Metformin Promotes Acquisition of Immune Tolerance in Allergen-Specific Immunotherapy

Purpose: Subcutaneous immunotherapy (SCIT) is a safe, effective immunotherapy method.However, it has several limitations, most notably the prolonged build-up phase.Metformin regulates Th17/regulatory T-cell (Treg) homeostasis by increasing Tregs and antiinflammatory cytokines.To overcome the limitation of the long build-up phase of SCIT, we propose combining SCIT with metformin.Methods: Sensitized BALB/c mice received intraperitoneal metformin (100 mg/kg or 300 mg/kg) for 9 days, except for the negative, positive, and SCIT groups.The SCIT, SCIT combined with 100 mg/kg metformin (SCIT-Met(100)), and SCIT combined with 300 mg/kg metformin (SCIT-Met(300)) groups received 3 subcutaneous injections of house dust mite (HDM) extract at 2-day intervals for immunotherapy.All groups except the negative control were given intranasal HDM extract for 5 days.Nasal symptoms, ear swelling, eosinophil count in nasopharyngeal wash-out lavage, antibody levels, and nasal mucosa histopathology were analyzed.Results: All immunotherapy groups exhibited reduced nasal symptoms, ear swelling, eosinophil counts in nasopharyngeal lavage, eosinophils, mast cells, and goblet cells in the nasal mucosa compared to the positive and metformin-injected (Met) groups.HDM-specific immunoglobulin G1 levels increased in all immunotherapy groups.The SCIT-Met groups induced more Treg than the Met(100), Met(300) and SCIT groups.Interleukin (IL)-4, IL-5 and IL-13 mRNA levels were lower in the Met groups and SCIT-Met(300) group than in the SCIT and SCIT-Met(100) groups.Foxp3 mRNA level was significantly higher in the Met groups and SCIT-Met groups than in the SCIT group.Conclusions: Overall, the SCIT-Met(300) group showed relatively favorable outcomes compared with the other groups.Combining immunotherapy with metformin may alleviate allergy symptoms and enhance immune tolerance in a murine model of allergic rhinitis.Further studies are needed to confirm these findings.