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

Abstract

Russkamp and Aguilar-Pimentel are contributed equally to this work as first authors.Abbreviations: AIT, allergen-specific immunotherapy; Alum, aluminum hydroxide magnesium hydroxide formulation; BAL, bronchoalveolar lavage; CHO, Chinese hamster ovary; FoxP3, forkhead box P3; GATA3, GATA-binding protein 3; HE, hematoxylin and eosin stain; IL-4M, IL-4 mutein, interleukin-4/interleukin-13 antagonist; i.n. AbstractBackground: Allergen-specific immunotherapy (AIT) is the only causal treatment for allergy. However, success rates vary depending on the type of allergy and disease background of the patient. Hence, strategies targeting an increased therapeutic efficacy are urgently needed. Here, the effects of blockade of IL-4 and IL-13 signaling on different phases of AIT were addressed. Methods:The impact of the recombinantly produced IL-4 and IL-13 antagonist IL-4 mutein (IL-4M) on allergic sensitization and AIT outcome in experimental allergic asthma were analyzed in a murine model. The effects of IL-4M administration were assessed prior/during sensitization, immediately after AIT under allergen challenge, and two weeks post-treatment. Results:Intervention with IL-4M prior/during sensitization led to strong induction of IgG1, IgG2a, IgG2b, and IgG3, decrease of specific and total IgE, as well as of IL-5 in serum. Similar effects on the serum immunoglobulin levels were observed immediately after IL4M-supplemented AIT during allergen challenge. Additionally, IL4M markedly suppressed type-2 cytokine secretion of splenocytes beyond the effect of AIT alone. These effects were equaled to those of AIT alone two weeks post-treatment. Intriguingly, here, IL-4M induced a sustained decrease of Th2-biased Tregs (ST2 + FOXP3 + GATA3 intermediate ).Conclusions: IL-4 and IL-13 blockade during experimental AIT demonstrates beneficial effects on immunological key parameters such as immunoglobulin and cytokine secretion immediately after AIT. Although two weeks later these effects were dropped to those of AIT alone, the number of potentially disease-triggering Th2-biased Tregs was further significantly decreased by IL-4M treatment. Hence, IL-4/IL13targeting therapies prime the immune memory in therapy success-favoring manner.

Advances and recent developments in asthma in 2020

“…In a murine allergic asthma model, IL‐4 receptor‐α blockade decreased serum IgE and IL‐5 levels and increased the level of IgG1, IgG2a, IgG2b, and IgG3 prior to/during sensitization. Thus, following the IL‐4 receptor‐α blockage, an immediate immunoglobulin response is induced accompanying the suppression of type 2 cytokines with a potential long‐lasting reduction in Th2‐biased T regulatory (Treg) cells 84 …”

Role of IL‐25, IL‐33, and TSLP in triggering united airway diseases toward type 2 inflammation

“…Allergen exposure ultimately evokes mast cell activation and degranulation, eosinophil recruitment and infiltration, type 2 (eg, T‐helper cells) cell activation and polarization, and antigen‐specific immunoglobulin E (IgE) production. Meanwhile, type 2 cytokine response bias characterized by an over‐production of interleukin (IL)‐4 (a cytokine that causes isotype class switching in B cells to produce IgE), IL‐5 (a cytokine that promotes eosinophil activation and recruitment), and IL‐13 (a cytokine that triggers mucus hypersecretion and airway hypersensitivity) can be observed in both upper and lower airways 9‐19 . Nasal allergen exposure tests in nonasthmatic AR patients result in eosinophilia in both upper and lower airway mucosa as well as peripheral blood 20,21 .…”

Th2 cells promote eosinophil‐independent pathology in a murine model of allergic bronchopulmonary aspergillosis

“…IL‐4 and IL‐13 activate STAT6‐regulated genes in various cell types and play a central role in mediating the effector phase of type 2 immune responses, including ABPA [14–18]. Both cytokines can be produced by many different cell types of the innate and adaptive immune system including Th2 cells, basophils, mast cells, type 2 innate lymphoid cells (ILC2s), and eosinophils [19–21].…”