A randomized controlled trial to evaluate inhibition of T-cell costimulation in allergen-induced airway inflammation

Rationale: T lymphocytes are important in the pathogenesis of allergic asthma. Costimulation through CD28 is critical for optimal activation of T cells, and inhibition of this pathway with CTLA4Ig has been shown to be effective in preventing airway inflammation and hyperresponsiveness in animal models of asthma. Abatacept, a humanized version of CTLA4Ig, has been approved for treatment of rheumatoid arthritis, providing the opportunity to test whether inhibition of costimulation is an effective strategy to treat people with asthma. Objectives: To determine if 3 months of treatment with abatacept reduced allergen-induced airway inflammation in people with mild atopic asthma. Methods: Randomized, placebo-controlled, double-blinded study. Bronchoscopically directed segmental allergen challenge was performed on 24 subjects followed by bronchoalveolar lavage 48 hours later. Subjects were randomized 1:1 to receive abatacept or placebo, followed by a second allergen challenge protocol after 3 months of study drug. Measurements and Main Results: There was no significant reduction in allergen-induced eosinophilic inflammation in the abatacepttreated group compared with placebo (17.71% ± 17.25% vs. 46.39% ± 29.21%; P = 0.26). In addition, we did not detect an effect of abatacept on FEV ₁, provocative concentration of methacholine sufficient to induce a 20% decline in FEV₁, or asthma symptoms. Subjects treated with abatacept had an increased percentage of naive and a corresponding decrease in memory CD4₁ T cells in the blood compared with placebo. Conclusions: Inhibition of CD28-mediated costimulation with abatacept does not seem to alter the inflammatory response to segmental allergen challenge or clinicalmeasures of asthma symptoms in people with mild atopic asthma.