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

doi:10.1016/j.jaci.2010.12.1119

Journal of Allergy and Clinical Immunology

Volume 127, Issue 6, June 2011, Pages 1543-1551.e3

https://doi.org/10.1016/j.jaci.2010.12.1119 Get rights and content

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.

Section snippets

Donor characteristics

Lymphocytes were isolated from blood of 3 patients with cystic fibrosis and 3 patients without cystic fibrosis each with a history of nonimmediate hypersensitivity to sulfamethoxazole (Table I shows clinical information) and drug-exposed volunteers. Volunteers receiving sulfamethoxazole did not develop clinical features of hypersensitivity. Approval for the study was acquired from Liverpool and Leeds local research ethics committees; informed written consent was obtained from each donor.

Generation of autologous APCs

Stimulation of hypersensitive patient lymphocytes with sulfamethoxazole and/or SMX-NO

Lymphocytes from sulfamethoxazole-hypersensitive patients without cystic fibrosis were stimulated to proliferate with sulfamethoxazole and SMX-NO. Antigen-specific proliferative responses were also detected with lymphocytes from hypersensitive patients with cystic fibrosis, but only with SMX-NO (Table I). Lymphocyte responses were not detected with cells from drug-exposed volunteers (SI < 2).

Generation of T-cell clones

A total of 293 antigen-specific T-cell clones was generated from the hypersensitive patients without

Discussion

Factors that predispose drug hypersensitivity have been explored and discussed in detail. A recent success has been the discovery of a strong association between the presence of HLA-B*5701 and abacavir hypersensitivity,²⁰ which resulted in the development of a genetic test and effectively the eradication of reactions to abacavir.²¹ Abacavir has also been shown to stimulate specific T cells when associated with B*5701, but not closely related HLA allotypes.²² Unfortunately, the picture is not so

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It was used extensively in the treatment of pneumocystis pneumonia, urinary-tract infections, meningococcal meningitis, acute otitis, Whipple’s disease, chronic bronchitis, skin and soft tissue infections and toxoplasmosis [4–6]. It is often prescribed along with other drugs for synergism especially in bacterial and HIV infections but is associated with numerous complications such as hypersensitivity, gastrointestinal disorders and many hematological abnormalities [7,8]. SMX has also been reported other side effects such as sulfhemoglobinemia (SulfHb), thrombocytopenia, C. difficile colitis, agranulocytosis, eosinophilia, megaloblastosis, drug interactions, renal and electrolyte problems and rare life-threatening reactions (e.g., Stevens–Johnson syndrome) [9,10].
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: 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).

: 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.

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Food, drug, insect sting allergy, and anaphylaxisEnhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis

Background

Objective

Methods

Results

Conclusion

Section snippets

Donor characteristics

Generation of autologous APCs

Stimulation of hypersensitive patient lymphocytes with sulfamethoxazole and/or SMX-NO

Generation of T-cell clones

Discussion

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Immunity

J Biol Chem

Chem Biol Interact

J Invest Dermatol

Drug metabolite-specific lymphocyte responses in sulfamethoxazole allergic patients with cystic fibrosis

Chem Res Toxicol

Retrospective clinical study of hypersensitivity reactions to aztreonam and six other beta-lactam antibiotics in cystic fibrosis patients receiving multiple treatment courses

Rev Infect Dis

Is cystic fibrosis a TH17 disease?

Inflamm Res

Cystic fibrosis-related diabetes: from CFTR dysfunction to oxidative stress

Clin Biochem Rev

Stimulation of human T cells with sulfonamides and sulfonamide metabolites

J Allergy Clin Immunol

Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals

J Immunol

Detection and quantification of drug-specific T cells in penicillin allergy

Allergy

Drug antigenicity, immunogenicity and co-stimulatory signalling: evidence for formation of a functional antigen through immune cell metabolism

J Immunol

“Danger” conditions increase sulfamethoxazole-protein adduct formation in human antigen-presenting cells

J Pharmacol Exp Ther

The lymphocyte transformation test for the diagnosis of drug allergy: sensitivity and specificity

Clin Exp Allergy

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

Br J Pharmacol

Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+ T-cells

Br J Pharmacol

Food, drug, insect sting allergy, and anaphylaxis
Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis