The effect of terfenadine on histamine release from human basophils and LTC4 production and release from human eosinophils was evaluated. Eosinophils and basophils were obtained by discontinuous gradient centrifugation of the peripheral blood of atopic asthma patients who were off medication. Anti-IgE-induced histamine release from human basophils was significantly inhibited by terfenadine. Maximum inhibition was obtained at 1 x 10(-5) M terfenadine (percentage inhibition = 57.0 +/- 20.1; P less than 0.05). However, only the highest dose of terfenadine used in this study, i.e. 2 x 10(-5) M, significantly inhibited calcium ionophore (A23187)-induced histamine release from human basophils (percentage inhibition = 40.0 +/- 14.6; P less than 0.05), and LTC4 production from human eosinophils (percentage inhibition = 59.8 +/- 9.9; P less than 0.05. These findings demonstrate that terfenadine, in addition to its known antihistamine property, also has an inhibitory effect on chemical mediator release.

Eosinophils play a major role in the pathogenesis of bronchial asthma. In this study, we examined the density characteristics of blood eosinophils from 9 normal healthy individuals and 9 allergic asthmatic patients. Furthermore, the effect of platelet-activating factor, a potent mediator of inflammation, and calcium ionophore, A23187, on the density of normodense eosinophils (density > 1.085 g/ml) has also been examined. Initially, asthmatic patients had 27.0 +/- 1.1% eosinophils of lighter density (density < or = 1.081 g/ml), significantly greater than that in the normal individuals (7.5 +/- 0.5%). After exposure to platelet-activating factor (1 microM) or calcium ionophore (A23187, 1 microgram/ml), the normodense eosinophils switched to hypodense in both groups: 16.7 +/- 2.1% and 54.2 +/- 3.7%, respectively, in normal individuals, and 30.6 +/- 5.7% and 77.4 +/- 2.3%, respectively, in asthmatic patients. These data demonstrated that a certain percentage of normodense eosinophils from asthmatics and normal subjects switched to hypodense after activation with platelet-activating factor or calcium ionophore. Furthermore, eosinophils from asthmatics switched to a greater degree than in normal subjects, suggesting that the normodense eosinophils in asthmatics become primed probably by endogenously released mediators.

We have examined the potential of IL-3, IL-5, and granulocyte-macrophage (GM)-CSF to enhance basophil activation by eosinophil granule major basic protein (MBP). Preincubating basophil-containing mononuclear cells with 0.01 to 10 ng/ml IL-3 or IL-5 for 15 min at 37 degrees C caused a concentration-dependent enhancement of histamine release stimulated by 1.5 microM MBP. Statistically significant enhancement was evident at 1 ng/ml and was maximal at 10 ng/ml. Preincubation with GM-CSF similarly enhanced MBP-induced histamine release. A 10- to 15-min preincubation with IL-5 maximally increased the level of MBP-stimulated histamine release. Preincubation of cells with 10 ng/ml IL-3 or IL-5 reduced the MBP concentrations required for histamine release by three- to fourfold and enhanced the rate of MBP-induced histamine release. MBP-stimulated histamine release before or after cytokine priming was independent of cytotoxicity as measured by 51Cr release. Consistent with a direct action of the cytokines on basophils, flow cytometric analysis demonstrated the presence of IL-3 and GM-CSF receptors on basophils. MBP also stimulated low levels of leukotriene C4 (LTC4) release from basophils of 84 to 99% purity, and experiments using enriched (18-63%) basophil preparations demonstrated that preincubation with IL-3, IL-5, and GM-CSF also potentiated MBP-stimulated leukotriene C4 release up to threefold in parallel with histamine release. These results indicate that IL-3, IL-5, and GM-CSF may contribute to the pathogenesis of allergic and other disorders characterized by eosinophilia in part through potentiation of basophil mediator release stimulated by MBP.

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