Abstract
BackgroundAllergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma.ObjectiveOur aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways.MethodsIn C57BL/6J mice, a model of ovalbumin (OVA)-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor) from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3+CD4+ T cells was studied in vitro.ResultsAIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1β and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-α and IL-6 compared to AIT alone. Furthermore, TOFA co-administration significantly reduced systemic IL-6, IL-1β and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3+CD4+ T cells.ConclusionsThis proof of concept study shows that JAK inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation. The improved control of local inflammation might extend the use of AIT in more severe conditions such as polyallergy, asthma and high-risk patients suffering from mastocytosis or anaphylaxis.
Highlights
Allergen-specific immunotherapy (AIT) is the only curative therapy for allergic diseases, which is able to maintain its efficacy after discontinuation of treatment and which may significantly reduce allergic symptoms [1,2,3]
AIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1β and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-α and IL-6 compared to AIT alone
This proof of concept study shows that Janus kinase (JAK) inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation
Summary
Allergen-specific immunotherapy (AIT) is the only curative therapy for allergic diseases, which is able to maintain its efficacy after discontinuation of treatment and which may significantly reduce allergic symptoms [1,2,3]. The indication of AIT is mainly limited to allergic rhinitis and mild asthma, while this treatment is contra-indicated in severe allergic asthma [4] and of limited help in polyallergic rhinitis patients and atopic eczema [5]. It is of considerable interest to extend the application of AIT to atopic eczema and polyallergic patients, where this treatment is less efficient, because the local inflammatory process is causing side effects, and impairs the induction of immune tolerance [7]. Allergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma
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