Abstract
Background: Dupilumab, a fully human monoclonal antibody that binds IL-4Raand inhibits signaling of both IL-4 and IL-13, has shown robust efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma and atopic dermatitis.
Aim: To distinguish the roles of IL-4 and IL-13 in driving type 2 inflammation by comparing IL-4 vs IL-13 vs dual IL-4/13 blockade.
Methods: Human mast cells, eosinophils or endothelial cells were treated with IL-4 or IL-13 and assessed for cytokine/chemokine release and/or FceR1aexpression. Humanized mice were exposed to house dust mite thrice weekly for 4 weeks and received twice‐weekly injections of dupilumab, anti‐IL-4, IL-13Rα2 fusion protein, control antibodies, or no antibody.
Results: IL-4 and IL-13 differentially induced different patterns of cytokine release from human endothelial cells, mast cells and eosinophils. Similarly, IL-4 and IL-13 to a lesser extent, induced mast cell FceR1aexpression. In a murine asthma model, antigen specific responses were IL-4-dependent, whereas mucus production was IL-13-dependent. Lung eosinophil infiltration and cytokine/chemokine induction were dependent on both IL-4 and IL-13. Notably, dual receptor blockade with dupilumab, but not individual ligand blockade, prevented all of these type 2 associated pathologies.
Conclusion: IL-4 and IL-13 act independently and synergistically to drive type 2 inflammation highlighting the need for dual blockade. This could explain in part the benefit of dupilumab across multiple type 2 diseases and key mechanistic differences between IL-4 and IL-13.
Footnotes
Cite this article as: European Respiratory Journal 2019; 54: Suppl. 63, PA5206.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2019