Enhancement of basophil histamine release by a human basophil-like cell promoting activity

A basophil-like cell promoting activity (BaPA) is a lymphokine which has the ability to proliferate metachromatically staining cells in human bone marrow. We studied the effect of BaPA on histamine release from human peripheral basophils. BaPA did not directly induce histamine release from basophils. However BaPA ranging from 0.001 to 0.5 U/ml enhanced histamine release from basophils stimulated with anti-IgE, calcium ionophore A23187 or FMLP in a dose-dependent manner. On the basis of recent observations that in addition to their capacity for proliferating progenitor cells, colony-stimulating factors are capable of regulating functions of end-stage cells of the same lineage, this finding that BaPA is able to modulate a basophil function raises the possibility that BaPA also regulates progenitors of basophils.     

Enhancement of basophil histamine release by interleukin-3: reduced effect in atopic subjects

The inducing and enhancing effects of interleukin-3 (IL-3) on basophil histamine release in patients with respiratory allergy ( n = 28) and in normal subjects ( n = 22) were compared. Leukocyte suspensions, prepared by dextran sedimentation, were stimulated with anti-IgE (1/5000), N-formyl-methionyl-leucyl-phenylalanine (FMLP, 1 μM), and IL-3 (0.1–10 ng/ml), and histamine concentration was measured by an automated fluorometric method. A trend toward higher histamine release after challenge with anti-IgE, FMLP, and IL-3 was found in atopic subjects. Preincubation of basophils with IL-3 resulted in a dose-dependent increase of anti-IgE- and FMLP-induced histamine release, with a more marked effect in nonatopic than in atopic subjects. Mean net enhancement of anti-IgE-induced histamine release by 10 ng/ml IL-3 was 2.5±5% in atopic subjects and 29.6±4.2% in nonatopic subjects ( P < 0.001). The enhancement of FMLP-induced histamine release by IL-3 was 10.3 ±3.9% in atopic patients and 29±2.4% in nonatopic subjects ( P < 0.01). In atopic subjects, a negative correlation was found between anti-IgE- or FMLP-induced histamine release and net enhancement by IL-3 ( r = -0.45, P < 0.02; r = 0.48, P < 0.01, respectively). The results of this study indicate that in atopic subjects IgE-mediated histamine release can scarcely be enhanced by a basophil response modifier such as IL-3. It is conceivable that the frequent basophil stimulation in atopic patients leads to a reduced sensitivity to the enhancing effect of IL-3.     

Regulation of histamine release from human basophil leucocytes: role of H1, H2 and H3 receptors

A novel class of histamine receptors (H3), controlling histamine synthesis and release, was described in rat and human brain and peripheral nerve endings. The present study was undertaken to evaluate whether H3 receptors contribute to the regulation of histamine release from human basophils. Basophil leucocytes were incubated with a H3 antagonist (thioperamide; concentrations ranging from 1 nM to 10 microM) or with a H3 ((R)alpha methyl-histamine; concentrations ranging from 1 to 100 mM), and subsequently were stimulated with optimal doses of anti-IgE and formyl-methionyl-leucyl-phenyl-alanine (f-met peptide). No significant modifications of histamine release were observed after incubation either with the H3 agonist or with the H3 antagonist. By contrast, a H2 antagonist (cimetidine; concentrations ranging from 1 to 100 microM) exerted a dose-dependent enhancing effect on anti-IgE- and, to a lesser extent, on f-met peptide-induced histamine release. A H1 antihistamine (chlorpheniramine; concentrations ranging from 100 nM to 1 microM), at the highest concentration employed, displayed an inhibitory activity on IgE-dependent and IgE-independent histamine release. Exogenous histamine was shown to exert a dose-dependent inhibitory effect on two-staged anti-IgE-induced histamine release. Taken as a whole, these results suggest that H3 receptors are not involved in the regulation of histamine release from human basophils; by contrast, H2 receptors participate in controlling histamine release from human basophils, as previously demonstrated by other authors.     

Comparison of intestinal mast cell and basophil histamine release in children with food allergic reactions

The in vitro histamine release response of human intestinal mast cells and basophils challenged with anti-IgE, Concanavalin A, ionophore A23187 and food extracts was compared with skin prick test, RAST analysis and open food challenge. It was not possible to perform food challenge in all patients; however, seven children underwent open food challenge and in five the clinical diagnosis of "true" food allergy was confirmed. The intestinal mast cells were pooled from enzymatically dispersed duodenal biopsies obtained by duodenoscopy from 15 selected children suspected of food allergy, and five age-matched controls. In nine of 10 patients classified as "food allergic" intestinal mast cells released histamine to various food extracts in a dose-dependent fashion. From the mast cells of the nine food-allergic patients compared with non-allergics, the anti-IgE mediated mast cell histamine release was increased. Additionally, at 1000 U/ml anti-IgE the mast cell histamine release was increased compared with their corresponding basophils. However, in non-allergic subjects the histamine release of basophils was increased compared with their corresponding mast cells. Histamine release from basophils was positively correlated to the test scores of the RAST analysis, skin prick test, and food challenge. No apparent correlation between tests scores obtained from histamine release of intestinal mast cell and the other tests was demonstrated, except in children with diarrhoea as only symptom. However, the study gives evidence that duodenal mast cells actually are sensitized with specific IgE and thus may play a pathophysiological role in food hypersensitivity. In addition, the study shows that the ability of different stimuli, including food extracts, to trigger basophil histamine release does not correlate with their potency to induce histamine release from mast cells.     

Regulation of human basophil activation; the role of Na+ and Ca2+ in IL-3-induced potentiation of IgE-mediated histamine release from human basophils.

The release of mediators from human basophils is strongly enhanced by IL-3. However, the signalling pathways of IL-3 are poorly defined in these cells. Since external Ca2+ and Na+ play important regulating roles in histamine release, the possibility that these cations could be involved in the potentiation by IL-3 of the anti-IgE-induced histamine release from human basophils was considered, and it was observed that: (i) IL-3 dramatically decreased the external Ca2+ requirement for IgE-mediated histamine release. However, histamine release from IL-3-treated basophils became only partially independent of external Ca2+, since addition of EGTA in the external medium abolished the effect of IL-3; (ii) decreasing Na+ influx by lowering external Na+ concentration in isosmotic medium inhibited the potentiating effect of IL-3 on IgE-mediated release; (iii) amiloride, an inhibitor of Na+/Ca2+ and Na+/H+ exchanges, and its derivative, benzamil, more specific for Na+/Ca2+ exchanges, inhibited the release potentiated by IL-3. In contrast, the amiloride derivative 5-(N,N-dimethyl)-amiloride, more specific for Na+/H+ exchanges, slightly increased the IL-3-enhanced release. Thus, the decreased requirement for external Ca2+ and the dependence on external Na+, taken with the effect of the Na+/Ca2+ exchange inhibitors, suggest that Na+/Ca2+ exchanges are involved in the IL-3-induced enhancement of IgE-mediated human basophil histamine release.     

Priming and inducing effects of interleukin-3 on histamine release from cord-blood basophils

The effects of inlerleukin-3 (IL-3) on histamine release from cord and adult blood basophils were evaluated. Leukocyte suspensions, obtained from adult patients with respiratory allergy ( n = 15), normal adult subjects ( n = 15), and neonates with ( n = 15) and without ( n = 19) atopic disposition, were stimulated with anti-IgE, fMLP, and IL-3. IgE-mediated histamine release was significantly higher in adult patients, either allergic or normal, than in neonates with or without atopic disposition. A trend toward higher fMLP-induced histamine release was found in allergic adult subjects. IL-3 had a weak direct histamine-releasing activity in allergic adult subjects and in neonates, but not in normal adult donors. A significant enhancing effect of IL-3 on histamine release induced by anti-IgE was observed in neonates with and without atopic disposition and in normal adult subjects, but not in atopic adult patients. IL-3 exerted a priming effect also when basophils were stimulated with fMLP, without any significant difference between neonates and adult subjects. Passive sensitization with IgE-rich serum resulted in a significant increase in anti-IgE-induced, but not in IL-3–induced, histamine release from cord-blood basophils. In conclusion, IL-3 primes cord-blood as well as adult blood basophils for a consecutive anti-IgE- or fMLP-induced histamine release, and its activity is not limited by the low density of membrane IgE in cord-blood basophils.     

Effect of Terbutaline, a β2-adrenergic Receptor Stimulating Compound, on Cutaneous Responses to Histamine, Allergen, Compound 48/80, and Trypsin

The beta-adrenoceptor stimulating agent terbutaline (2 ng-2 microgram) injected intradermally in eight atopic subjects produced a dose-dependent inhibition of the skin reactions induced by subsequently injected allergen. After injection of 0.5 microgram terbutaline inhibition of the flare and weal responses was demonstrable throughout the observation period of 90 min. The flare response induced by histamine, the histamine liberator compound 48/80 and the proteolytic enzyme trypsin was not inhibited by terbutaline in the doses used, suggesting a selective action of terbutaline on the allergen-induced response. The weal response elicited by histamine and compound 48/80 was slightly reduced by 2 microgram terbutaline. It is suggested that pretreatment of the skin with terbutaline interferes with the ability of the cutaneous mast cells to respond to challenge with allergen and that terbutaline produces this effect in doses lower than those needed to counteract the permeability increasing effect of released mediator substances.     

Validation of basophil histamine release against the autologous serum skin test and outcome of serum-induced basophil histamine release studies in a large population of chronic urticaria patients

BACKGROUND: Endogenous histamine-releasing factors (HRFs) are involved in 30-60% of patients with chronic urticaria (CU). Evidence for their existence comes from in vivo studies of autoreactivity with the autologous serum skin test (ASST), in vitro immunoassays demonstrating autoantibodies against the immunoglobulin E (IgE) or the high affinity IgE receptor (FcepsilonRI) and serum-induced histamine release (HR) from basophils and mast cells. We have examined the correlation between the ASST and a new basophil histamine-releasing assay (the HR-Urtikaria test) in a group of well-characterized CU patients and subsequently determined the frequency of HR-Urticaria-positive sera from a larger population of CU patients. SUBJECTS: Group 1 consisted of 28 patients with CU (16 were ASST-positive) 20 patients with atopic dermatitis, 24 patients with allergy to birch and nine healthy controls. Group 2 consisted of 873 unselected CU patients. METHODS: White blood cells containing 1-2% basophils from a healthy nonatopic donor were incubated with patients sera in the presence of interleukin (IL)-3. Histamine was measured by the glass fibre method. RESULTS: Using the ASST as the true outcome, the HR-Urticaria test showed a sensitivity and specificity of 75% in group 1 using a cut-off value for HR of >16.5%. None of the controls was positive in the HR-Urticaria test. In group 2, we found no difference in the frequency of positives between male (34.6%, n = 254) and female adults (35.1%, n = 576) but twice as many females as males were tested. CONCLUSIONS: Our studies have shown that the HR-Urticaria test has a good sensitivity and specificity for endogenous HRFs demonstrated by the ASST in patients with CU and that about one-third of unselected patients with CU have a positive result.     

Piceatannol is an effective inhibitor of IgE-mediated secretion from human basophils but is neither selective for this receptor nor acts on syk kinase at concentrations where mediator release inhibition occurs

BACKGROUND: Syk kinase is probably an early necessary tyrosine kinase involved in IgE-mediated secretion from human basophils. Causal testing of the role of syk kinase in the secretion requires a selective pharmacological agent. Piceatannol has previously been used to demonstrate the causal role of syk in secretion but its selectively has recently come into question. OBJECTIVE: To determine whether piceatannol inhibits IgE-mediated signalling events in a manner consistent with its putative inhibitory effects on syk kinase and at concentrations relevant to its inhibition of mediator release. METHODS: Human basophils were examined for the effects of piceatannol on mediator release or various signalling steps. RESULTS: We show that while piceatannol has an IC50 for inhibition of IgE-mediated histamine release of 3-5 microm, these same concentrations inhibit secretion of phorbol 12-myristate 13-acetate (PMA)-induced histamine release (as previously shown) and leukotriene C (LTC)4 release induced by fMLP. Concentrations of piceatannol up to 100 microm also did not inhibit IgE-mediated phosphorylation of shc, a immediate downstream target of syk kinase. Similar concentrations also did not inhibit IgE-mediated cytosolic calcium elevations, another downstream signal thought to be dependent on syk kinase. In contrast, piceatannol did modify the cytosolic calcium response that follows stimulation with formyl methionyl-leucyl-phenylalanine (fMLP). CONCLUSION: Taken together with published studies using other cell types, we conclude that piceatannol does not inhibit secretion from human basophils by inhibiting the activity of syk kinase.     

Loratadine and desethoxylcarbonyl-loratadine inhibit the immunological release of mediators from human FcɛRI+cells

Background Loratadine, a novel histamine H₁-receptor antagonist, is effective in the treatment of patients with seasonal and perennial rhinitis and some allergic skin disorders. Histamine and other chemical mediators are synthesized and immunologically released by human peripheral blood basophils and tissue mast cells (Fc?RI⁺ cells). Objective To evaluate the effects of loratadine and its main metabolite, desethoxylcarbonyl-loratadine (des-loratadine), on the immunological release of preformed (histamine and tryptase) and de novo synthesized mediators (leukotriene C₄: LTC₄ and prostaglandin D₂: PGD₂) from human Fc?RI⁺ cells. Methods Human Fc?RI⁺ cells purified from peripheral blood and from skin (HSMC) and lung tissue (HLMC) were preincubated with loratadine and des-loratadine before immunological challenge with Der p 1 antigen or anti-Fc?RI. The release of preformed mediators (histamine and tryptase) and de novo synthesized eicosanoids was evaluated in the supernatants of human FcRI⁺ cells. Results Preincubation (15m in, 37°C) of purified (36–74%) basophils with loratadine (3 × 10^–6–10^–4M) and des-loratadine before Der p 1 antigen or anti-Fc?RI challenge concentration-dependency (5–40%) inhibited the release of histamine and LTC₄. Loratadine (3 × 10^–6–l0^–4M) and des-loratadine also inhibited (10–40%) histamine, LTC₄, and PGD₂ release from purified HLMC (16–68%) activated by anti-Fc?RI. Loratadine (3 × 10^–6–10^–4M) and des-loratadine caused concentration-dependent inhibition (10–40%) of histamine, tryptase. LTC₄, and PGD₂ release from purified HSMC (24– 72%) immunologically challenged with anti-Fc?RI. Conclusion These results indicate that loratadine and its main metabolite have anti- inflammatory activity by inhibiting the release of preformed and de novo synthesized mediators from human Fc?RI⁺ cells.     

Comparison of basophil histamine release, eosinophil cationic protein and non-specific airway responsiveness between mite-sensitive asthmatic and non-asthmatic children and non-allergic controls

To understand the relevance of allergy to the development of asthma in children, we examined basophil hislamine release (HR) with Df antigen, blood cosinophii counts, serum eosinophil cationic protein (ECP) levels, and bronchial responsiveness to methacholine (PC₂₀) in three groups of children, including 36 asthmatics with high RAST titre for Df (group 1), 36 non-asthmatics with similarly high RAST titre for Df (group 2) and 21 non-asthmatics with negative RAST titre for Df (group 3). The amount of Df antigen inducing 50% HR from basophils did not vary significantly between group 1 and 2 (P>0.05), while none of the cells responded to higher concentrations of Df in group 3. The mean number of blood eosinophils and level of serum ECP were highest in group 1, and lowest in group 3, with group 2 being intermediate, and the differences were significant between all three groups (P<0.01). The mean PC₂₀ value was the lowest in group 1, intermediate in group 2, and the highest in group 3, and the differences were significant between all three groups (P<0.01). While correlation studies showed that PC₂₀ values of group 2 subjects signficantly correlated with their eosinophil numbers (r=–0.48, P<0.01) and ECP levels (r =–0.49, P < 0.01), such correlations were not found in group 1 subjects. These results suggest that the degree of the eosinophilic inflammation caused by the allergic reaction to mites is an important factor in determining the clinical expression of asthma in atopic subjects.     

Inhibition of anti-IgE induced skin responsein normals by formoterol, a new β2-adrenoceptor agonist, and terbutaline

Formoterol, a new beta 2-selective long-acting bronchodilator, was compared with terbutaline in terms of ability to inhibit dual phase skin reactions to anti-human IgE in volunteers. Anti-IgE induced an early wheal and flare reaction (WFR) followed by a progressively increasing induration, the late phase reaction (LCR), lasting greater than or equal to 24 h. Intradermal injection of formoterol 20 ng or terbutaline 500 ng 5 min before challenge gave equal inhibition of the WFR. The subsequent LCR was suppressed by formoterol (30%) for the whole 24 h period, while terbutaline only attenuated the first 4 h period. Increasing the dose range of both drugs 25-fold, caused a further analogous reduction of the WFR to anti-IgE. In this higher dose range formoterol (0.5 micrograms) antagonized the following 1-24 h LCR by 50%, while terbutaline (25 micrograms) only attenuated the LCR by an average of 20%, with higher effect in the first 6 h period. The anti-LCR capacity of formoterol was highly superior to that of terbutaline (P less than 0.001). The histamine-elicited wheal response was attenuated by both drugs, but they had no effect on the flare response, favouring an anti-permeability action of both compounds. The data support the concept that terbutaline, given locally in a single dose shortly before challenge, inhibits the mast cell mediator release reaction with limited consequences for the following LCR. In contrast to terbutaline, formoterol exerted a substantial anti-LCR action, probably by interfering with inflammatory mechanisms after the initial mast cell mediator release.     

Relevance of Ara h1, Ara h2 and Ara h3 in peanut-allergic patients, as determined by immunoglobulin E Western blotting, basophil–histamine release and intracutaneous testing: Ara h2 is the most important peanut allergen

BACKGROUND: A number of allergenic proteins in peanut has been described and the relative importance of these allergens is yet to be determined. OBJECTIVES: We have investigated the relevance of previously identified peanut allergens in well-characterized peanut-allergic patients by in vitro, ex vivo and in vivo assays. METHODS: Thirty-two adult peanut-allergic patients were included based on careful and standardized patient history and the presence of peanut-specific IgE. The diagnosis peanut allergy was confirmed using double-blind placebo-controlled food challenges in 23 patients. Major peanut allergens Ara h1, Ara h2 and Ara h3 were purified from peanuts using ion-exchange chromatography. IgE immunoblotting was performed and IgE-cross-linking capacity was examined by measuring histamine release (HR) after incubating patient basophils as well as passively sensitized basophils with several dilutions of the allergens. Intracutaneous tests (ICTs) using 10-fold dilution steps of the purified allergens and crude peanut extract were performed. RESULTS: Ara h2 was recognized most frequently (26 out of 32) in all tests and induced both positive skin tests and basophil degranulation at low concentrations, whereas Ara h1 and Ara h3 were recognized less frequently and reacted only at 100-fold higher concentrations as analysed with HR and intracutaneous testing (ICT). Next to the three tested allergens, proteins with molecular weights of somewhat smaller than 15 kDa were identified as a IgE-binding proteins on immunoblot in the majority of the patients (20 out of 32). CONCLUSION: We conclude that Ara h2 is, for our patient group, the most important peanut allergen, and that previously unidentified peanut proteins with molecular weights of somewhat smaller than 15 kDa may be important allergens as well. ICT in combination with basophil-HR and IgE immunoblotting provides insight in the patient specificity towards the individual peanut allergens.     

Localization and function of histamine H3 receptor in the nasal mucosa

Background Histamine is an important chemical mediator of allergic rhinitis (AR). Histamine H₃ receptors (H₃R) are located on cholinergic and NANC neurons of the myenteric plexus, and activation of H₃R regulates gastric acid secretion. However, little is known about the localization and function of H₃R in the upper airway.
Objective The objective of this study was to examine the localization and possible function of H₃R in the nasal mucosa.
Methods We extracted total RNA from the inferior turbinate mucosa of patients with AR. H₃R mRNA and β-actin mRNA were amplified by RT-PCR. We used immunohistochemistry to examine localization of H₃R protein in the inferior turbinate mucosa excised during clinically indicated surgery. We used alcian blue/periodic acid-shiff staining to examine the effects of the H₃R agonist (R)-α-methylhistamine and the H₃R antagonist thioperamide on secretion from rat submucosal glands.
Results H₃R protein was expressed around submucosal gland cells. Thioperamide induced degranulation in the submucosal gland in the nasal septum.
Conclusion The present results suggest that H₃R is localized mainly around submucosal glands, and that H₃R plays an important role in the secretion of submucosal glands in the nose.     

A double-blind placebo-controlled birch allergy vaccination study II: correlation between inhibition of IgE binding, histamine release and facilitated allergen presentation

Background The pathogenesis of IgE‐mediated allergic disease is closely related to the production of T‐helper type 2 (Th2) cytokines, which lead to IgE production pivotal for activation of mast cells and basophils. Proliferating T cells along with eosinophils expanded and attracted by Th2 cytokines are major contributors to the late‐phase reaction. The activation of these Th2 cells is strongly enhanced by CD23‐mediated IgE facilitated allergen presentation (FAP). Objective The present study aims to investigate the effect of specific immunotherapy (SIT)‐induced allergen‐specific non‐IgE antibodies (blocking antibodies) on IgE binding to allergen, histamine release (HR) and CD23‐mediated allergen uptake in antigen‐presenting cells. Methods Competition between IgE and non‐IgE for allergen binding was studied by Advia Centaur antibody measurements, passively sensitized basophils were used to study HR and IgE‐facilitated binding of allergen to B cells (FAP) was studied by flow cytometry. FAP measurements were performed both with and without the addition of a reference IgE serum, which was included to obtain optimal complex formation. The serum samples were obtained from birch pollen immunotherapy (n=21) or placebo control patients (n=21) before and after 1 and 2 years of treatment. Results Statistically significant reduction of all parameters investigated was observed after 1 year of treatment and the effect was maintained during the second year of treatment. There was a clear correlation between the two FAP measurements and between each of them and the level of T cell activation reported upon previously. Moreover, strong correlations were found between changes in FAP, IgE binding and HR. Conclusion The present study clearly demonstrates that SIT induces changes in the composition of serum antibodies that inhibit IgE binding, HR and FAP to a similar extent. This suggests that these measurements, individually or in combination, may be used to monitor the immunological effect of SIT, even though direct correlations to changes in clinical parameters could not be demonstrated.     

Inhibition of anti-IgE induced skin response in normals by formoterol, a new β2 adrenoceptor agonist, and terbutaline

The intention of the present study was to compare formoterol and terbutaline regarding ability to inhibit immediate wheal and flare responses (WFR) to anti-human IgE with focus on the duration of anti-WFR action. Formoterol is a novel beta 2-adrenergic agonist with a prolonged duration of bronchodilation capacity after inhalation. The drugs injected intradermally 2 min prior to challenge with anti-IgE in volunteers produced a dose-dependent inhibition of the WFR in the range 1pg-100ng (formoterol) and 1ng-1 microgram (terbutaline). Formoterol was 70 times (flare) and 25 times (wheal) more potent (ID40) than terbutaline on a weight basis. The duration of the anti-WFR action for formoterol, injected in a 25 times lower dose than terbutaline, was significantly longer, namely greater than 24 h versus 8 h for terbutaline. The histamine-induced wheal reaction was attenuated by 15% and 25% by terbutaline and formoterol, respectively. The results indicate a higher beta 2-receptor activity for formoterol with respect to inhibition of IgE-dependent mast cell mediator release in addition to an anti-leak effect exerted by both drugs. The prolonged duration of antagonistic effect by formoterol on the WFR to anti-IgE might be due to the lipophilic property of the drug, with an expected higher retention of formoterol at the target tissue compared with the more hydrophilic compound terbutaline.     

Relationships between Responsiveness of the Bronchi to Acetylcholine and Cyclic AMP Response of Lymphocytes to Beta1- and Beta2-Adrenergic Receptor Stimulation in Patients with Asthma

Decreased response of beta-adrenergic receptor has been considered to he one of the causes of increased responsiveness of the bronchi in asthma. Since beta-adrenergic receptor has two subtypes, beta₁ and beta₂, and the bronchodilating effect of beta stimulants is mediated by beta₂-receptor, responsiveness of the bronchi is expected to correlate to the cyclic AMP response of lymphocytes to a beta₂-stimulant. Responsiveness of the bronchi was expressed as respiratory threshold to acetylcholine (RT-Ach), which was the minimal concentration of acetylcholine solution to cause an initial decrease of FEV₁ of more than 20% of the baseline value. Beta₁ and heta₂-responses were expressed as the increments of cyclic AMP content of 10⁶ lymphocytes incubated with norepinephrine (beta₁-stimulant) and salbutamol (beta₂-stimulant).
RT-Ach showed a significant correlation with the beta₂-cyclic AMP response of lymphocytes, but not with the beta₁ -response among patients with asthma. Sixteen symptomatic patients on continuous beta-stimulants showed lower RT-Ach value and diminished beta₂-receptor activity of lymphocytes compared with 14 patients in remission. These results suggest that selective beta₂-adrenergic blockade may he one of the causes of bronchial hypersensitivity in asthma, though it should be noted that in this study beta-adrenergic responses were examined in lymphocytes and were compared with the responsiveneness of the bronchi. Possible beta-receptor subsensitivity induced by administration of beta-stimulants is discussed.     

In vitro effects of H1-antihistamines on histamine and PGD2 release from mast cells of human lung, tonsil, and skin

Mast cells from different anatomic sites differ in cytochemistry and response to various secretory stimuli. We have investigated whether responsiveness to the second-generation H₁-receptor antagonists, which are important first-line drugs for the relief of symptoms in patients with chronic urticaria and allergic rhinoconjunctivitis, also differs according to the site of origin of mast cells. The effects of terfenadine, ketotifen, and cetirizine were therefore examined in relation to the IgE-dependent release of histamine and prostaglandin D₂ (PGD₂) from dispersed human lung, tonsil, and skin mast cells. Terfenadine had a biphasic effect on lung and skin mast cells: at low concentrations, a concentration-dependent inhibition of histamine release from lung and skin mast cells was observed, whereas at higher concentrations the drug stimulated mediator release. Even at a high concentration, terfenadine inhibited mediator release from tonsil mast cells. Ketotifen had low potency as an inhibitor of mediator release from lung and tonsil mast cells. In skin mast cells, no inhibition of mediator release was observed below 1.0 μM, and above that concentration it induced mediator release. Cetirizine, a much less lipophilic drug than the others tested, did not induce mediator release from mast cells even at concentrations up to 100 μM. This drug showed concentration-dependent inhibition of IgE-dependent mediator release from lung and tonsil mast cells only. Our results show that human mast cells are heterogeneous with respect to modulation of mediator release by these H₁-antihistamines. In particular, differences were observed between skin mast cells and those dispersed from lung and tonsils.