1. TACI-Ig prevents the development of airway hyperresponsiveness in a murine model of asthma.
- Author
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Bilsborough J, Chadwick E, Mudri S, Ye X, Henderson WR Jr, Waggie K, Hebb L, Shin J, Rixon M, Gross JA, and Dillon SR
- Subjects
- Allergens adverse effects, Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal therapeutic use, Asthma blood, Asthma etiology, Asthma immunology, B-Cell Activating Factor genetics, B-Lymphocytes immunology, Bronchoalveolar Lavage Fluid immunology, Chemokines genetics, Chemokines metabolism, Disease Models, Animal, Eosinophils immunology, Immunoglobulin E blood, Immunoglobulin E immunology, Inflammation pathology, Injections, Intraperitoneal, Interleukin-4 genetics, Interleukin-4 metabolism, Lung metabolism, Lung pathology, Mice, Mice, Inbred BALB C, Neutrophils immunology, Ovalbumin adverse effects, RNA, Messenger genetics, Recombinant Fusion Proteins administration & dosage, Tumor Necrosis Factor Ligand Superfamily Member 13 genetics, Asthma prevention & control, Recombinant Fusion Proteins therapeutic use
- Abstract
Background: Increased levels of serum IgE are associated with greater asthma prevalence and disease severity. IgE depletion using an anti-IgE monoclonal antibody has met with success in the treatment of moderate-to-severe and severe persistent allergic asthma., Objective: To test whether B cell-targeted therapy is a more effective treatment for airway hyperresponsiveness (AHR) in a murine model compared with IgE-depletion., Methods: We delivered soluble mTACI-Ig, a receptor for the B cell survival factors BLyS (B Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), or anti-IgE to allergen-sensitized mice before airway challenge with allergen., Results: mTACI-Ig treatment reduced circulating mature B cell levels in the blood, while anti-IgE treatment had no effect on B cell counts. Both mTACI-Ig and anti-IgE decreased the levels of total and allergen-specific IgE in the serum. Histopathologic analysis of lungs showed a reduction in disease severity scores for both treatment groups, but results were more pronounced in mTACI-Ig-treated mice. Neutrophil and eosinophil numbers in the bronchoalveolar lavage (BAL) were significantly reduced following mTACI-Ig treatment, but not after anti-IgE delivery. BLyS and APRIL blockade also resulted in a significant decrease in IL-4 and eotaxin mRNA and IL-4 and KC protein levels in total lung homogenates and BAL fluid, respectively. Finally, mTACI-Ig treatment was more effective than anti-IgE treatment in reducing AHR to inhaled antigen., Conclusions: Our data demonstrate that delivery of mTACI-Ig is a more effective treatment than anti-IgE mAb in a murine model of AHR.
- Published
- 2008
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