title: TACI-Ig prevents the development of airway hyperresponsiveness in a murine model of asthma.
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.
authors.affiliation: Department of Autoimmunity and Inflammation, ZymoGenetics Inc., Seattle, WA 98102, USA. bilsborj@zgi.com
authors.forename: J
authors.initials: J
authors.lastname: Bilsborough
authors.forename: E
authors.initials: E
authors.lastname: Chadwick
authors.forename: S
authors.initials: S
authors.lastname: Mudri
authors.forename: X
authors.initials: X
authors.lastname: Ye
authors.forename: W R
authors.initials: WR
authors.lastname: Henderson
authors.forename: K
authors.initials: K
authors.lastname: Waggie
authors.forename: L
authors.initials: L
authors.lastname: Hebb
authors.forename: J
authors.initials: J
authors.lastname: Shin
authors.forename: M
authors.initials: M
authors.lastname: Rixon
authors.forename: J A
authors.initials: JA
authors.lastname: Gross
authors.forename: S R
authors.initials: SR
authors.lastname: Dillon
mesh_terms: D000485:Allergens / Q000009:adverse effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D001249:Asthma / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D053264:B-Cell Activating Factor / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000473:pathology; D007274:Injections, Intraperitoneal; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D010047:Ovalbumin / Q000009:adverse effects; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics
chemical_list: D000485:Allergens; D000911:Antibodies, Monoclonal; D053264:B-Cell Activating Factor; D018925:Chemokines; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C074302:keratinocyte-derived chemokines; D015847:Interleukin-4; D007073:Immunoglobulin E; D010047:Ovalbumin; C524618:TACI receptor-IgG Fc fragment fusion protein