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Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole- hypersensitive patients with cystic fibrosis  Ayman Elsheikh, MSc, Luis Castrejon,

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Presentation on theme: "Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole- hypersensitive patients with cystic fibrosis  Ayman Elsheikh, MSc, Luis Castrejon,"— Presentation transcript:

1 Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole- hypersensitive patients with cystic fibrosis  Ayman Elsheikh, MSc, Luis Castrejon, PhD, Sidonie N. Lavergne, PhD, Paul Whitaker, MBChB, Manal Monshi, MRes, Hayley Callan, BSc, Sabah El-Ghaiesh, MSc, John Farrell, MPhil, Werner J. Pichler, MD, Daniel Peckham, FRCP, B. Kevin Park, PhD, Dean J. Naisbitt, PhD  Journal of Allergy and Clinical Immunology  Volume 127, Issue 6, Pages e3 (June 2011) DOI: /j.jaci Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Stimulation of sulfamethoxazole (SMX)–responsive, SMX-NO–responsive, and cross-reactive T-cell clones from hypersensitive patients with and without cystic fibrosis. Results are given as mean [3H]thymidine incorporation. Differences in replicate cultures at each antigen concentration were less than 15%. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Protein adduct formation in APCs from patients with and without cystic fibrosis. A and B, Concentration-dependent and time-dependent adduct formation in sulfamethoxazole (SMX) and SMX-NO–treated APCs. C, The enzyme inhibitors 1-aminobenzotriazole (1-ABT) and methimazole (meth) block SMX-derived protein adducts. NS, Not significant. ∗P < .05; ∗∗P < .005. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 T cells from hypersensitive patients with cystic fibrosis are stimulated exclusively with sulfamethoxazole (SMX) metabolites. A, APCs pulsed with SMX for 16 hours stimulate SMX-responsive T-cell clones from hypersensitive patients with cystic fibrosis. B, T-cell clones from hypersensitive patients without cystic fibrosis. Panel 1, SMX-responsive clones are not stimulated with SMX-pulsed or SMX-NO–pulsed APCs; panels 2 and 3, SMX-NO–responsive and cross-reactive clones are stimulated with APCs pulsed with SMX-NO for 1 and 16 hours. Certain clones are stimulated with APCs pulsed with SMX (16 hours). C, The response of T-cell clones from patients with cystic fibrosis toward SMX is blocked by glutathione and enzyme inhibitors. D, The response of T-cell clones from patients with and without cystic fibrosis toward SMX-NO is blocked by glutathione, but not by enzyme inhibitors. Results are given as mean [3H]thymidine incorporation of individual clones (P < .05; P < .005). 1-ABT, 1-Aminobenzotriazole; GSH, glutathione; meth, methimazole; NS, not significant. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Cytokine secretion from drug antigen stimulated T-cell clones from hypersensitive patients with and without cystic fibrosis. Each data point shows mean cytokine secretion from individual clones. NS, Not significant. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Proliferation and cytolytic activity of sulfamethoxazole (SMX) and SMX-NO–responsive T-cell clones from hypersensitive patients with and without cystic fibrosis. The involvement of MHC molecules in antigen presentation was shown through the addition of anti-MHC class I and class II antibodies to the proliferation assay. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Synthetic SMX-NO and SMX-NO generated through APC drug metabolism is presented to T-cell clones via both processing-dependent and processing-independent pathways. T-cell clones were incubated with irradiated or fixed APCs. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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