SN, Whitaker, P, Monshi, M, Callan, H, El-Ghaiesh, S, Farrell, J, Pichler, WJ, Peckham, D, Park, BK & Naisbitt, DJ 2011, 'Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis', Journal of Allergy and Clinical Immunology, vol. 127, no. 6, pp. 1543-1551.e3. https://doi.org/10.1016/j.jaci.2010.12.1119

TY - JOUR

T1 - Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis

AU - Elsheikh, Ayman

AU - Castrejon, Luis

AU - Lavergne, Sidonie N.

AU - Whitaker, Paul

AU - Monshi, Manal

AU - Callan, Hayley

AU - El-Ghaiesh, Sabah

AU - Farrell, John

AU - Pichler, Werner J.

AU - Peckham, Daniel

AU - Park, B. Kevin

AU - Naisbitt, Dean J.

N1 - Funding Information: A.E. and S.E.-G. are PhD students supported by the Egyptian government . L.C. is a PhD student supported by the Mexican National Council for Science and Technology . M.M. is a PhD student supported by the Saudi Arabian government . This work was supported by a grant from the Wellcome Trust ( 078598/Z/05/Z ) as part of the Centre for Drug Safety Science supported by the Medical Research Council ( G0700654 ). Funding Information: Disclosure of potential conflict of interest: S. N. Lavergne and D. J. Naisbitt have received research support from the Wellcome Trust . B. K. Park has received research support from the Medical Research Council . The rest of the authors have declared that they have no conflict of interest.

PY - 2011/6

Y1 - 2011/6

N2 - Background: Exposure of patients with cystic fibrosis to sulfonamides is associated with a high incidence of hypersensitivity reactions. Objective: To compare mechanisms of antigen presentation and characterize the phenotype and function of T cells from sulfamethoxazole-hypersensitive patients with and without cystic fibrosis. Methods: T cells were cloned from 6 patients and characterized in terms of phenotype and function. Antigen specificity and mechanisms of antigen presentation to specific clones were then explored. Antigen-presenting cell metabolism of sulfamethoxazole was quantified by ELISA. The involvement of metabolism in antigen presentation was evaluated by using enzyme inhibitors. Results: Enzyme inhibitable sulfamethoxazole-derived protein adducts were detected in antigen-presenting cells from patients with and without cystic fibrosis. A significantly higher quantity of adducts were detected with cells from patients with cystic fibrosis. Over 500 CD4+ or CD8 + T-cell clones were generated and shown to proliferate and kill target cells. Three patterns of MHC-restricted reactivity (sulfamethoxazole- responsive, sulfamethoxazole metabolite-responsive, and cross-reactive) were observed with clones from patients without cystic fibrosis. From patients with cystic fibrosis, sulfamethoxazole metabolite-responsive and cross-reactive, but not sulfamethoxazole-responsive, clones were observed. The response of the cross-reactive clones to sulfamethoxazole was dependent on adduct formation and was blocked by glutathione and enzyme inhibitors. Antigen-stimulated clones from patients with cystic fibrosis secreted higher levels of IFN-γ, IL-6, and IL-10, but lower levels of IL-17. Conclusion: Sulfamethoxazole metabolism and protein adduct formation is critical for the stimulation of T cells from patients with cystic fibrosis. T cells from patients with cystic fibrosis secrete high levels of IFN-γ, IL-6, and IL-10.

AB - Background: Exposure of patients with cystic fibrosis to sulfonamides is associated with a high incidence of hypersensitivity reactions. Objective: To compare mechanisms of antigen presentation and characterize the phenotype and function of T cells from sulfamethoxazole-hypersensitive patients with and without cystic fibrosis. Methods: T cells were cloned from 6 patients and characterized in terms of phenotype and function. Antigen specificity and mechanisms of antigen presentation to specific clones were then explored. Antigen-presenting cell metabolism of sulfamethoxazole was quantified by ELISA. The involvement of metabolism in antigen presentation was evaluated by using enzyme inhibitors. Results: Enzyme inhibitable sulfamethoxazole-derived protein adducts were detected in antigen-presenting cells from patients with and without cystic fibrosis. A significantly higher quantity of adducts were detected with cells from patients with cystic fibrosis. Over 500 CD4+ or CD8 + T-cell clones were generated and shown to proliferate and kill target cells. Three patterns of MHC-restricted reactivity (sulfamethoxazole- responsive, sulfamethoxazole metabolite-responsive, and cross-reactive) were observed with clones from patients without cystic fibrosis. From patients with cystic fibrosis, sulfamethoxazole metabolite-responsive and cross-reactive, but not sulfamethoxazole-responsive, clones were observed. The response of the cross-reactive clones to sulfamethoxazole was dependent on adduct formation and was blocked by glutathione and enzyme inhibitors. Antigen-stimulated clones from patients with cystic fibrosis secreted higher levels of IFN-γ, IL-6, and IL-10, but lower levels of IL-17. Conclusion: Sulfamethoxazole metabolism and protein adduct formation is critical for the stimulation of T cells from patients with cystic fibrosis. T cells from patients with cystic fibrosis secrete high levels of IFN-γ, IL-6, and IL-10.

KW - Human

KW - T cells

KW - cystic fibrosis

KW - drug hypersensitivity

KW - drug metabolism

UR - http://www.scopus.com/inward/record.url?scp=79957834898&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2010.12.1119

DO - 10.1016/j.jaci.2010.12.1119

M3 - Artículo

SN - 0091-6749

VL - 127

SP - 1543-1551.e3

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 6

ER -

Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis

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Keywords

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