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Background: Allergen-specific immunotherapy (AIT) is able to restore immune tolerance to allergens in allergic patients. However, some patients do not or only poorly respond to current treatment protocols. Therefore, there is a need for deeper mechanistic insights and further improvement of treatment strategies. The relevance of the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, has been investigated in several inflammatory diseases, including allergic asthma. However, its potential role in AIT still needs to be addressed. Methods: Amurinemodel of AIT in ovalbumin-induced allergic airway inflammation was performed in AhR-deficient (AhR-/-) and wild-type mice. Furthermore, AIT was combined with the application of the high-affinity AhR agonist 10-chloro-7Hbenzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ) as an adjuvant to investigate the effects of AhR activation on therapeutic outcome. Results: Although AhR-/- mice suffer stronger allergic responses than wild-type mice, experimental AIT is comparably effective in both. Nevertheless, combining AIT with the administration of 10-Cl-BBQ improved therapeutic effects by an AhRdependent mechanism, resulting in decreased cell counts in the bronchoalveolar fluid, decreased pulmonary Th2 and Th17 cell levels, and lower sIgE levels. Conclusion: This study demonstrates that the success of AIT is not dependent on the AhR. However, targeting the AhR during AIT can help to dampen inflammation and improve tolerogenic vaccination. Therefore, AhR ligands might represent promising candidates as immunomodulators to enhance the efficacy of AIT. [ABSTRACT FROM AUTHOR]

Background: Native allergen extracts or chemically modified allergoids are routinely used to induce allergen tolerance in allergen‐specific immunotherapy (AIT), although mechanistic side‐by‐side studies are rare. It is paramount to balance optimal dose and allergenicity to achieve efficacy warranting safety. AIT safety and efficacy could be addressed by allergen dose reduction and/or use of allergoids and immunostimulatory adjuvants, respectively. In this study, immunological effects of experimental house dust mite (HDM) AIT were investigated applying high‐dose HDM extract and low‐dose HDM allergoids with and without the adjuvants microcrystalline tyrosine (MCT) and monophosphoryl lipid A (MPL) in a murine model of HDM allergy. Methods: Cellular, humoral, and clinical effects of the different AIT strategies were assessed applying a new experimental AIT model of murine allergic asthma based on physiological, adjuvant‐free intranasal sensitization followed by subcutaneous AIT. Results: While low‐dose allergoid and high‐dose extract AIT demonstrated comparable potency to suppress allergic airway inflammation and Th2‐type cytokine secretion of lung‐resident lymphocytes and draining lymph node cells, low‐dose allergoid AIT was less effective in inducing a potentially protective IgG1 response. Combining low‐dose allergoid AIT with MCT or MCT and dose‐adjusted MPL promoted Th1‐inducing mechanisms and robust B‐cell activation counterbalancing the allergic Th2 immune response. Conclusion: Low allergen doses induce cellular and humoral mechanisms counteracting Th2‐driven inflammation by using allergoids and dose‐adjusted adjuvants. In light of safety and efficacy improvement, future therapeutic approaches may use low‐dose allergoid strategies to drive cellular tolerance and adjuvants to modulate humoral responses. [ABSTRACT FROM AUTHOR]