Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 144, Issue 1, Pages 204-215Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2019.02.028
Keywords
IL-33; soluble ST2; antagonist; airway inflammation; allergic asthma
Categories
Funding
- VIB (Belgium)
- Fund for Scientific Research Flanders (FWO
- Belgium)
- Foundation Against Cancer
- Ghent University Concerted Research Actions (GOA
- Belgium)
- Ghent University Industrial Research Fund (IOF
- Belgium) [F2016/IOF-Advanced/307]
- FWO research grant
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Background: The emergence of IL-33 as a key molecular player in the development and propagation of widespread inflammatory diseases, including asthma and atopic dermatitis, has established the need for effective IL-33 neutralizing biologics. Objective: Here we describe the development and validation of a new antagonist of IL-33, termed IL-33trap, which combines the extracellular domains of the IL-33 receptor (ST2) and its coreceptor, IL-1 receptor accessory protein, into a single fusion protein. Methods: We produced and purified recombinant IL-33trap from human cells and analyzed its IL-33 binding affinity and IL-33 antagonistic activity in cultured cells and mice. IL-33trap activity was also benchmarked with a recombinant soluble ST2 corresponding to the naturally occurring IL-33 decoy receptor. Finally, we studied the effect of IL-33trap in the Alternaria alternata mouse model of allergic airway inflammation. Results: In vitro IL-33trap binds IL-33 and inhibits IL-33 activity to a much stronger degree than soluble ST2. Furthermore, IL-33trap inhibits eosinophil infiltration, splenomegaly, and production of signature cytokines in splenic lymphocytes and lung tissue on IL-33 injection. Finally, administration of IL-33trap at the time of allergen challenge inhibits inflammatory responses in a preclinical mouse model of acute allergic airway inflammation. Conclusions: IL-33trap is a novel IL-33 antagonist that outperforms the natural IL-33 decoy receptor and shows anti-inflammatory activities in a preclinical mouse model of acute allergic airway inflammation when administered at the time of allergen challenge.
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