Inhibition of immediate hypersensitivity reactions in the rat by disodium cromoglycate and nitroindanedione.

A nitroindanedione (BRL 10833) and disodium cromoglycate (DSCG) showed similar activities as inhibitors of IgE-mediated passive cutaneous anaphylaxis (PCA) and passive peritoneal anaphylaxis (PPA) reactions in the rat. BRL 10833 was more active than DSCG when given parenterally and unlike DSCG it inhibited the PCA reaction in the rat after oral administration. In the PCA test both compounds produced a state of refractoriness both to themselves and to each other. Isoprenaline also inhibited the PCA reaction but its activity was not reduced when the rats were refractory to DSCG.     

The mechansim of tachyphylaxis to ICI 74,917 and disodium cromoglycate.

Pre-incubation in vitro of sensitised peritoneal mast cells for 10 min with either ICI 74,917 (10-5 M) abolished the ability of either drug to inhibit histamine release when subsequently presented to the cells at the same time as antigen. In the case of disodium cromoglycate, tachyphylaxis was abolished by washing the cells after pre-incubation with the drug. The failure to abolish tachyphylaxis to ICI 74,917 was due to the high pre-incubation concentration employed, as at lower concentrations (10-8 M) tachyphylaxis to ICI 74917 was readily abolished by washing. Tachyphylaxis to these anti-allergic agents may be related to a physical blocking of drug receptor sites on or in mast cells.     

Inhibition of immediate hypersensitivity reactions by disodium cromoglycate. Requirements for activity in two laboratory models

The ability of disodium cromoglycate to inhibit IgE-mediated cutaneous anaphylaxis in the rat in vivo and release of histamine from peritoneal mast cells in vitro has been studied. Only when drug and antigen were presented to the sensitized cells simultaneously was a dose-dependent inhibition demonstrable. After the drug had been given alone, in the absence of antigen, either in vivo or in vitro it had little or no action when given again at antigen challenge. In vivo, this refractory state was reversible. It is suggested that disodium cromoglycate may act by releasing some factor capable of inhibiting the release of mediators from the mast cell.     

A controlled clinical trial comparing disodium cromoglycate and ICI 74,917 in extrinsic asthma

A controlled clinical trial comparing inhalation of disodium cromoglycate (DSCG) and of ICI 74,917 was carried out using a double-placebo technique in thirty-two patients with extrinsic asthma already shown to be reasonably responsive to DSCG. In view of the fact that ICI 74,917 is 300 times more potent than DSCG in inhibiting antigenic challenge in animals a better effect was anticipated from the new drug in the human asthmatic subject. Whilst this was not obtained, there appeared to be no lesser effect than that of DSCG.     

Mode of action of disodium cromoglycate, studies on immediate type hypersensitivity reactions using `double sensitization'' with two antigenetically distinct rat reagins

The mode of action of disodium cromoglycate has been investigated to determine at what stage in immediate type hypersensitivity reactions the compound is effective. In vitro studies using rat subcutaneous connective tissue sensitized with rat reagin revealed that the compound inhibited the allergic release of histamine if present during antigen challenge. The presence of the compound during sensitization had no effect on antigen-induced release of histamine provided the compound was removed prior to antigen challenge. Tissues which had undergone a primary antigen challenge in the presence of disodium cromoglycate did not release histamine when the compound was removed and the tissues rechallenged. These findings indicated that antigen/antibody interaction occurred in the presence of the compound resulting in desensitization to a subsequent antigen challenge. To corroborate the evidence of the in vitro studies in vivo passive cutaneous anaphylactic reactions (PCA) were undertaken using tissue sites sensitized with two reaginic antibodies which permitted a sequence of antigen challenges. Results from these in vivo reactions demonstrated that it was possible to desensitize tissue, without the release of the mediators of anaphylaxis, by an antigen challenge and disodium cromoglycate treatment. In these sites sensitized with two antibodies the immunological reactivity was maintained following a primary antigen challenge and disodium cromoglycate treatment, as a subsequent challenge with the dissimilar antigen produced a good PCA reaction. It would appear that disodium cromoglycate acts either directly or indirectly at a stage following antigen/antibody reaction but prior to the release of the mediators of anaphylaxis.     

Inhibition of human allergic skin reactions in vivo by pretreatment with cromolyn (disodium cromoglycate)

The effect of cromolyn on allergen-induced allergic skin reactions was studied. Two patients with allergic rhinitis, two patients with bronchial asthma and atopic dermatitis and two patients with allergic rhinitis and atopic dermatitis were included in this study. They were allergic to cedar pollen, house dust mite and house dust, respectively. Scratching with allergen induced wheal and erythema reactions in each patient. Simultaneous application of allergen and cromolyn solution did not modulate allergic reactions; however, pretreatment with cromolyn solution inhibited allergen-induced wheal and erythema reactions significantly.     

Inhibition of C5a-induced basophil degranulation by disodium cromoglycate

Injection of purified porcine C5a into 24-hr basophil-rich cutaneous basophil hypersensitivity sites in the dose range 10^–12–10^–10 moles/site produced cutaneous basophil anaphylaxis (CBA). The H₁ anti-histamine antagonist mepyramine, given orally (3.0–30 mg/kg), inhibited the vasopermeability, but not the basophil degranulation, characteristic of CBA. The antiallergy agent disodium cromoglycate (DSCG), administered intravenously (3.0–30 mg/kg), inhibited vasopermeability and basophil degranulation. DSCG inhibition of mast cell degranulation was not important in the inhibition of CBA, since intact mast cells were found to be depleted at basophil-rich sites and absent at C5a-induced CBA sites from animals treated with DSCG.C5a at 10^–11 moles/site also induced vasopermeability and mast cell degranulation in normal guinea pig skin. Vasopermeability, but not mast cell degranulation, was inhibited by mepyramine at 30 mg/kg p.o. However, DSCG at 10 mg/kg i.v. failed to inhibit either the vasopermeability or the mast cell degranulation of this reaction. These results indicate that C5a induces the degranulation of both basophils and mast cells in the guinea pig, and that C5a-induced degranulation of basophils, but not mast cells, is inhibited by DSCG.     

Assay of specific IgE antibodies to disodium cromoglycate in serum from a patient with an immediate hypersensitivity reaction

A 29-year-old man with pollen allergy had experienced immediate adverse reactions, such as itching of the eyes, rhinitis, wheezing, and general urticaria, after using disodium cromoglycate (DSCG) eye drops. The local symptoms were reproducible, and skin tests were strongly positive. With serum from the patient, a RAST was developed for the assay of IgE antibodies. The uptake on RAST disks was 6% of the total activity added, which was a significantly higher level than was found in sera from 35 randomly selected blood donors or in sera from 25 patients tolerating DSCG. By addition of DSCG to the patient's serum, 95% of the binding to paper disks could be inhibited. The induction of specific IgE antibodies was proposed to be a result of a combination of electrostatic and hydrophobic interaction of DSCG and a protein carrier. The substance would thus act as a hapten without any covalent binding to the carrier. DSCG may serve as a model for other nonreactive low-molecular-weight substances suspected to elicit type I-like adverse reactions.     

Specific inhibition of allogeneic reactions with disodium cromoglycate

Milligram amounts of disodium cromoglycate (DSCG) inhibit allogeneic responses in mixed lymphocyte culture (MLC) reactions, but do not affect cell viability or suppress lymphocyte responses to either phytohemagglutinin (PHA) or pokeweed (PKW) mitogens. Preincubation of lymphocytes with DSCG is without effect, indicating that membrane binding is an unlikely explanation for inhibition. The HLA-DR tissue typing of cells in the presence of optimal MLC-inhibitory doses of DSCG is normal suggesting that MLC-reactive lymphocytes are not denied recognition of these antigens. Timed studies demonstrate that DSCG must be present continuously during the induction period, for removal of DSCG after 16 hr culture restores MLC reactivity and addition of the drug after 48 hr is without effect. Both natural killing (NK) and cell mediated lympholysis (CML) assays proceed normally in the presence of optimal MLC-inhibitory concentrations of DSCG; however, CML reactions are eliminated by the addition of drug during cytotoxic T cell priming. Background CML reactivity also disappears when lymphocytes are continuously cocultured in DSCG, implying that such killing cannot be attributed to NK activity. DSCG is said to inhibit allergic reactions by impeding calcium flux across mast cell membranes, thereby preventing degranulation, but other mechanisms are required to explain the selective effects on in vitro lymphocyte reactivity.     

Inhibition by disodium cromoglycate of anaphylactic histamine secretion from rat peritoneal mast cells in the presence of phosphatidylserine

The lipid phosphatidylserine (PS) markedly potentiated anaphylactic histamine secretion from isolated rat peritoneal mast cells in the presence of extracellular calcium ions. The compound correspondingly reduced the inhibitory effect of disodium cromoglycate on the secretion induced by optimal concentrations of antigen. However, at a constant concentration of PS, suboptimal amounts of antigen were effectively inhibited by the drug. The inhibitory power of cromoglycate increased as the concentration of antigen was decreased and the corresponding control release of histamine declined. At control values similar to those observed without addition of PS, the drug inhibited secretion to a similar extent as in the absence of the lipid. At given concentrations of PS and antigen, the potency of the drug increased with decreasing degrees of sensitization of the experimental animals. These effects are not likely to reflect a direct interaction between the drug and PS since increasing the concentration of the lipid by one hundred-fold did not affect the inhibitory effect of the chromone. Further, the latter was essentially equiactive in the presence and absence of PS in calcium-free media, conditions under which the lipid did not enhance histamine release. These results are discussed in terms of the proposed modes of action of PS and cromoglycate.     

Tumour-associated inhibition of immediate hypersensitivity reactions in mice.

The intensity of anaphylactic shock was lower in C3H mice carrying a methylcholanthrene-induced tumour (McC3) than in their normal counterparts when immunized with ovalbumin and challenged i.v. after 14 days. This tumour-associated inhibitory effect on active systemic anaphylaxis was exerted mainly on events occurring after homocytotropic antibody synthesis because the serum titres of these antibodies were comparable in normal and tumour-bearing animals. In addition, passive systemic anaphylactic reactions were suppressed in animals carrying the tumour and the sensitivity of these animals to challenge with histamine and serotonin mixtures was also reduced. The presence of a growing McC3 tumour did not, however, diminish the amine-sensitizing effect of treatment with Bordetella pertussis vaccine. The McC3 tumour inhibited the generation of passive cutaneous anaphylactic reactions, an effect that was also exerted by a tumour extract, particularly when administered to the recipients shortly before antigen challenge. Thus immediate hypersensitivity reactions, like a variety of other immunological processes, can be inhibited by tumour products which by compromising the immune status of the host might permit tumour growth. The nature of the inhibiting factor is unknown, except that it is probably not the amine-degrading enzyme histaminase. In addition, which it is uncertain whether the inhibitory effect is exerted directly or indirectly, the possible importance of prostaglandins in the phenomenon is discussed.     

Effect of disodium cromoglycate on asthmatic reactions to alcoholic beverages

Eleven asthmatic patients with a history of asthma with or without rhinitis following the ingestion of alcoholic drinks were challenged by oral ingestion of the suspected drink, and some with equivalent amounts of ethyl alcohol. Asthma was provoked in six cases, four having falls in the FEV₁ of more than 15%. Three of the latter studied in detail gave immediate asthmatic reactions to the alcoholic beverage, but not to the ethyl alcohol tested by oral ingestion, and in one case by administration through a naso-gastric tube. Pre-treatment by inhalation of disodium cromoglycate inhibited the asthmatic reactions to the alcoholic beverages.     

A trial of ICI 74,917 in seasonal allergic rhinitis

Twenty-four patients with seasonal allergic rhinitis were treated in a randomized double-blind trial of 6 weeks’ duration, using either ICI 74,917 (0.5 mg in each nostril four times a day) or an identical placebo aerosol. Four patients receiving placebo were withdrawn from the trial because of the deterioration in their rhinitis. The twelve patients using ICI 74,917 were protected as assessed by a combined total symptom score, which was statistically significant (P <0.05), from weeks 1 to 4 when the pollen counts were highest.     

Effector cell heterogeneity in immediate hypersensitivity reactions

Clinical Reviews in Allergy & Immunology -     

Inhibition of the development of immediate hypersensitivity by staphylococcal enterotoxin B

We investigated the ability of staphylococcal enterotoxin B (SEB) to modify the immediate hypersensitivity response induced in BALB/c mice following sensitization to ovalbumin (OVA), a response mediated by OVA-reactive Vβ8 T cells. Mice were sensitized by skin painting with OVA every second day over a period of 2 weeks. SEB, a potent activator of Vβ8⁺ T cells, was administered at the same site where OVA was applied (skin of the lower abdomen) following two different protocols. In protocol (A) SEB was injected intradermally 1 day before painting with OVA and on day 7; in protocol B, SEB was injected each time OVA was applied to the skin (eight times). SEB (but not SEA) altered the development of immediate hypersensitivity to OVA, as demonstrated by the reduction in allergen-specific IgE, decreased OVA-specific immediate skin test responsiveness, and prevented the development of increased airways responsiveness after bronchial challenge with OVA. Injections of SEB did not alter the proliferative responses of local draining lymph node cells or spleen mononuclear cells to OVA, indicating that administration of SEB did not inhibit the sensitization to OVA, but shifted the immune response away from an immediate type response (IgE/IgG₁) to IgG_2a, IgG_2b and IgG₃. Although both protocols of SEB treatment did not lead to a major deletion of the Vβ8 T cell population, they did reduce the proliferative response of Vβ8⁺ T cells to OVA. These data indicate that the bacterial toxin SEB is capable of modifying the immediate hypersensitivity response induced by OVA by altering the functional capacity of antigen-reactive Vβ8 T cells.     

Inhibition of compound 48/80-induced intradental sensory nerve activity by disodium cromoglycate and serotonin antagonists.

Local application of compound 48/80 induced long lasting nerve activity in intradental sensory nerves in the teeth of cats and dogs. This effect was inhibited by pretreatment with disodium cromoglycate (DSCG) given locally (2 X 10(-2) M) or i.a. (20 mg/min). DSCG did not have any effect on the nerve excitability per se, as judged from the responses to hypertonic NaCl and air blasta applied to exposed dentin before and after administration of DSCG. Local treatment with lysergic acid diethylamide (0.1--1 mg/ml) and methysergide (0.05--0.5 mg/ml) selectively reduced or inhibited the compound 48/80 induced nerve activity. Systemic administration of methysergide (12.5 microgram/kg) prevented the excitatory effects of compound 48/80 but was without effect when administrated during a state of established activity. The present findings support the hypothesis that compound 48/80 has an indirect effect on intradental sensory nerves and indicate that vascular reactions take part in intradental sensory nerve excitation.     

Factors in the tissue eosinophil responses in human immediate hypersensitivity reactions.

Factors underlying the eosinophil responses in the tissue sites of immediate hypersensitivity reactions have been investigated. A quantitative assessment of the number of eosinophils appearing in skin test reactions to ragweed antigen and compound 48/80 in ragweed-sensitive humans has been compared with several other parameters. There was a moderate, statistically significant, correlation with serum levels of IgE-class antiragweed antibody; also, eosinophil responses were minimal or absent in minimally positive threshold dilution skin tests. Tissue eosinophil responses were generally limited to those with baseline blood eosinophil levels of at least 150 mm3; however, there was no correlation between blood and tissue eosinophil levels in individual subjects. These findings suggest that the pathogenesis of the observed tissue eosinophil responses may be multifactorial.