In their recent article, Twiss et al. clearly indicate that calcium channel blockers are not clinically effective as maintenance therapy for persistent asthma . Their hypothesis was that the results of broncoprovocation studies could be used to predict whether two calcium channel blockers, nifedipine and diltiazem, or which of them would be clinical effective to suppress the signs and symptoms of persistent asthma. Previous studies demonstrated nifedipine efficacy in broncoprovocation studies [2, 3] while diltiazem was consistently ineffective , so that the authors were not surprised by the results for diltiazem.
Herein we present experimental evidence that might explain the results obtained in clinical studies. We have published that diltiazem, in vitro, affects the maturation of monocyte-derived dendritic cells by reducing their interleukin(IL)-12 production and, consequently, by preventing T helper(Th)1 polarization . More recently, we extended our study by analysing Th2 cytokine production. Figure 1 shows that human naïve T lymphocytes, after incubation with dendritic cells pretreated with a high dose of diltiazem (10−4m), produce a lower amount of interferon-γ (produced by Th1 lymphocytes), and, very interestingly, a higher level of IL-5. No change of the level of IL-4 and IL-10 was observed. IL-5 is produced by T cells that belong to the Th2 but not the Th1 subset. By virtue of the pattern of cytokines that they synthesize, Th2 cells are thought to control the growth and effector function of those cell types that are involved in allergic inflammatory responses . In fact, IL-5 is responsible for the maturation of eosinophils in the bone marrow and for their release into the blood. It may also be important for the recruitment of eosinophils from blood vessels into tissues. In humans, IL-5 is a very selected cytokine as a result of the restricted expression of its receptor on eosinophils and basophils. Several allergic diseases, first of all asthma, have prominent inflammatory components that are characterized by pronounced eosinophilic infiltration. Eosinophils are therefore an ideal target for selectively inhibiting the tissue damage that characterizes allergic disease.
Several studies demonstrated a correlation among the activation of T lymphocytes, increased concentration of IL-5 in serum and broncoalveolar lavage (BAL) fluid, and increased severity of the asthmatic response [7, 8]. In particular, Robinson et al. found a strong correlation among the number of BAL cells that expressed mRNA for IL-5, the magnitude of baseline airflow obstruction and brochoconstrictor reactivity to methacholine. For this reason, humanized antibodies against IL-5 are now tested in clinical studies in asthmatic patients .
From the above observation, our evidence that diltiazem is able to up-regulate IL-5 production by T cells may substantiate the clinical effect observed by Twiss et al. Therefore, our results might contribute to discourage the clinical use of diltiazem in attenuating airway responsiveness in asthmatic patients.