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 anti-inflammatory 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.