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Interruption of CD28-mediated costimulation during allergen challenge protects mice from allergic airway disease

2012; Elsevier BV; Volume: 130; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2012.08.049

1097-6825

Tea Gogishvili, Fred Lühder, Frank Kirstein, Natalie E. Nieuwenhuizen, Sandra Goebbels, Sandra Beer‐Hammer, Klaus Pfeffer, Sebastian Reuter, Christian Taube, Frank Brombacher, Thomas Hünig,

Respiratory and Cough-Related Research

BackgroundAllergic asthma is a TH2-promoted hyperreactivity with an immediate, IgE, and mast cell–dependent response followed by eosinophil-dominated inflammation and airway obstruction.ObjectiveBecause costimulation by CD28 is essential for TH2 but not TH1 responses, we investigated the effect of selective interference with this pathway in mice using the models of ovalbumin and house dust mite–induced airway inflammation.MethodsTo study the role of CD28 in the effector phase of allergic airway inflammation, we developed an inducibly CD28-deleting mouse strain or alternatively used a CD28 ligand-binding site–specific mouse anti-mouse mAb blocking CD28 engagement.ResultsWe show that even after systemic sensitization to the allergen, interruption of CD28-mediated costimulation is highly effective in preventing airway inflammation during challenge. In addition to improving airway resistance and histopathologic presentation and reducing inflammatory infiltrates, antibody treatment during allergen challenge resulted in a marked relative increase in regulatory T-cell numbers among the CD4 T-cell subset of the challenged lung.ConclusionSelective interference with CD28-mediated costimulation during allergen exposure might be an attractive therapeutic concept for allergic asthma. Allergic asthma is a TH2-promoted hyperreactivity with an immediate, IgE, and mast cell–dependent response followed by eosinophil-dominated inflammation and airway obstruction. Because costimulation by CD28 is essential for TH2 but not TH1 responses, we investigated the effect of selective interference with this pathway in mice using the models of ovalbumin and house dust mite–induced airway inflammation. To study the role of CD28 in the effector phase of allergic airway inflammation, we developed an inducibly CD28-deleting mouse strain or alternatively used a CD28 ligand-binding site–specific mouse anti-mouse mAb blocking CD28 engagement. We show that even after systemic sensitization to the allergen, interruption of CD28-mediated costimulation is highly effective in preventing airway inflammation during challenge. In addition to improving airway resistance and histopathologic presentation and reducing inflammatory infiltrates, antibody treatment during allergen challenge resulted in a marked relative increase in regulatory T-cell numbers among the CD4 T-cell subset of the challenged lung. Selective interference with CD28-mediated costimulation during allergen exposure might be an attractive therapeutic concept for allergic asthma.