IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis Hyun-Woo Shin, MD, PhD, Dong-Kyu Kim, MD, Min-Hyun Park, MD,

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Presentation transcript:

IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis Hyun-Woo Shin, MD, PhD, Dong-Kyu Kim, MD, Min-Hyun Park, MD, PhD, Kyoung Mi Eun, BSc, Mingyu Lee, BSc, Daeho So, BSc, Il Gyu Kong, MD, PhD, Ji-Hun Mo, MD, PhD, Min-Suk Yang, MD, Hong Ryul Jin, MD, PhD, Jong-Wan Park, MD, PhD, Dae Woo Kim, MD, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 6, Pages 1476-1485.e7 (June 2015) DOI: 10.1016/j.jaci.2015.01.003 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Expression of IL-25 in patients with CRSwNP or those with CRSsNP. A, Control UP mucosa from patients without nasal diseases, UPs from patients with CRSsNP and CRSwNP, and NP tissues from patients with CRSwNP were immunostained with IL-25 antibody. The negative control was immunostained with isotype IgG. B, Comparison of IL-25 expression levels in each tissue (n = 6 for control UP, n = 10 for CRSsNP-UP, n = 10 for CRSwNP-UP, and n = 10 for CRSwNP-NP). Numbers of IL-25+ epithelial cells per 100 cells were counted and averaged from 3 different areas of epithelium. C, Numbers of IL-25+ inflammatory cells were counted from the 5 densest areas (hpfs; magnification ×400) and averaged in each group (n = 8 for control-UP, n = 25 for CRSsNP-UP, n = 19 for CRSwNP-UP, and n = 43 for CRSwNP-NP). D, Relative IL-25 mRNA expression of whole tissues from each group were compared (n = 17 for control-UP, n = 40 for CRSsNP-UP, n = 35 for CRSwNP-UP, and n = 48 for CRSwNP-NP). E, Protein levels of IL-25 were measured by means of ELISA and compared (n = 9 for control-UP, n = 15 for CRSsNP-UP, n = 14 for CRSwNP-UP, and n = 15 for CRSwNP-NP). F, Double immunohistochemical staining for major basic protein, tryptase, CD68, CD11c or 2D7, and IL-25 was performed, and double-positive cells were counted (n = 7 for each group). G, Immunostaining of representative cells with both tryptase (red, asterisks) and IL-25 (green, arrowheads) in NP tissue. Arrows indicate double-positive immune cells (magnification ×1000). Scale bar = 20 μm. *P < .05, **P < .01, ***P < .001, and ****P < .0001, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Expression of IL-17RB in patients with CRSwNP or those with CRSsNP. A, Control UP mucosa from patients without nasal diseases, UPs from patients with CRSsNP, and NP tissues from patients with CRSwNP were immunostained with IL-17RB antibody. Negative controls were immunostained with isotype IgG. B, Comparison of IL-17RB expression in each tissue (n = 6 for control-UP, n = 9 for CRSsNP-UP, n = 11 for CRSwNP-UP, and n = 13 for CRSwNP-NP). Expression levels of IL-17RB were reviewed under the hpf (magnification ×400). The final score of each sample is presented as the average of scores from the 5 densest areas (hpf; magnification ×400). C, Protein levels of IL-17RB were measured by means of ELISA and compared (n = 9 for control-UP, n = 15 for CRSsNP-UP, n = 15 for CRSwNP-UP, and n = 15 for CRSwNP-NP). *P < .05, **P < .01, and ***P < .001, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Correlation between mRNA expression of IL-25 and inflammatory markers. A-F, mRNA expression levels of T-bet, RORC, GATA-3, ECP, TGF-β1, and TGF-β2 were measured in NPs (n = 43), and correlations between IL-25 and each inflammatory marker were investigated. The Pearson correlation test was used, and R values indicate Pearson correlation coefficients. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of anti–IL-25 on NP formation in the mouse model. A, Protocol for generating the murine NP model. OVA and SEB were instilled into the nasal cavity to induce nasal polyp formation. Anti–IL-25 or dexamethasone (1 mg/kg) was administered intraperitoneally to investigate their effects on nasal inflammation and polyp formation. B, Photographs of representative maxillary sinus mucosa in each group of mice. Dotted lines represent the border between glandular structure and maxillary sinus mucosa. Arrows and arrowheads indicate polypoid lesions and epithelial ingrowth, respectively. C-H, Numbers of nasal polypoid lesions (Fig 4, C), mucosal edema thickness (Fig 4, D), numbers of infiltrated eosinophils (Fig 4, E), numbers of infiltrated neutrophils (Fig 4, F), subepithelial collagen deposition (Fig 4, G), and numbers of goblet cells (Fig 4, H) were counted from 10 different hpfs (magnification ×400) and compared among each group (n = 5). The Mann-Whitney U test was used to analyze the results of these experiments. *P < .05, **P < .01, and ***P < .001, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IL-25 expression and cytokine profiles in the murine NP model. A, Representative photographs of IL-25 expressions in epithelia from each group of mice. B, Comparison of IL-25 expression among the indicated groups. The number of IL-25+ epithelial cells was counted in hpfs (magnification ×400). The final score of each sample is presented as the average score from 5 different hpfs. C, Cytokine profile from nasal lavage fluid (n = 8 for each group). Control, PBS-instilled group; Polyp, mouse polyp model; POLYP+αIL-25, mouse polyp model treated with anti–IL-25; POLYP+Steroid, mouse polyp model treated with dexamethasone. *P < .05 and **P < .01, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Anti–IL-25 therapy suppresses expression of both leukocyte chemotactic cytokines and ICAMs in a murine nasal polyp model. A, Relative mRNA expression levels of leukocyte-recruiting cytokines from each group were compared. B, Relative mRNA expression levels of ICAMs from each group were compared. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Expression of IL-25 in infiltrated inflammatory cells. Control UP mucosa from patients without nasal diseases, UPs from patients with CRSsNP and CRSwNP, and NP tissues from patients with CRSwNP were immunostained with IL-25 antibody. Negative controls were immunostained with isotype IgG. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Immunologic characteristics of NPs in this study. mRNA expression of T-bet, RORC, GATA-3, ECP, TGF-β1, and TGF-β2 were measured. *P < .05 and **P < .01, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 IL-25 expression in epithelium from a murine polyp model. A, Representative photographs in control mice (PBS) and the mouse polyp model. B, Expression of IL-25 in epithelium from murine nasal mucosa was compared with that in control mucosa by means of Western blotting (n = 3). Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Representative photographs for polyp lesions, eosinophils, neutrophils, collagen deposition, and goblet cells in each group. A, Sinonasal mucosa with or without polyps stained with hematoxylin and eosin. B, Eosinophils stained with Sirius red. C, Neutrophils immunostained with neutrophilic antibody. D, Masson trichrome stain for collagen deposition. Arrows indicate thickening of collagen deposition. E, Alcian blue stain for goblet cells. PBS, Control group; Polyp, mouse polyp model; Polyp+αIL-25, mouse polyp model treated with anti–IL-25; Polyp+Steroid, mouse polyp model treated with dexamethasone. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Correlation between mRNA expression of IL-25 and inflammatory markers in the mouse polyp model. mRNA expression levels of IL-4, IL-5, IFN-γ, IL-17a, TGF-β1, TGF-β2, CCL11, CCL24, CCL26, CXCL1, CXCL2, and CXCL5 were measured in nasal tissues from the mouse polyp model, and correlations between IL-25 and each inflammatory marker were investigated. Total RNA was isolated from whole sinonasal tissues from the control (n = 10) and polyp (n = 10) models. If the mRNA level was not detected on quantitative RT-PCR, that pair was deleted in a list-wise manner from the correlation analysis. Spearman correlation test was used, and R values indicate Spearman correlation coefficients. Journal of Allergy and Clinical Immunology 2015 135, 1476-1485.e7DOI: (10.1016/j.jaci.2015.01.003) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions