CTLA4-IgG reverses asthma manifestations in a mild but not in a more "severe" ongoing murine model.
We investigated whether CTLA4-Ig can reverse established asthma manifestations in a novel murine model of ongoing disease. In BALB/c mice, sensitized to ovalbumin (OVA) without adjuvant, airway inflammation was induced by a first series of OVA aerosol challenges. Murine CTLA4-IgG was then administered, followed by a second series of OVA inhalations. In control-treated mice, two series of OVA challenges induced upregulation of OVA-specific IgE in serum, eosinophils in the bronchoalveolar lavage fluid (BALF), and IL-5 production by lung lymphocytes upon OVA restimulation in vitro, compared with saline-challenged mice. CTLA4-IgG significantly inhibited all of these parameters in OVA-challenged mice. Importantly, mCTLA4-IgG performed better than the gold-standard dexamethasone because this corticosteroid did not inhibit the upregulation of OVA-specific IgE in serum. In a more "severe" ongoing model, induced by sensitization to OVA emulsified in aluminum hydroxide, resulting in airway hyperresponsiveness to methacholine and stronger inflammatory responses, mCTLA4-IgG was less effective in that only the number of eosinophils in the BALF was reduced (P = 0.053), whereas dexamethasone inhibited both BALF eosinophilia and cytokine production by lung lymphocytes. Thus, CTLA4-Ig might be an effective alternative therapy in established allergic asthma, especially in situations of mild disease.
Deurloo
D T
DT
Department of Pharmacology and Pathophysiology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands. d.t.deurloo@pharm.uu.nl
van Esch
B C
BC
Hofstra
C L
CL
Nijkamp
F P
FP
van Oosterhout
A J
AJ
D000069594:Abatacept; D000336:Aerosols; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000536:Aluminum Hydroxide; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D004655:Emulsions; D004804:Eosinophils / Q000276:immunology; D007114:Immunization / Q000379:methods; D018796:Immunoconjugates; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015848:Interleukin-5 / Q000096:biosynthesis / Q000235:genetics; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D009299:Nasal Provocation Tests; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000336:Aerosols; D000485:Allergens; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D004655:Emulsions; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D000536:Aluminum Hydroxide; D000069594:Abatacept; D003907:Dexamethasone; D010047:Ovalbumin