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Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma  Donavan T. Cheng, PhD, Cynthia Ma,

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Presentation on theme: "Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma  Donavan T. Cheng, PhD, Cynthia Ma,"— Presentation transcript:

1 Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma  Donavan T. Cheng, PhD, Cynthia Ma, MD, Jens Niewoehner, PhD, Martin Dahl, PhD, Angela Tsai, BA, Jun Zhang, MSc, Waldemar Gonsiorek, MSc, Subbu Apparsundaram, PhD, Achal Pashine, PhD, Palanikumar Ravindran, PhD, Jimmy Jung, BS, Julie Hang, MS, John Allard, PhD, Hans Bitter, PhD, Catherine Tribouley, PhD, Satwant Narula, PhD, Stephen Wilson, BA, Maria E. Fuentes, PhD  Journal of Allergy and Clinical Immunology  Volume 132, Issue 2, Pages (August 2013) DOI: /j.jaci Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 A, Inhibition of CCL17 production in DCs by using TSLPR mAb. CCL17 determinations were done 48 hours after stimulation with 10 ng/mL TSLP. Human IgG4 was used as an isotype control. B, Decrease in IL-13 production by TSLPR mAb after stimulation of in vitro–differentiated mast cells with 10 ng/mL each of TSLP and IL-33. C and D, CCL17 production was tested in human (Fig 1, C) and cynomolgus monkey (Fig 1, D) whole blood after stimulation with TSLP in the presence or absence of TSLPR mAb. A representative curve is shown. VEH, Vehicle. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Fold change and −log10(P false discovery rate [FDR]) values are plotted for all profiled genes 8 and 24 hours after A suum challenge at baseline. Red dots indicate genes specifically expressed in eosinophils, whereas blue dots indicate genes in the TSLP-activated DC signature. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 A, Schematic of the cynomolgus monkey study design. B, BAL fluid eosinophil counts after A suum challenge expressed as absolute numbers. C, IL-13 cytokine levels in BAL fluid (in picograms per milliliter) 8 hours after challenge at week 6 minus baseline levels. D, Lung resistance after allergen challenge is shown as the difference in area under the curve (AUC) of week 6 measurements minus baseline measurements for each monkey. Day 1 is after the first challenge, and day 2 is after the second challenge. BL, Baseline. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 A, Expression profiles of 11 coexpressed TSLP-activated DC signature genes displayed as heat maps. Pre-Ch, Pre-challenge. B, Pathway score indicates the gene set variation analysis score of CCL17, PPP1R14A, ALDH1A2, CD1B, CD1E, AUH, ANXA3, SOCS1, MAOA, NFIL3, and CD80. A positive difference in the pathway score indicates net upregulation of gene set 8 hours after versus before challenge. C, Animals were ordered from left to right in terms of increasing pathway scores 8 hours after challenge at week 6. The leftmost animal had the lowest increase in pathway score, whereas the rightmost animal had the greatest increase. Open bars, Antibody-treated animals; gray bars, vehicle-treated animals. The y-axis shows change in response to challenge for (1) IL-13 cytokine levels in BAL fluid (in picograms per milliliter), (2) area under the lung resistance curve (AUC), and (3) BAL fluid eosinophil counts (1000 cells/μL). Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 4 A, Expression profiles of 11 coexpressed TSLP-activated DC signature genes displayed as heat maps. Pre-Ch, Pre-challenge. B, Pathway score indicates the gene set variation analysis score of CCL17, PPP1R14A, ALDH1A2, CD1B, CD1E, AUH, ANXA3, SOCS1, MAOA, NFIL3, and CD80. A positive difference in the pathway score indicates net upregulation of gene set 8 hours after versus before challenge. C, Animals were ordered from left to right in terms of increasing pathway scores 8 hours after challenge at week 6. The leftmost animal had the lowest increase in pathway score, whereas the rightmost animal had the greatest increase. Open bars, Antibody-treated animals; gray bars, vehicle-treated animals. The y-axis shows change in response to challenge for (1) IL-13 cytokine levels in BAL fluid (in picograms per milliliter), (2) area under the lung resistance curve (AUC), and (3) BAL fluid eosinophil counts (1000 cells/μL). Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 4 A, Expression profiles of 11 coexpressed TSLP-activated DC signature genes displayed as heat maps. Pre-Ch, Pre-challenge. B, Pathway score indicates the gene set variation analysis score of CCL17, PPP1R14A, ALDH1A2, CD1B, CD1E, AUH, ANXA3, SOCS1, MAOA, NFIL3, and CD80. A positive difference in the pathway score indicates net upregulation of gene set 8 hours after versus before challenge. C, Animals were ordered from left to right in terms of increasing pathway scores 8 hours after challenge at week 6. The leftmost animal had the lowest increase in pathway score, whereas the rightmost animal had the greatest increase. Open bars, Antibody-treated animals; gray bars, vehicle-treated animals. The y-axis shows change in response to challenge for (1) IL-13 cytokine levels in BAL fluid (in picograms per milliliter), (2) area under the lung resistance curve (AUC), and (3) BAL fluid eosinophil counts (1000 cells/μL). Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E1 Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E2 Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E3 Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E4 Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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