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

Abstract

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 abatacept-treated 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 FEV1, 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 CD4(+) 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 clinical measures of asthma symptoms in people with mild atopic asthma. Clinical trial registered with ClinicalTrials.gov (NCT 00784459).

Trial registration: ClinicalTrials.gov NCT00784459.

Figure 1.

(A) Overview of study design. (B) Disposition of participants evaluated for the study. BAL = bronchoalveolar lavage; IV = intravenous; SAC = segmental allergen challenge.

Figure 2.

The percentage of eosinophils recovered in the bronchoalveolar lavage (BAL) fluid from bronchoscopy performed before and after challenge at the start of the study (before randomization) and again at the end of the intervention period (after randomization). Values shown are the mean ± standard deviation, although for clarity of presentation, the overlapping segments of the error bars have been omitted from the figure. SAC = segmental allergen challenge.

Figure 3.

Bronchoalveolar lavage (BAL) cell counts and cellular differential analysis from participants randomized to either placebo (top) or abatacept (bottom) for the preintervention and postintervention segmental allergen challenge (SAC). (Left) Total number of cells recovered in the BAL. (Right) Change in the percentage of each cell type recovered in the BAL after allergen challenge, calculated by subtracting the preallergen value from the postallergen value (postallergen % cell type − preallergen % cell type). P values were calculated by matched paired t test.