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


CONCLUSIONS
Our results suggest that bortezomib treatment has only limited value as plasma cell-depleting therapy against allergic bronchial asthma.
Bereich Experimentelle Pneumologie, Forschungszentrum Borstel, Borstel, Deutschland. mwegmann@fz-borstel.de
Michael
M
Wegmann
Lars
L
Lunding
Zane
Z
Orinska
David M
DM
Wong
Rudolf A
RA
Manz
Heinz
H
Fehrenbach
D000485:Allergens / Q000276:immunology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002908:Chronic Disease; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology; D011719:Pyrazines / Q000627:therapeutic use*; D017211:Treatment Failure
D000485:Allergens; D018927:Anti-Asthmatic Agents; D001897:Boronic Acids; D007074:Immunoglobulin G; D011719:Pyrazines; D007073:Immunoglobulin E; D000069286:Bortezomib