Virus enhances histamine release from human basophils

Histamine release from human basophil leukocytes was triggered byStaph. aureus or by complement activation caused by endotoxins isolated fromE. coli or Salmonella bacteria. Influenza A virus was found to enhance the mediator release and the effects was caused by synergism, since the virus itself did not release histamine. The potentiating effect of the virus was abolished by a potent neuraminidase inhibitor. Furthermore, a purified neuraminidase preparation obtained fromVibrio cholerae caused a similar potentiating effect, which was also abolished by the neuraminidase inhibitor. These findings indicate that the neuraminidase on the surface of influenza A virus is responsible for the potentiating effect of the virus on basophil histamine release.     

Recombinant human interleukin-1 beta causes histamine release from human basophils

Histamine releasing factors (HRFs) have been demonstrated to be secreted by human lymphocytes and monocytes (alveolar macrophages); however, none has been purified to date. Because of the similarity of our HRF to the physical chemical properties of interleukin-1 (IL-1) and tumor necrosis factor (TNF), we have assessed the ability of preparations of IL-1 and TNF to cause basophil histamine release (HR). Human recombinant pro-IL-1 beta, recombinant mature IL-1, and, to a lesser extent, human recombinant TNF caused significant HR from a subpopulation of donor basophils. The pro-IL-1 beta elicited a dose response between 40 and 800 ng/ml; higher concentrations were inhibitory. Approximately 30% of subjects tested are responsive to either mature IL-1 or TNF. These share the same responder subset, but the magnitude of the TNF response is considerably less. A response to the pro-IL-1 was restricted to those subjects with prominent HR to anti-IgE; the response to mature IL-1 and TNF was unrelated to the response to anti-IgE. As in other functional assays, the pro-IL-1 is 50- to 100-fold less potent than mature IL-1, and unlike human HRF, it is highly unstable and rapidly loses activity. Mononuclear cell-derived HRF differs in physicochemical properties from IL-1 or TNF; nevertheless, it appears likely that a variety of cytokines may possess histamine-releasing capability.     

Immunologic histamine release from isolated human basophils during specific immunotherapy

Anti-IgE- and antigen-induced histamine release from basophils isolated from 20 atopic patients sensitive to grass pollen allergens was evaluated. The studies were made before and after short-term immunotherapy with Pollinex. It was shown, that after hyposensitization a significant decrease on anti-IgE and specific antigen-induced histamine release from basophils occurs.This work was supported by the Polish Academy of Sciences (Grant No. 10.5).     

Unique serum requirement for histamine release from human basophils.

Basophil histamine release in a patient with an IgE-mediated seminal plasma allergy had a requirement for serum. Washed leukocytes, in the absence of serum, released little histamine on challenge with seminal plasma antigen. The addition of serum markedly enhanced the release. However, serum had only a mild effect on ragweed antigen induced histamine release from the same cells of this individual. Serum from normal donors was equally effective as autologous serum. Heating the serum and treating it with mercaptoethanol did not destroy this activity. The serum effect was unique in that another patient with seminal plasma allergy did not demonstrate this phenomenon. It is postulated that the effect of the serum is to stabilize the antibody-antigen step at the basophil surface.     

Antigen-induced histamine release from guinea pig basophils

Guinea pig blood was found to contain an average of 106 +/- 21 ng/ml of histamine. Of this total, approximately 85-90% was of platelet origin and the rest from basophils. Basophils contain about 0.72 pg of histamine/cell. Concanavalin A (1-5 microgram/ml) induced the release of approximately 65% of the basophilic histamine. When basophils were isolated from animals sensitized to ovalbumin or keyhole limpet hemocyanin, addition of the appropriate antigen induced histamine release at concentrations of 0.01 microgram/ml or lower. Individual animals were studied over time by repetitive bleeding. The circulating basophils remained sensitized for at least 17 weeks postsensitization. However, release did not occur if animals had been sensitized less than 7 days earlier. This assay facilitates the investigation of basophil sensitization since animals can be studied on several occasions following immunization. The mechanisms, timing and role of basophil sensitization in various types of immune and hypersensitivity reactions can now be evaluated.     

Enhancement of histamine release from human basophils pretreated with different sialidases

Histamine release from human basophils was investigatedin vitro after removal of cell membrane sialic acid by three different sialidases. Pretreatment of the cells with sialidases fromCl. Perfringens, V. Cholera orInfluenza virus A ₂ enhanced histamine release induced by subsequent stimulation of the cells with anti-IgE or the plant lectin Concanavalin A and caused a shift to the left of the dose-response curve for anti-IgE. The enhanced histamine release was reflected in a increased calcium sensitivity, thus suggesting that cell membrane sialic acid might be involved in the calcium fluxes preceeding histamine release. In higher doses the sialidase fromCl. Perfringens caused the cells to release histamine by itself, whereas the sialidases fromV. Cholera andInfluenza virus A ₂ in high does inhibited the cell response to Concanavalin A.     

Concanavalin A induced histamine release from human basophils in vitro.

The site of interaction for concanavalin A (Con-A)-induced histamine release from human basophils was studied in vitro. Blocking the epsilon one determinant (D leads to 1) of IgE with high concentrations of monomer (Fab) anti-Depsilon1 does not significantly inhibit the quantity of histamine released by suboptimum concentrations of Fc specific anti-IgE. This indicates that the monomer anti-Depsilon1 does not have the capacity to sterically hinder the bridging of all of the determinants in the Cepsilon3 and Cepsilon4 domains (Fc'-epsilon-region) of IgE. The monomer anti-Depsilon1 does effectively inhibit release induced by suboptimum concentrations of Con-A. The data indicate that for suboptimum concentrations, Con-A activation is IgE mediated and takes place in the proximity of Depsilon1 and not at the membrane receptor for IgE.     

Role of protein kinase C in histamine release from human basophils

In this study, we investigated the role of calcium and phospholipid-dependent protein kinase (protein kinase C, PKC) in the modulation of histamine release from human basophils. A novel and potent inhibitor of PKC, K-252a, inhibited the release of histamine induced by anti-IgE in a dose-dependent manner with ID50 (the dose required for 50% inhibition of histamine release) of 2.2 x 10(-8) M. Histamine release stimulated with 12-0-tetradecanoyl-phorbol-13-acetate(TPA) was also suppressed by K-252a with maximal inhibition of 48.0 +/- 9.3% at 10(-7) M. In contrast, K-252a did not inhibit the release of histamine in response to FMLP and ionophore A23187. Another inhibitor of PKC, H-7, exhibited a dose-dependent inhibition of anti-IgE-induced histamine release with ID50 of 8.6 x 10(-4) M. H-8 and HA1004, which closely resemble H-7 in chemical structure but are less potent in inhibiting PKC, did not inhibit histamine release stimulated with anti-IgE, but rather enhanced the release at higher concentrations. These results strongly suggest that PKC activation plays a crucial role in the mediation of IgE-mediated histamine release from human basophils.     

Inhibition of histamine release from human basophils in vitro by calmodulin antagonists

Calmodulin is a ubiquitous and versatile Ca2+-binding protein that plays a pivoting role in cellular metabolism. We have investigated the possibility that calmodulin plays a role in immediate hypersensitivity reactions by evaluating the effects of two agents, trifluoperazine dihydrochloride (TFP) and the sulfonamide derivative N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) which selectively bind to calmodulin. TFP and W-7 cause a dose-dependent inhibition of histamine secretion from human basophils in vitro induced by several immunological (i.e., antigen and anti-IgE) and nonimmunological (i.e., formyl-methionine-containing peptide and the Ca2+ ionophore A23187) stimuli. These results indicating that two specific calmodulin antagonists are potent inhibitors of the secretory response of human basophils support the hypothesis that calmodulin may play a role in the control of the release of preformed mediators from human inflammatory cells.     

Enhancement of IgE-mediated histamine release from human basophils by immune-specific lymphokines.

Human leucocytes (basophils) release histamine when exposed to ragweed antigen E or anti-IgE. The present study shows that when leucocytes from BCG-positive donors are first incubated with PPD and then challenged with anti-IgE, histamine release is enhanced. In contrast, when leucocytes from BCG-negative donors are incubated with PPD and then challenged with anti-IgE there is no enhancement of histamine release. The enhancement of histamine release was detected within 24 hr after addition of PPD, but was maximal at 48 to 72 hr. Supernatant fluids collected from these leucocyte cultures revealed the presence of a soluble mediator(s) which, when incubated with leucocytes from BCG-negative donors, enhanced the release of histamine. Examination of the supernatant fluids from BCG-positive leucocyte cultures stimulated with PPD showed a correlation between histamine-release enhancing activity and interferon. Treatment of the culture fluids at pH 2.0 abolished the anti-viral activity, indicating that the interferon was of the type II or ''immune'' class. The same treatment only partly abolished the histamine-release enhancing activity. It is concluded that immune-specific stimulation of leucocytes results in the release of soluble mediators that are capable of enhancing IgE-mediated histamine release.     

Platelet augmentation of IgE-dependent histamine release from human basophils and mast cells

A factor(s) from human platelets enhances IgE-mediated histamine release from human basophils and mast cells. This effect is directly related to the platelet number; at physiological platelet/leukocyte ratios (40:1), the enhancement was 66 +/- 11%. Platelet stimulation by thrombin more than doubled the enhancement, to 172 +/- 10% at 40:1. Mast cell release was also enhanced by platelets although the magnitude was more limited (86 +/- 13% at 40:1 with thrombin). Direct basophil/platelet contact was unnecessary in that platelet supernatants were fully active; a direct platelet factor/basophil interaction is suggested, however, by the fact that basophils purified 100-fold with respect to other leukocytes were enhanced by the platelet factors. The appearance of platelet-enhancing activity is associated with the release of an alpha-granule marker (PF4) rather than with products of arachidonic acid metabolism (thromboxane B2). The platelet factor(s) responsible for these effects are not dialyzable, are heat stable and do not appear to be identical to PF4 or platelet-derived growth factor (PDGF). Since anti-IgE-stimulated basophils cause PF4 release and this correlates with the release of enhancing factor, we suggest that a pro-inflammatory feed forward relationship exists. Together with our previous data showing that platelets are activated in vivo during antigen challenge of allergic asthmatic subjects, these results suggest that platelets may be important in modulating IgE-mediated allergic reactions in man.     

Forskolin inhibits the release of histamine from human basophils and mast cells

We found that forskolin (10^–7 to 3×10^–5 M) caused dose-related inhibition of antigen-induced histamine release from human basophil leukocytes. The dose-response inhibition curve was paralleled by a forskolin-induced increase in cyclic AMP (cAMP) levels in human leukocyte preparations. The kinetics of inhibition of histamine release and of the increase in leukocyte cAMP were the same.In a second series of experiments we evaluated the effect of forskolin on antigen-induced histamine release from chopped human lung passively sensitized with serum from an allergic patient. Forskolin (10^–7 to 3×10^–5 M) dosedependently inhibited the release of histamine from human lung mast cells. Thus forskolin appears to modulate the release of mediators of the immediate hypersensitivity reaction, presumably through activation of adenylate cyclase in human basophils and mast cells.Supported by Grants from the C.N.R. (83.00430.04 and 84.01756.04) and M.P.I. (Rome, Italy).     

Cytokine-induced histamine release from basophils of AIDS patients

Basophil leukocytes obtained from AIDS patients, allergic patients and healthy controls were stimulated in vitro with interleukin 4, lymphotoxin, tumour necrosis factor alpha and interferon gamma to examine the histamine releasing effect. The cytokines caused histamine release from the basophils of approximately half the AIDS patients and from 8-17% of the allergic patients. No response was obtained in the control group. Removal of cell surface immunoglobulins abolished the response to cytokines, indicating an Ig-dependent mechanism. Passive sensitization with cell-derived Ig, with Ig deprived of IgE, or with IgG, indicated that cell-bound IgE was responsible for the cytokine-induced histamine release in AIDS patients. This response may be mediated by cytokine-selective IgE antibodies.     

Cyclosporin A inhibits histamine release from human peripheral basophils and human skin mast cells

Cyclosporin A (CSA) is a strong immunosuppressive substance which is widely used for prevention of transplant rejection. Moreover, this compound is clinically active in different cutaneous inflammatory reactions. In the present study the effects of CSA on mediator release from activated human basophils and isolated human skin mast cells, as important effector cells of such skin diseases, were investigated. CSA exterted a dose-dependent inhibition of the IgE-mediated histamine release from both cell populations. The maximum inhibition was 64.4±9.3% and 85.8±14.2% for basophils and skin mast cells, respectively. Non-immunological histamine release induced by calcium ionophore A23817 was also inhibited. The present data suggest, therefore, that the anti-allergic properties of CSA on basophils and skin mast cells may be partially responsible for the strong anti-inflammatory effects of CSAin vivo.

     

Studies of the mechanism of desensitization of anti-IgE-mediated histamine release from human basophils

Human basophils became hyporesponsive to anti-IgE when exposed to this agent in the absence of Ca²⁺ for more than 10 min. The desensitization process proceeded in parallel to the releasing-process. The mechanism of desensitization seems to involve a very early step in the release-reaction, since the response to phospholipase A₂ and diolein, agents involved in the release-reaction, was not affected by the desensitization.This work was supported by grants from the Swedish Medical Research Council (04X-4498) and the 80 Years Foundation of King Gustaf V.     

Glucocorticosteroids rescue basophils from dasatinib-augmented immunoglobulin e-mediated histamine release

Background: Dasatinib is a multikinase inhibitor active against several tyrosine kinases including ABL, KIT, Lyn and Btk. Apart from its known antileukemic activity, the drug produces several side effects including edemas and pleural effusions, which are supposedly triggered by activated immune cells. Effusion formation can be treated effectively by glucocorticosteroids. We have recently shown that low concentrations of dasatinib (<0.1 μM) promote IgE-dependent secretion of histamine in basophils, especially in allergic individuals. In the current study, we asked whether glucocorticosteroids inhibit dasatinib-induced activation of basophils. Methods: Basophils were preincubated with dexamethasone, prednisolone and hydrocortisone for 24 h, and were then exposed to an anti-IgE antibody (normal basophils) or the allergens Bet v 1 and Phl p 5 (allergic patients) with or without low concentrations of dasatinib (0.025 μM). After incubation, basophils were examined for histamine release and expression of CD63 and CD203c. Results: All three glucocorticosteroids were found to counteract IgE-dependent and dasatinib-enhanced histamine release in basophils in nonallergic and allergic individuals. In addition, glucocorticosteroids were found to inhibit anti-IgE-induced upregulation of CD63 and CD203c in the presence or absence of dasatinib. The inhibitory effects of glucocorticosteroids were dose-dependent (effective range: 1-10 μM) and seen in all donors examined. Conclusions: Glucocorticosteroids rescue IgE receptor cross-linked basophils from additional costimulatory effects of low-dose dasatinib which may have clinical implications in dasatinib-treated patients.