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Calcium Channel Blocker Prevents T Helper Type 2 Cell–mediated Airway Inflammation

¹ INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; ² Université Toulouse III Paul Sabatier, Toulouse, France; ³ CNRS UMR 5547, Centre de Biologie du Développement GDR 2688, Toulouse, France; and ⁴ Groupement de Recherche (GDR) 2688, Toulouse, France

Correspondence and requests for reprints should be addressed to Lucette Pelletier, M.D., Ph.D., INSERM, U563, CHU Purpan, Place du Dr Baylac, 31024 Toulouse Cedex 3, France. E-mail: lucette.pelletier{at}toulouse.inserm.fr

Rationale: Ca²⁺ signaling controls the production of T helper (Th) type 2 cytokines known to be deleterious in asthma. Recently, we showed that Ca²⁺ signaling was dihydropyridine (DHP)-sensitive in Th2 lymphocytes and that the DHP derivate, nicardipine, used in the treatment of cardiovascular pathologies, prevents Th2-dependent B cell polyclonal activation.

Objectives: We tested the effect of nicardipine in experimental allergic asthma.

Methods: BALB/c mice immunized with ovalbumin (OVA) in alum and challenged with intranasal OVA were treated with nicardipine once the Th2 response, or even airway inflammation, was induced. We also tested the effect of nicardipine in asthma induced by transferring OVA-specific Th2 cells in BALB/c mice exposed to intranasal OVA. We checked the impact of nicardipine on T-cell responses and airway inflammation.

Measurements and Main Results: Nicardipine inhibited in vitro Ca²⁺ response in Th2 cells. In vivo, it impeded the development of Th2-mediated airway inflammation and reduced the capacity of lymphocytes from lung-draining lymph nodes to secrete Th2, but not Th1, cytokines. Nicardipine did not affect antigen presentation to CD4⁺ T lymphocytes, nor the initial localization of Th2 cells into the lungs of mice exposed to intranasal OVA; however, it reduced the production of type 2 cytokines and the amplification of the Th2 response in mice with asthma. Conversely, nicardipine had no effect on Th1-mediated airway inflammation.

Conclusions: Nicardipine improves experimental asthma by impairing Th2-dependent inflammation. This study could provide a rationale for developing drugs selectively targeting DHP receptors of Th2 lymphocytes, potentially beneficial in the treatment of asthma.

Key Words: calcium signaling • IL-4 • nicardipine

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Nicardipine is a calcium channel blocker considered as potentially effective in asthma due to its expected effect on smooth muscle. What This Study Adds to the Field Nicardipine selectively impaired Ca2+ signaling in Th2 lymphocytes and prevented experimental asthma. The fact that nicardipine selectively inhibits Ca2+-dependent production of cytokines IL-4, IL-5, and IL-13, all of which contribute to the development of asthma, offers a rationale for developing drugs targeting Ca2+ signaling in Th2 effectors.

 

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