Long-term Bortezomib treatment reduces allergen-specific IgE but fails to ameliorate chronic asthma in mice

Abstract

Background: Allergen-specific immunoglobulin (Ig) E initiates the effector cascade of allergic asthma and has been identified as a valuable target for therapeutic treatment of this disease. The proteasome inhibitor bortezomib was previously shown to deplete Ig-secreting plasma cells and to efficiently suppress Ig serum titers. The present study aimed at evaluating the therapeutic potential of the proteasome inhibitor bortezomib in allergic bronchial asthma. Methods: To address this question, a chronic experimental asthma mouse model was used in a therapeutic setting. Mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol for 12 weeks. After 6 weeks of challenge, bortezomib treatment was started and continued for 1 week (short-term) or 6 weeks (long-term) with a dosage of 0.75 mg/kg body weight twice a week. Lung function, lung histology, Ig serum titers and plasma cell numbers were assessed. Results: Whereas short-term treatment lowered bronchoalveolar lavage eosinophils, long-term treatment considerably reduced serum titers of anti-OVA IgE in mice with chronic experimental asthma. However, neither short-term nor long-term treatment significantly reduced plasma cell numbers, anti-OVA IgG1 serum titers or allergic airway inflammation or ablated airway hyperresponsiveness. Conclusion: Our results suggest that bortezomib treatment has only limited value as plasma cell-depleting therapy against allergic bronchial asthma.