Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Oct 1;5(10):e13136.
doi: 10.1371/journal.pone.0013136.

Neutralisation of interleukin-13 in mice prevents airway pathology caused by chronic exposure to house dust mite

Kate L Tomlinson  1 , Gareth C G Davies, Daniel J Sutton, Roger T Palframan
Affiliations

Neutralisation of interleukin-13 in mice prevents airway pathology caused by chronic exposure to house dust mite

Kate L Tomlinson et al. PLoS One. .

Abstract

Background: Repeated exposure to inhaled allergen can cause airway inflammation, remodeling and dysfunction that manifests as the symptoms of allergic asthma. We have investigated the role of the cytokine interleukin-13 (IL-13) in the generation and persistence of airway cellular inflammation, bronchial remodeling and deterioration in airway function in a model of allergic asthma caused by chronic exposure to the aeroallergen House Dust Mite (HDM).

Methodology/principal findings: Mice were exposed to HDM via the intranasal route for 4 consecutive days per week for up to 8 consecutive weeks. Mice were treated either prophylactically or therapeutically with a potent neutralising anti-IL-13 monoclonal antibody (mAb) administered subcutaneously (s.c.). Airway cellular inflammation was assessed by flow cytometry, peribronchial collagen deposition by histocytochemistry and airway hyperreactivity (AHR) by invasive measurement of lung resistance (R(L)) and dynamic compliance (C(dyn)). Both prophylactic and therapeutic treatment with an anti-IL-13 mAb significantly inhibited (P<0.05) the generation and maintenance of chronic HDM-induced airway cellular inflammation, peribronchial collagen deposition, epithelial goblet cell upregulation. AHR to inhaled methacholine was reversed by prophylactic but not therapeutic treatment with anti-IL-13 mAb. Both prophylactic and therapeutic treatment with anti-IL-13 mAb significantly reversed (P<0.05) the increase in baseline R(L) and the decrease in baseline C(dyn) caused by chronic exposure to inhaled HDM.

Conclusions/significance: These data demonstrate that in a model of allergic lung disease driven by chronic exposure to a clinically relevant aeroallergen, IL-13 plays a significant role in the generation and persistence of airway inflammation, remodeling and dysfunction.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: This study was funded entirely by UCB. All authors were employees of UCB at the time these studies were performed. This does not alter the adherence of all authors to all policies of PLoS ONE involving the sharing of data and materials.

Figures

Figure 1
Figure 1. Experimental protocols for chronic exposure to house dust mite (HDM).
(A) Mice received intranasal HDM on 4 consecutive days per week for 5 consecutive weeks with concomitant administration of anti-IL-13 mAb, isotype control or vehicle s.c. weekly (prophylactic treatment). (B) Mice received intranasal HDM on 4 consecutive days per week for 8 consecutive weeks with concomitant administration of anti-IL-13 mAb, isotype control or vehicle s.c. weekly starting on week 6 (therapeutic treatment). AHR and baseline lung function was assessed as RL and Cdyn in terminally anaesthetised mice 24 hours after the last HDM instillation on day 32 (A) or day 53 (B). BAL and lungs were removed on day 32 (A) or day 53 (B) for assessment of airway inflammation and histological analysis. In addition, lungs were taken from an additional group on day 35 for histological analysis prior to therapeutic treatment (week 5 lungs, B).
Figure 2
Figure 2. Up regulation of IL-13 in HDM sensitised mice.
(A) IL-13 concentration in lung homogenate after 5 weeks of HDM sensitisation. (B) IL-13 mRNA expression in lung tissue relative to saline sensitised mice. Data are shown as mean ± SEM, n = 8 mice per group. ** p<0.01, *** p<0.001 relative to saline group by unpaired t test.
Figure 3
Figure 3. Effect of IL-13 neutralisation on BAL leukocytes.
(A–E) Mice were treated prophylactically with anti-IL-13 mAb (10 mg/kg, s.c., weekly) administered immediately prior to and throughout HDM exposure. (F–J) Effect of IL-13 neutralisation on established airway inflammation. Mice were exposed to HDM for 8 consecutive weeks and treated with anti-IL-13 mAb therapeutically (10 mg/kg, s.c., weekly from week 6). Data are shown as mean ± SEM, n = 8 mice per group. *p<0.05, ** p<0.01, *** p<0.001 relative to HDM group by one-way ANOVA followed by Dunnett's post test.
Figure 4
Figure 4. Effect of IL-13 neutralisation on epithelial goblet cell upregulation.
(A–C) Representative photomicrographs of airway sections stained with AB/PAS (original magnification ×200) from mice exposed for 5 weeks to saline (A) or HDM (B–C) and treated prophylactically with vehicle (B) or anti-IL-13 mAb (C) (10 mg/kg s.c., weekly) immediately prior to and throughout HDM exposure. (D) Mice were treated prophylactically with anti-IL-13 mAb (10 mg/kg, s.c., weekly) administered immediately prior to and throughout the 5 consecutive weeks of exposure to HDM. (E) Effect of anti-IL-13 neutralisation on established goblet cell upregulation. Mice were exposed to HDM for 8 consecutive weeks and treated therapeutically with anti-IL-13 mAb (10 mg/kg, s.c., weekly from week 6) Week 5 HDM mice represent lung pathology immediately prior to therapeutic treatment, after 5 weeks of HDM exposure. Data are shown as mean ± SEM. n = 9–10 mice per group. *** p<0.001 relative to HDM group by one-way ANOVA followed by Dunnett's post test.
Figure 5
Figure 5. Effect of IL-13 neutralisation on peribronchial collagen thickness.
(A–C) Representative photomicrographs of airway sections stained with Masson's trichrome (original magnification ×200) from mice exposed for 5 weeks to saline (A) or HDM (B–C) and treated prophylactically with vehicle (B) or anti-IL-13 mAb (10 mg/kg s.c., weekly) (C) immediately prior to and throughout HDM exposure. (D) Mice were treated prophylactically with anti-IL-13 mAb (10 mg/kg, s.c., weekly) administered immediately prior to and throughout the 5 consecutive weeks of exposure to HDM. (E) Effect of anti-IL-13 neutralisation in mice with an established increase in collagen thickness. Mice were exposed to HDM for 8 consecutive weeks and treated therapeutically with anti-IL-13 mAb (10 mg/kg, s.c., weekly from week 6). Week 5 HDM mice represent lung pathology immediately prior to therapeutic treatment, after 5 weeks of HDM exposure. Data are shown as mean ± SEM. n = 9–10 mice per group. * p<0.05, *** p<0.001 relative to HDM group by one-way ANOVA followed by Dunnett's post test.
Figure 6
Figure 6. Effect of IL-13 neutralisation on lung function and AHR to inhaled MCh.
AHR to MCh was determined as changes in lung resistance (RL) and dynamic compliance (Cdyn) measured after 5 weeks (A–D) or 8 weeks (E–H) of exposure to HDM. (A–D) Mice were treated prophylactically with anti-IL-13 mAb (10 mg/kg, s.c., weekly) or isotype control administered immediately prior to and throughout the 5 consecutive weeks of exposure to HDM. (A, B) Baseline RL and Cdyn were determined prior to MCh exposure. (C, D) Changes in RL and Cdyn in response to MCh relative to PBS response. (E–H) Mice were exposed to HDM for 8 consecutive weeks and treated therapeutically with anti-IL-13 mAb or isotype control from week 6 (10 mg/kg, s.c., weekly). (E, F) Baseline RL and Cdyn were determined prior to MCh exposure. (G, H) Changes in RL and Cdyn in response to MCh relative to PBS response. Data are shown as mean ± SEM. n = 7–8 mice per group. * p<0.05, ** p<0.01, *** p<0.001 relative to HDM group by one-way ANOVA followed by Dunnett's post test.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Willart MA, Lambrecht BN. The danger within: endogenous danger signals, atopy and asthma. Clin Exp Allergy. 2009;39:12–19. - PubMed
    1. Chiou YL, Lin CY. Der p2 activates airway smooth muscle cells in a TLR2/MyD88-dependent manner to induce an inflammatory response. J Cell Physiol. 2009;220:311–318. - PubMed
    1. Trompette A, Divanovic S, Visintin A, Blanchard C, Hegde RS, et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 2009;457:585–588. - PMC - PubMed
    1. Hewitt CR, Foster S, Phillips C, Horton H, Jones RM, et al. Mite allergens: significance of enzymatic activity. Allergy. 1998;53:60–63. - PubMed
    1. Johnson JR, Wiley RE, Fattouh R, Swirski FK, Gajewska BU, et al. Continuous Exposure to House Dust Mite Elicits Chronic Airway Inflammation and Structural Remodeling. Am J Respir Crit Care Med. 2004;169:378–385. - PubMed

Publication types