Inhibition Of Antigen-induced Histamine Release Research Articles

Effects of a newly synthesized leukotriene antagonist, NZ-107, on immediate-type hypersensitivity reaction in rats and guinea-pigs

The effects of 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone (NZ-107) on immediate type hypersensitivity reactions in rats and guinea-pigs were studied. 1. 1. When NZ-107, at a dose of 50 mg/kg (i.p.) or 100 mg/kg (orally), was administered to rats, 48-h homologous passive cutaneous anaphylaxis (PCA) reaction and histamine-, leukotriene C 4 (LTC 4)- and leukotriene D 4 (LTD 4)-induced skin reactions were suppressed by the agent. 2. 2. NZ-107 (10 −6 g/ml) inhibited both LTC 4- and LTD 4-induced contractions of isolated rat stomach smooth muscle. 3. 3. NZ-107 inhibited antigen-induced histamine release from rat peritoneal mast cells by 26% at a concentration of 10 −4 g/ml. 4. 4. NZ-107, at doses of 25 and 50 mg/kg (orally), significantly inhibited guinea-pig 3-h heterologous PCA reaction. 5. 5. NZ-107 inhibited antigen-induced histamine release from guinea-pig lung tissue by 17% and 48% at concentrations of 5 × 10 −5 and 10 −4 g/ml, respectively. 6. 6. NZ-107, at doses of 25 and 50 mg/kg (i.p.), inhibited antigen-induced bronchoconstriction and eosinophil accumulation in the bronchoalveolar lavage fluid (BALF) of guinea-pigs. These results suggest that NZ-107 has anti-allergic action including inhibition of eosinophil accumulation in an antigen-challenged airway lesion in rats and guinea-pigs. The anti-allergic action of this agent is thought to be due to its action as a histamine and LT antagonist and its consequent inhibition of antigen-induced histamine release.

Blocking of passive sensitization of human mast cells and basophil granulocytes with IgE antibodies by a recombinant human epsilon-chain fragment of 76 amino acids.

The recombinant peptide corresponding to residues 301-376 at the junction of constant regions 2 and 3 of the human IgE epsilon chain blocked the in vivo passive sensitization of human skin mast cells and in vitro sensitization of human basophil granulocytes with human IgE antibodies. An injection of the recombinant peptide or E myeloma protein into normal skin sites 1 hr before sensitization with an allergic serum blocked passive sensitization. In this system, approximately 10-fold higher molar concentration of the recombinant peptide than E myeloma protein was required for 50% inhibition of Prausnitz-Küstner reactions. When the mononuclear cells of two normal individuals were preincubated with the recombinant peptide or E myeloma protein for 15 min before passive sensitization with the same allergic serum and the cells were challenged with an optimal concentration of an antigen, approximately 11- to 13-fold higher concentration of the recombinant peptide than E myeloma protein was required for 50% inhibition of antigen-induced histamine release. Further studies with several recombinant peptides indicated that amino acid resides 363-376 in the Fc epsilon-chain fragment are not essential for binding of the peptide to Fc epsilon-chain receptor I.

A review of in-vitro assays for IgG and IgG4 antibodies: concept and potential applications.

In-vitro assays for the diagnosis of allergy presently are quite common, having been demonstrated by a number of investigators to possess a high degree of specificity and sensitivity. These assays are for the most part rapid, flexible, and when utilized properly, cost effective. It has long been known that antibodies, other than the homocytotropic antibodies, are involved in allergy. The concept of "blocking antibodies" was first introduced by Cooke in 1935. He demonstrated that these antibodies could neutralize the effects of reagins present in the sera of allergic individuals. Since that time investigators have developed a series of techniques to assess and define blocking antibodies. These techniques include inhibition of antigen-induced histamine release from peripheral blood leukocytes, hemagglutination with allergen coated erythrocytes, radio-allergo-sorbent test (RAST), define antigen substrate sphere (DASS), antigen binding radioimmuno assay, and more recently, enzyme-linked immunosorbent assays (ELISA). These methods have been utilized to show that "blocking antibodies" are predominantly of the IgG class. Recently, several assays have been introduced to the clinical laboratory for the purpose of monitoring the production of blocking antibodies (i.e., IgG) in response to immunotherapy. These assays, while adding an important tool to the arsenal of the clinical practitioner, may have limited utility because of a lack of specificity and sensitivity. Recently, 3M Diagnostic Systems (3MDS) has introduced an assay via its Reference Laboratory designed for the measurement of what many investigators feel is the appropriate marker for monitoring immunotherapy . . . the IgG4 subclass.(ABSTRACT TRUNCATED AT 250 WORDS)

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

We found that forskolin (10(-7) to 3 X 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 X 10(-5) M) dose-dependently 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.

Immunologic release of histamine from dog lung: Comparison of in vivo and in vitro responses in the same animal

The purpose of this study was 10 compare, for the first time, antigen-induced histamine release from the lung in the same natively allergic dogs both in vitro and in vivo. In six dogs, maximal antigen-induced histamine release from the lung correlated closely in vitro and in vivo (r = 0.94), although it varied widely between dogs (0% to 75.5% of total tissue histamine content); similarly, the antigen concentration to produce 50% of maximal histamine release varied sixfold between dogs (40 μg/ml to 250 μg/ml). In each of five other dogs, terbutaline sulfate administered intravenously caused a dose-dependent inhibition of antigen-induced histamine release from lung fragments in vitro: the maximal inhibition produced by 1 mg/kg was 60 ± 4.5% (mean ± SEM). In these same dogs, 10 − 3 M terbutaline incubated with lung fragments in vitro caused inhibition of antigen-induced histamine release comparable to 1 mg/kg terbutaline in vivo. Increasing the dose of terbutaline in vitro produced maximal inhibition at 10 − 4 M with no greater effect of the drug at 10 − 3 M (71.4 ± 3.8% inhibition). In both experimental situations propranolol caused a dose-dependent inhibition of β-adrenergic modulation of Ascaris-induced release of histamine. This result supports the conclusion that terbutaline produced its effects by actions mediated by β-adrenergic receptors on pulmonary mast cells. This experimental approach provides a suitable preparation in which to estimate the effective dose of agonists that modulate antigen-induced mast cell function in vivo.

Biochemical analysis of glucocorticoid-induced inhibition of IgE-mediated histamine release from mouse mast cells.

Pretreatment of mouse mast cells with 10(-7) to 10(-6) M dexamethasone (DM) during overnight sensitization with mouse IgE antibody resulted in inhibition of antigen-induced histamine release and degranulation. The inhibition of both degranulation and histamine release increased linearly with the duration of the treatment; maximal inhibition was obtained after approximately 16 hr with DM. The addition of DM to sensitized mast cells immediately before antigen challenge did not affect the antigen-induced histamine release. DM interacted directly with mast cells by binding to DM-specific cytoplasmic receptors. The treatment of mast cells with DM did not affect the binding of IgE to mast cells or intracellular cAMP levels. Bridging of cell-bound IgE anti-DNP antibody on mouse mast cells either by multivalent DNP-HSA or by anti-IgE induced phospholipid methylation at the plasma membrane and Ca++ influx into the cells. Pretreatment of mast cells with DM inhibited the antigen-induced phospholipid methylation and Ca++ uptake but failed to affect histamine release by Ca++ ionophore A23187. The results suggest that DM treatment inhibits histamine release by the inhibition of the early stage of biochemical processes leading to opening Ca++ channels but does not affect the process distal to Ca++ influx or the binding of IgE molecules to IgE receptors.

Effects of flavonoids and transitional metal cations on antigen-induced histamine release from human basophils

Structure-activity relationship studies have been performed on the inhibition of antigen-induced histamine release from human basophils by various naturally occurring flavonoids. Quercetin was the most active compound. Of the transitional metal ions, Cu2+ most effectively blocked the inhibitory activity of quercetin, possibly through a chelation mechanism.

Inhibition of antigen-induced histamine release from rat mast cells by a cyclic GMP-phosphodiesterase inhibitor and sodium nitrite.

Antianaphylactic properties have been attributed to cyclic nucleotide phosphodiesterase inhibitors through increase of cyclic AMP levels, according to the concept that increases in cyclic AMP reduce release and increases in cyclic GMP enhance release. However, Coulson et al. [3] showed that the inhibition of histamine release from human lung is correlated to the inhibition of cyclic GMP hydrolysis. We studied the effect of specific inhibitors of cyclic AMP and cyclic GMP hydrolysis on the antigen-induced mediator release from rat mass cells and human basophils and on airways relaxation [4]. The results suggested that the modulation of mediator release was different from one cell type to the other, enhancement of cyclic AMP levels leading to the inhibition of release from basophils, while cyclic GMP appears to be predominantly involved in mast cells. The present paper shows that high concentrations of sodium nitrite, a stimulating agent of guanylate cyclase, inhibit histamine release from rat mast cells in the presence or absence of M&B 22948, a selective cyclic GMP phosphodiesterase inhibitor.

Inhibition of antigen-induced histamine release and thromboxane synthase by FPL 55712, a specific SRA-A antagonist?

Inhibition of antigen-induced histamine release and thromboxane synthase by FPL 55712, a specific SRA-A antagonist?

Effect of synthetic cyclic nucleotides on immunologic histamine release from calf granulocytes.

Sensitized bovine granulocytes release histamine when exposed to specific antigens. A unique modulation of histamine release by adrenergic agents has been shown in the bovine; beta-adrenergic agonists enhance and alpha-adrenergic agonists inhibit histamine release. This is an opposite response to that reported in other species. The present study was undertaken to determine the possible relationship between cyclic nucleotides and adrenergic agents in this species. Dibutyryl cAMP enhanced antigen-induced histamine release over the complete concentration range tested (10(-6)--10(-3)M); it also overcame, in a dose-dependent manner, the inhibition of antigen-induced histamine release produced by 10(-4) M phenylephrine. The 8-bromo cGMP AND 0-MONOBUTYRYL CGMP had no significant effect on antigen-induced histamine release nor did 8-bromo-cGMP have any significant effect on the enhancement of histamine release produced by 10(-4) M dibutyryl cAMP. These findings suggest that only cAMP has a role in the modulation of antigen-induced histamine release from bovine granulocytes.

Effects of Arachidonic Acid and Its Metabolites on Antigen-Induced Histamine Release from Human Basophils in Vitro

Abstract We have studied the role of arachidonic acid (AA) metabolism in immediate hypersensitivity reactions. The AA analog, eicosa-5,8,11,14-tetraynoic acid (ETYA), which inhibits both the cyclo-oxygenase and lipoxygenase pathways of AA metabolism, was found to cause a dose-dependent inhibition of antigen-induced histamine release from human basophils; complete inhibition occurred at 10-4 M. In contrast, nonsteroidal anti-inflammatory drugs (NSAID) including indomethacin (10-9 to 10-6 M), meclofenamic acid (10-6 to 10-4 M), and aspirin (10-5 to 10-3 M), which block the cyclo-oxygenase pathway of AA metabolism, enhanced mediator release. AA (10-7 to 10-5 M) also enhanced basophil mediator release, an effect that was not affected by preincubation with indomethacin. Other fatty acids including linoleic, linolenic, and stearic acids were without effect. Indomethacin (and the other NSAID studied) reversed the inhibition caused by the AA metabolite, prostaglandin (PG) E2, in a dose-dependent fashion. This reversal of inhibition was not unique to PG, but was observed with all inhibitors of histamine release studied that act via activation of adenylate cyclase including isoproterenol and the H2 agonist, dimaprit. NSAID, however, did not reverse the inhibition caused by drugs that do not act on adenylate cyclase, i.e., dibutyryl cAMP, isobutylmethylxanthine, and 2-deoxyglucose. In the leukocyte preparations studied, the NSAID did not block the increase in the intracellular cAMP levels caused by agonists that act via adenylate cyclase. It appears that a product(s) of AA metabolism, generated via the lipoxygenase pathway, is involved in IgE-mediated histamine release and that the same or a different product(s) modulates the control mechanisms that are linked to adenylate cyclase.

Ethanol inhibition of antigen-induced histamine release from guinea pig lung: Correlation with intracellular levels of cyclic nucleotides

The effect of ethanol on histamine release from lungs of sensitized guinea pigs was studied in conjunction with measurements of tissue concentrations of cyclic AMP and cyclic GMP. Addition of antigen in vitro elicited a rapid increase in cyclic AMP and cyclic GMP and stimulated release of histamine. Ethanol (2%) inhibited antigen-induced release of histamine over 95% and completely inhibited the increase in both cyclic nucleotides. The activity of cyclic AMP-dependent protein kinase was only slightly affected by ethanol. Metiamide blocked the ovalbumin stimulated increase in cyclic AMP but not cyclic GMP. Pyrilamine did not prevent the rise in either cyclic nucleotide. This suggests that the antigen-induced rise in cyclic AMP is an indirect result of histamine released from the tissue. The inability of H 1 and H 2 receptor antagonists to affect antigen-induced elevation of cyclic GMP in sensitized lung fragments suggests that an elevation in cyclic GMP might be either a primary event in the mediator release sequence or secondary to the release of a mediator other than histamine. The ability of ethanol to inhibit mediator release might be due to its capacity to attenuate the antigen-induced elevation of cyclic GMP in sensitized lung.

Inhibition by isoproterenol of ovalbumin-induced contraction of tracheal strips and release of histamine from lung isolated from the actively sensitized guinea-pig

Tracheal strips and lung parenchyma were obtained from guinea pigs actively sensitized with egg albumin (ovalbumin). Dose-response curves to ovalbumin for producing tracheal contraction and histamine release from chopped lung were shifted to the right and the maximum response reduced by isoprotenol. Small concentrations of isoproterenol exerted a selective inhibitory effect on ovalbumin-induced tracheal contractions and 100-fold larger concentrations were required to inhibit ovalbumin-induced histamine release. Practocol, a cardioselective beta adrenergic receptor antagonist, bloked the inhibitory effect of isoproterenol on histamine release at a concentration which did not alter the effect of isoproterenol on antigen-induced tracheal contraction. The dose-response curve for ovalbumin in producing tracheal contraction was approx. 2 log units to the left of that in producing histamine release. This difference cannot be explained by the presence of a receptor reserve for histamine. These results suggest that the beta adrenergic receptors mediating inhibition of antigen-induced histamine release and tracheal contraction have some different pharmacological properties. Also, histamine does not appear to be the principal mediator of the anaphylactic tracheal contraction.

The nature of the β-adrenoceptor involved in the inhibition of antigen-induced histamine release

Antigen stimulated release of histamine from chopped sensitized guinea-pig lung is inhibited by the addition of β-adrenoceptor agonists in a manner indicating a β 2 response. Preaddition of β-adrenoceptor antagonists blocks this inhibition in a manner indicating a β 1 response. This apparent dichotomy probably results from a hybrid receptor, though the danger of the use of chemical analogues for classifying receptors is highlighted. Inhibition of histamine release by β-stimulation is shown to be species rather than organ specific.

Studies on the mechanism of tachyphylaxis to disodium cromoglycate.

The tachyphylaxis to disodium cromoglycate's (DSCG) inhibition of antigen-induced histamine release is readily demonstrable utilizing passively sensitized rat lung fragments. This tachyphylaxis to DSCG is evident whether or not calcium is present during drug preincubation. An attempt to relate the mechanism of tachyphylaxis to the DSCG-induced release of an endogenous cellular inhibitory material was unsuccessful insofar as could be demonstrated by an effect on mediator release.

Inhibition of antigen-induced histamine release by ouabain

The effect of ouabain, a specific sodium-potassium dependent adenosine triphosphatase (Na +-K +-ATPase) inhibitor, on antigen-induced histamine release was studied using guinea pig lung fragments sensitized in vitro with rabbit antibodies against bovine serum albumin. Histamine was assayed spectrafluorometrically. When sensitized tissue had been preincubated with ouabain (≤ 1.0 × 10 −4 M) for 10 min prior to antigenic challenge, release of histamine was significantly inhibited (maximum 54%, p < 0.001, N = 9, paired t test). The most significant inhibition was obtained, near the optimal concentration of antigen. The inhibition was dependent on the length of preincubation (≤ 20 min), and was partially reversible upon washing the tissue removing the ouabain. Ouabain did not seem to prolong the duration of the histamine release process. Increase in potassium ion (≤ 1.1 × 10 −2 M) inhibited the histamine release and had additive effects to ouabain action. Dibutyryl cyclic AMP (≤ 5 × 10 −3 M), which could enhance the release, strongly antagonized the inhibition. Glucose removal from the medium did not abolish the ouabain effect. The results seem to indicate that immunologic release of histamine is under the influence of the membrane Na +-K +-ATPase activity.

The β-adrenoceptors of the lung mediating inhibition of antigen-induced histamine release

The β-adrenoceptor stimulants, isoprenaline (IPR), orciprenaline (OPR), terbutaline (TRB), and ITP ∗∗ were studied for effects on antigen-induced release of histamine from guinea-pig lung tissue and for effects on guinea-pig isolated trachea and heart. The order of potency for the agents in the four functions studied were: (a) inhibition of histamine release, IPR > OPR ≈ TRB ⪢ ITP = 0; (b) heart stimulation, chronotropic effect, IPR > OPR > ITP ≈ TRB; (c) heart stimulation, inotropic effect, IPR > OPR > ITP > TRB; (d) trachea relaxation: IPR > TRB > OPR ⪢ ITP. These findings suggest that the β-adrenoceptors mediating inhibition of antigen-induced release of histamine are more related to those mediating trachea relaxation ( β 2) than those mediating cardiac stimulation ( β 1).

β-Adrenoceptors involved in inhibition of histamine release from sensitized guinea-pig lung

Selective β-adrenoceptor agonists and antagonists were used to study the type of β-adrenoceptors involved in inhibiting antigen-induced histamine release from actively sensitized guinea-pig lung. Results obtained with six non-catechol β-adrenergic agonists were compared with those found in guinea-pig atrial ( β 1) and tracheal ( β 2) preparations. In terms of rank order the relative activities of the compounds differed in the three preparations. Dissociation constants (K B values) for the cardioselective antagonist H93/26 were assessed using (−)-isoprenaline as an agonist. The K B value for inhibition of histamine release was significantly different from, and intermediate between, the K B values obtained in atria and trachea. In the guinea-pig tissues H35/25 was not a selective β-adrenoceptor antagonist; K B values were not significantly different in the three preparations. The results using the β-adrenoceptor agonists and antagonists suggest that the β-receptors involved in inhibition of antigen-induced histamine release in the guinea-pig lung differ from those found in guinea-pig atria and trachea.

Inhibition of cutaneous hypersensitivity by cyclic AMP.

The effect of drugs which increase the cellular concentration of cyclic AMP on IgE-mediated cutaneous hypersensitivity reactions in skin was studied using skin from ovalbumin-sensitised rats. Theophylline, which reduces degradation of cyclic AMP, caused inhibition of antigen-induced histamine release. Synergism was demonstrated when adrenaline in a concentration which was not itself inhibitory caused marked enhancement of theophylline inhibition. The pure &lt;i&gt;β&lt;/i&gt;-adrenergic agent isoprenaline produced inhibition in extremely low concentrations. Direct evidence of an inhibitory role for cyclic AMP was obtained using dibutyryl cyclic AMP which produced a dose-related inhibition of histamine release from skin. This evidence should lead to trials of &lt;i&gt;β&lt;/i&gt;-adrenergic drugs and xanthines in the treatment of immediate hypersensitivity reactions in human skin.