USE OF ANTAGONISTS OF TH17 CYTOKINES FOR THE TREATMENT OF BRONCHIAL REMODELING IN PATIENTS SUFFERING FROM ALLERGIC ASTHMA

Abstract

Bronchial remodelling is a prominent feature of severe asthma and a potential therapeutic target. Some data indicate that Th17 cytokines in particular IL-22 may be involved in remodelling processes in vitro, and in skin remodelling in vivo. The aim of the inventors was to evaluate if Th17 cytokines are involved in bronchial remodelling in a severe model of allergic asthma, and if this was amplified by co-sensitization with NOD2 agonist, MDP, a ligand favouring Th17 polarization. Dog allergen challenge led to a predominant neutrophilic infiltration in Broncho-alveolar lavage (BAL), increased dog-specific IgE production, airways hyperresponsiveness, and increased Th17 cytokine production. Increased bronchial remodeling was observed in dog allergen challenged mice compared to control. IL-22 deficiency decreased airway hyperresponsiveness, bronchial mucus production as well as peribronchial collagen deposition, in the allergen-challenged group. Th17 cytokines in particular IL-22 participate in the bronchial remodeling in a chronic model of neutrophilic asthma, and may represent a therapeutic target in severe asthma.

Claims

1. A method of treating bronchial remodeling in a patient suffering from allergic asthma comprising administering to the patient a therapeutically effective amount of an antagonist of Th17 cytokines.

2. The method of claim 1 wherein the patient suffers from severe asthma.

3. The method of claim 1 wherein the antagonist is an antagonist of IL-17.

4. The method of claim 1 wherein the antagonist is an antagonist of IL-22.

5. The method of claim 1 wherein the antagonist is selected from the group consisting of IL-17 or IL-22 binding molecules and IL-17 or IL-22 receptor binding molecules.

6. The method of claim 1 wherein the antagonist is an IL-17 or IL-22 antagonistic antibody.

7. The method of claim 6 wherein the IL-17 antagonistic antibody binds IL-17A, IL-17 receptor A or IL-17 receptor C.

8. The method of claim 7 wherein the IL-17 antagonistic antibodies is selected from the group consisting of ixekizumab, secukinumab, and brodalumab.

9. The method of claim 6 wherein the IL-22 antagonistic antibody binds IL-22, IL22RA1 receptor or IL22RA2 receptor.

10. The method of claim 9 wherein the antagonistic antibody is fezakinumab.

11. The method of claim 1 wherein the antagonist is a polypeptide comprising a functional equivalent of a receptor subunit of the cytokine.

12. The method of claim 1 wherein the antagonist is an inhibitor of the expression of Th17 cytokine or one of its receptors.

Description

FIGURES

[0029] FIG. 1. IgE humoral responses in dog-induced asthma co-sensitized or not with NOD2 agonist in WT mice versus IL-22 deficient mice.

[0030] Total IgE (A) and dog-specific IgE (B) levels in sera from mice sensitized or not with dog allergen and MDP and challenged with dog allergen in WT versus IL-22.sup.−/− C57BL6 mice in 4 independent experiments. Results are shown as mean±SEM of n=10-35 mice per group. ***p<0.001 versus PBS, § p<0.05, ##p<0.01.

[0031] FIG. 2. BAL cell counts in dog-induced asthma co-sensitized or not with NOD2 agonist in WT mice versus IL-22 deficient mice.

[0032] (A-D) Broncho alveolar lavage cell counts in mice sensitized or not with dog allergen and MDP and challenged with dog allergen in WT versus IL-22.sup.−/− C57BL6 mice in 4 independent experiments. Results are shown as mean±SEM of n=10-35 mice per group. ***p<0.001 versus PBS, § p<0.05, ##p<0.01.

[0033] FIG. 3. Bronchial remodeling in dog-induced asthma in WT mice versus IL-22 deficient mice. (A) Area of peribronchial Collagen deposition assessed by Masson trichrome staining in WT versus IL-22 KO mice. Quantification was performed by image J software after exclusion of the vascular zones on a 20 μm deep zone below the bronchial basal membrane as μm2 collagen per μm length of bronchus. Results are normalized on the PBS group set at 1 and shown as mean value for 4 (MDP/Dog) to 10 (all other groups) bronchi from 2 to 3 different mice per group. (B) Bronchial mucus score was assessed by periodic acid Schiff staining and quantified using a quantitative visual score (0: no mucus 1: less than 50% positive cells 2: between 50 and 75% positive cells 4: More than 75% positive cells). Results are shown as mean of score of mucus per bronchus for 10-20 bronchi from 2 to 3 different mice per group. ***p<0.01**p<0.01 versus PBS group (one way analysis of variance followed by Neuman-Keuls multiple comparison test). #p<0.02 WT versus KO mice.

[0034] FIG. 4. Airway hyperresponsiveness in dog-induced asthma co-sensitized or not with NOD2 agonist in WT mice (A) versus IL-22 deficient mice (B). (A-B) Airway resistances were measured using invasive plethysmography after increasing doses of metacholine. Results are shown as mean values±SEM for 9-11 mice per group from 3 to 4 different experiments. ***p<0.001**p<0.01*p<0.05 Dog versus PBS and ###p<0.001 #p<0.05 Dog/MDP versus PBS using two way analysis of variance.

EXAMPLE

[0035] Rationale:

[0036] Bronchial remodelling is a prominent feature of severe asthma and a potential therapeutic target. Some data indicate that IL-22 may be involved in remodelling processes in vitro, and in skin remodelling in vivo. The aim of this study was to evaluate if IL-22 was involved in bronchial remodelling in a severe model of allergic asthma, and if this was amplified by co-sensitization with NOD2 agonist, MDP (muramyl dipeptide), a ligand favouring Th17 polarization.

[0037] Methods:

[0038] A chronic model of dog allergen-induced asthma was developed over a 6 weeks period. Mice were or not co-sensitized with MDP and challenged with dog allergen alone. Parameters of bronchial remodeling and asthma were assessed in WT mice versus IL-22 deficient mice.

[0039] Results:

[0040] Dog allergen challenge led to a predominant neutrophilic infiltration in Broncho-alveolar lavage (BAL), increased dog-specific IgE production (FIGS. 1A and 1B), airways hyperresponsiveness, and increased Th17 cytokine production. NOD2 co-stimulated mice exhibited additional increases in BAL neutrophil counts and in dog-specific IgE production. Increased bronchial remodeling was observed in dog allergen challenged mice compared to PBS treated mice, with increased mucus production and peri bronchial collagen deposition. There was no additional bronchial remodeling when mice were cosensitized with MDP (FIGS. 3A and 3B). In IL-22 deficient mice, there was a decrease in BAL cell numbers including neutrophils and eosinophils, in dog-specific IgE, in particular in the MDP co-sensitized group (FIG. 2A-2D). IL-22 deficiency also decreased airway hyperresponsiveness, bronchial mucus production as well as peribronchial collagen deposition, in the allergen-challenged group (FIGS. 4A and 4B).

[0041] Conclusion:

[0042] IL-22 participates in the bronchial remodeling in a chronic model of neutrophilic asthma, and may represent a therapeutic target in severe asthma.

REFERENCES

[0043] Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.