Person:

Katz, Howard

BACKGROUND: Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of- principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyper- responsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma. METHODS: We conducted a randomized, double-blind, placebo-controlled, 24-week trial of ima- tinib in patients with poorly controlled severe asthma who had airway hyperrespon- siveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of metha- choline required to decrease the forced expiratory volume in 1 second by 20% (PC20 ). Patients also underwent bronchoscopy. RESULTS: Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P=0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activa- tion, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P=0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group. CONCLUSIONS: In patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast- cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694.)

Background: Prostaglandin D2 (PGD2) is the dominant cyclooxygenase product of mast cells and is an effector of aspirin-induced respiratory reactions in aspirin-exacerbated respiratory disease (AERD). Objective: We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in AERD. Methods: Urinary eicosanoids were measured in aspirin-tolerant controls and patients with AERD. Nasal polyp specimens from subjects with AERD and chronic rhinosinusitis were analyzed via qPCR, western blot, and immunohistochemistry. Human cord blood-derived and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation. Results: Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in subjects with AERD relative to controls, and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function, and with increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hPGDS) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hPGDS (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r=0.74). The cleaved, active form of TSLP was increased in AERD nasal polyps relative to aspirin-tolerant controls. Recombinant TSLP induced PGD2 generation by cultured human mast cells. Conclusions: Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP, and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.