Specific immunotherapy modifies allergen-specific CD4+ T-cell responses in an epitope- dependent manner Erik Wambre, PhD, Jonathan H. DeLong, BSc, Eddie.

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Presentation transcript:

Specific immunotherapy modifies allergen-specific CD4+ T-cell responses in an epitope- dependent manner Erik Wambre, PhD, Jonathan H. DeLong, BSc, Eddie A. James, PhD, Nadia Torres-Chinn, BSc, Wolfgang Pfützner, MD, Christian Möbs, PhD, Stephen R. Durham, MD, Stephen J. Till, MD, PhD, David Robinson, MD, William W. Kwok, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 3, Pages 872-879.e7 (March 2014) DOI: 10.1016/j.jaci.2013.10.054 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Ex vivo frequencies of group 1 and group 5 TGP-specific T cells in allergic subjects (solid circles) and nonatopic subjects (open squares). *P < .001. B, Contribution of each epitope to the global DR04:01-TGP allergen-specific T-cell response in allergic (n = 10) and nonatopic (n = 5) subjects. Data are presented as mean values from each group in pie charts. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A and B, Representative dot plots showing ex vivo multicolor phenotyping of Phl p 1120-139–specific CD4+ T cells in DR04:01-restricted nonatopic (Fig 2, A) and allergic (Fig 2, B) subjects. C and D, Side-by-side comparison of the ex vivo phenotype of group 1 and group 5 TGP-specific CD4+ T cells in 5 nonatopic subjects (Fig 2, C) and 10 subjects with TGP allergy (Fig 2, D). *P < .01. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 A and B, Cytokine expression of Phl p 1120-139–specific (Fig 3, A) and Phl p 5b197-216–specific (Fig 3, B) T cells in DR04:01-restricted allergic subjects. C and D, Cytokine profiles of DR04:01-restricted TGP epitope–specific T cells in nonatopic (Fig 3, C) and allergic (Fig 3, D) subjects. Data are representative of at least 5 subjects per group and are presented as mean values from each group in pie charts. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 A and B, Ex vivo expression of CD27, CCR7, and CD7 of DR04:01-restricted TGP epitope–specific T cells in 10 allergic subjects (Fig 4, A) and 5 nonatopic subjects (Fig 4, B). P < .01. C, IL-4, IFN-γ, Bcl-2, and T-bet expression by CD27+ (red histogram) and CD27− (blue histogram) Phl p 1120-139–specific T cells in allergic subjects. Data are representative of at least 4 DR04:01-restricted allergic subjects. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 A, Ex vivo frequencies of DR04:01-restricted TGP-specific CD4+ T cells in allergic subjects and ASIT-treated subjects. B, Contribution of each DR04:01-restricted TGP epitope to the global allergen-specific CD4+ T-cell response in ASIT-treated subjects. C, Overall frequencies of CD27− and CD27+ DR04:01-restricted TGP allergen–specific T cells in allergic subjects (n = 10), nonatopic subjects (n = 5), and subjects after ASIT (n = 6). *P < .01. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 A, Cytokine profiles of DR04:01-restricted TGP epitope–specific T cells in ASIT-treated subjects. Data are representative of at least 4 subjects per group. B, Ex vivo phenotype of DR04:01-restricted TGP epitope–specific CD4+ T cells in allergic subjects and ASIT-treated subjects. Differences between groups were analyzed by using the Mann-Whitney U test. *P < .01. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Tetramer-guided epitope mapping of the TGP major allergen. T cells from DRB1*07:01-restricted subjects with TGP allergy were stimulated with overlapping peptide mixtures spanning the entire Phl p 1 (A), Phl p 5a (B), or Phl p 5b (C) protein and stained with pooled peptide-loaded tetramers after 2 weeks. Data are representative of 3 DRB1*07:01-restricted subjects with TGP allergy. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Representative flow cytometric analysis of ex vivo PE-conjugated DRB1*04:01/Phl p 1, DRB1*04:01/Phl p 5a, and DRB1*04:01/Phl p 5b pMHCII tetramer staining in allergic (A) and nonallergic (B) subjects after magnetic bead enrichment for PE-positive cells. Plots are gated on live CD3+CD14−CD19− T lymphocytes. Frequencies of specific T cells per million CD4+ T cells are as indicated. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 A, Correlation between the proportion of CRTH2+ cells and the proportion of CD27− cells in TGP allergen-specific T cells. B, Scatter plot showing the correlation between the ex vivo frequency and the proportion of CRTH2+ cells in TGP allergen–specific T cells. Each data point represents the value for each TGP epitope from 10 DR04:01-restricted donors with TGP allergy. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Global DR04:01-restricted TGP-specific CD4+ T-cell response in allergic, nonallergic, and post-ASIT subjects. Data are representative of at least 5 subjects and are presented as the mean values from each group in pie charts. Journal of Allergy and Clinical Immunology 2014 133, 872-879.e7DOI: (10.1016/j.jaci.2013.10.054) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions