Inhibition of IL-4/IL-13 Does Not Enhance the Efficacy of Allergen Immunotherapy in Murine Allergic Airway Inflammation

Abstract

Background: Successful allergen-specific immunotherapy (SIT) is associated with reduced Th2 cytokine production and the induction of IL-10-producing regulatory T cells. To improve treatment efficacy, we investigated the impact of an IL-4/IL-13 inhibitor during SIT. Methods: BALB/c mice were sensitized intranasally with ovalbumin (OVA) for 4 weeks. Subsequently, they were subjected to intranasal SIT, with OVA being administered at doses increasing from 1 µg to 1 mg over 3 weeks with or without an IL-4/IL-13 inhibitor. Serum OVA-specific antibodies were measured and bronchoalveolar lavage (BAL) fluids were checked for airway eosinophilia. Subsequently, lung tissue was examined histologically for inflammatory infiltrates. Cytokines were detected in BAL fluids and spleen cell cultures. Furthermore, CD4 CD25 double-positive spleen T cells were checked for intracellular IL-10 production by flow cytometry. Results: OVA sensitization resulted in persistent IgE synthesis and an eosinophil-rich allergic airway inflammation combined with increased IL-4 and IL-5 levels. Therefore, intranasal SIT could efficiently reverse the allergic phenotype. This was associated with decreased IL-4 and IL-5 levels, and increased IL-10 levels in BAL fluids as well as increased amounts of IL-10-producing CD25+ regulatory T cells. However, mice treated with the IL-4/IL-13 inhibitor during SIT did not produce significantly different results . Conclusion: The use of an IL-4/IL-13 inhibitor as an adjuvant for SIT did not enhance anti-allergic effects. Thus, the observed reversal of Th2 responses during SIT may not be the keystone for successful therapy, but rather other factors, e.g. IL-10-producing regulatory T cells, may be crucial.

IL‐4 receptor α blockade prevents sensitization and alters acute and long‐lasting effects of allergen‐specific immunotherapy of murine allergic asthma

“…To elucidate the effects of IL‐4 and IL‐13 blockade on allergic sensitization and different phases of AIT, the IL‐4 receptor‐α (IL‐4Rα) antagonist IL‐4 mutein (IL‐4M) was used . In this study, IL‐4M was recombinantly produced in mammalian cells for the first time and, therefore, exhibits a significantly higher activity than E. coli ‐derived IL‐4M . This study underlines the suitability of non‐antibody‐based cytokine‐blocking approaches in atopic diseases.…”

Sustained Inhibition of the IL4/IL13 Receptor Complex during Allergen Specific Immunotherapy

“…The first step of this project focused on the large scale production of IL-4 Mutein and the determination of its biologic activity. In contrast to all previous publications that analyzed the effect of IL-4 Mutein produced in either Escherichia coli (E. coli) or insect cells (Gogishvili et al, 2007), (Grunewald, Kunzmann, et al, 1997) and (Hahn et al, 2003), our approach focused on the expression and evaluation of IL-4 Mutein produced in mammalian cells.…”