Enhancement of Immune Modulation by Toll-Like Receptor 9 Adjuvant Combination Subcutaneous Immunotherapy for Japanese Cedar Pollinosis

Allergy immunotherapy (AIT) plays a pivotal role in the treatment of type I allergic conditions such as allergic rhinitis and rhinoconjunctivitis. However, AIT faces persistent issues, notably the risk of anaphylaxis and the need for long-term treatment. To address these issues, various strategies have been explored, including the use of adjuvants, allergen delivery systems, and allergen modifications. This study used a prophylactic mouse model of allergic sensitization to explore the potential for improving the efficacy and safety of Japanese cedar pollen (JCP) subcutaneous immunotherapy (SCIT). In this model, JCP extract was combined with an adjuvant (K3 CpG oligodeoxynucleotide [CpG-ODN]) and/or a delivery system (dilauroyl phosphatidylcholine/deoxycholic acid [DLPC/DA] micelles) for subcutaneous immunization of naïve mice. Compared to immunization with JCP alone, the combination of JCP with K3 CpG-ODN and DLPC/DA micelles resulted in a general reduction of the JCP-induced T-helper 2 (Th2) immune response, including reduced airway inflammation and allergen-specific plasma immunoglobulin E. In addition, Th1 markers were either largely unaffected (interferon-γ) or markedly increased (allergen-specific plasma IgG2a). These immunological changes coincided with reduced sneezing frequency in response to allergen exposure. For most parameters, a synergistic effect was observed when both K3 CpG-ODN and DLPC/DA micelles were combined with JCP at the time of immunization. In conclusion, the data presented here indicate that the combination of JCP, K3 CpG-ODN, and DLPC/DA micelles is a promising candidate for the development of a more effective SCIT treatment for Japanese cedar pollinosis, which may include a shorter treatment regimen and reduced risk of anaphylactic reactions.