Terbutaline modulation of human allergic skin reactions

Terbutaline, a preferential beta 2-adrenergic agonist, has been shown to inhibit allergen-induced histamine release in vitro. In contrast, orally administered therapeutic doses of terbutaline do not inhibit antigen-induced wheal and flare reactions. We studied the effects of local terbutaline on antigen-induced whealing response, histamine release, cellular inflammatory response, and ultramicroscopic mast cell changes in antigen-challenged skin sites in ragweed-sensitive subjects. Results showed that ragweed challenge significantly induced increased histamine release in all subjects. In contrast, no such histamine release was observed at sites challenged with antigen in the presence of terbutaline. Thus locally applied terbutaline in nontoxic doses modulates mediator release in certain allergic reactions.     

Histamine suppression of in vivo eosinophil accumulation and histamine release in human allergic reactions

Although it has been shown that histamine inhibits antigen-induced in vitro histamine release from basophils, it is unclear whether histamine inhibits in vivo mediator release in human allergic reactions. We report effects of exogenous histamine on histamine release and inflammatory cell responses in antigen-challenged skin sites in eight ragweed-sensitive individuals. Four heat-suction blisters in each subject were unroofed, and a collection chamber was appended to each blister base. Chamber A contained 1000 PNU/ml ragweed extract; chamber B contained buffered saline (control fluid); chamber C contained 1000 PNU/ml ragweed and 50 ng (5 x 10(-7) M) of histamine; and chamber D contained histamine alone (50 ng). Comparative analyses of chamber histamine levels in individual subjects showed that (1) histamine levels in chamber A were significantly greater than those in chamber B (p less than 0.01) and that histamine levels in chamber C were not significantly different than those in chamber D (p less than 0.5). Likewise, comparison of eosinophils attaching to membrane filters appended to the chamber bases for 2 hr showed that there were significantly more eosinophils in chamber A than in chamber B (p less than 0.01) and that there was no significant difference in eosinophil numbers on filters appended to chamber C vs chamber D. In three of four subjects studied, addition of exogenous histamine (50 ng/ml) to ragweed before intradermal injection inhibited the ultrastructural mast cell alterations seen within 10 min after injection of ragweed alone. In the one subject in which mast cell alterations were not prevented, exogenous histamine also did not inhibit antigen-induced histamine release or subsequent eosinophil accumulation in the skin chambers.     

Release of eosinophil granule proteins during IgE-mediated allergic skin reactions.

To determine whether the eosinophil (EOS), a prominent component of human allergic skin reactions, releases its potentially pathogenic components in vivo, we appended collection chambers to the bases of unroofed skin blisters and challenged the sites for varying time periods with either pollen antigen (Ag) or buffer (B)-control solutions. In seven sensitive subjects, continuous challenge with pollen Ag consistently induced release of more major basic protein (MBP) and eosinophil-derived neutrophil (EDN) than did B solution. Low levels of both MBP and EDN were observed during the first hour with increased accumulation during the second to fifth hour. Comparison of Ag- versus B-challenged site responses in individual subjects demonstrated significantly higher levels of both MBP and EDN at Ag than at B sites during the second to fifth hour. Levels of both MBP and EDN in the second to fifth hour correlated significantly with histamine release in the same sites in the first hour (r = 0.66 and 0.83, respectively). Imprints of the skin bases of the chambers after 5 hours demonstrated variable numbers of EOS at the Ag-challenged sites and only occasional EOS at the B-challenged sites; most cells on the skin bases were neutrophils. However, immunofluorescence localization of MBP in biopsy specimens of the blister bases revealed striking extra cellular MBP deposition. These findings indicate that EOS components accumulate in vivo in IgE-mediated human skin reactions, even when prominent EOS accumulation is not visualized, possibly because the EOS are degranulated in the allergic-reaction site. Release of EOS components in these reactions may be linked to earlier mast cell activation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activation of the coagulation pathway during ongoing allergic cutaneous reactions in humans.

The levels of histamine, fibrinopeptide A (FPA), and IgG were determined in chamber fluids overlying sites of antigen versus buffer incubation for up to 7 hours in seven atopic and four antigen-nonreactive subjects. Significant increases in histamine were observed at antigen versus buffer sites in the atopic subjects throughout the 7-hour period. FPA and IgG levels were higher in antigen than in buffer sites from 0 to 5 hours in the atopic subjects. Furthermore, FPA levels correlated with the magnitude of induration at 6 hours after antigen injection in atopic subjects. There were no differences in the levels of histamine, FPA, or IgG at antigen versus buffer sites in the skin test-negative subjects. We suggest that the combination of vascular leakage of proteins, induced by vasoactive mediator release, and activation of these proteins during ongoing cutaneous reactions is responsible for fibrin formation that contributes to the pathophysiology of late-phase allergic responses in the skin.     

Neutrophil activation in human inflammatory skin reactions

To determine the functional activity of neutrophils emigrating to the sites of ongoing human allergic inflammatory reactions, we assessed the intensity of their intracellular oxidative metabolism by measuring the intracellular oxidation by H2O2 of the dye, 2',7'-dichlorofluorescein diacetate (DCFH-DA), to fluorescent 2',7'-dichlorofluorescein. The intensity of intracellular fluorescence was measured by flow cytometry. In 13 atopic subjects, two denuded skin blister bases were challenged for 5 hours with pollen antigen and two blister bases with buffer. Both the level of histamine and mean number of cells recovered at antigen sites were greater than at buffer sites. Oxidation of DCFH-DA by neutrophils recovered from both antigen and buffer sites was significantly greater than that of autologous peripheral blood neutrophils (PBNs), reflecting an increase in the spontaneous generation H2O2 of cells recovered from the sites of inflammation. DCFH-DA oxidation by cells recovered from sites of antigen incubation was significantly greater than cells from buffer site incubations. Neutrophils from both antigen and buffer sites could be stimulated further in vitro by phorbol myristate acetate to the same level of H2O2 generation as phorbol myristate acetate-stimulated PBNs. In five subjects studied, the noncellular component of chamber fluids collected at 1 and 5 hours stimulated PBNs to increase their oxidative metabolism by 42% to 62%; however, this increased level of intracellular H2O2 was still much less than the spontaneous H2O2 generation observed in cells recovered from sites of allergic inflammation. The increased oxidative metabolism of neutrophils in human allergic and inflammatory skin reactions has important pathophysiologic implications for the role of these cells in inflammatory responses.     

Cellular inflammatory responses in human allergic skin reactions

To define better the role of inflammation in the response to pollen antigens, we have used our skin chamber model to study inflammatory cells recovered from the sites of ongoing allergic reactions. In 15 atopic subjects, paired skin blister sites were simultaneously challenged with ragweed- or grass-pollen antigen or buffer for 5 hours. There were 10 times as many cells recovered at antigen (20.7 X 10(5)) than at buffer (2.0 X 10(5)) sites, p less than 0.005; greater than 97% of the cells recovered were neutrophils. The number of cells recovered at the antigen sites correlated with the total amount of histamine released (r = 0.57; p less than 0.05) but not with the extinction dilution skin test reactivity nor with the intensity of the late cutaneous allergic response measured 6 hours after the injection of antigen. Phase-contrast microscopic examination of the cells recovered from the antigen sites demonstrated that 82% to 95% were polarized compared to 0% to 1.5% of autologous blood neutrophils obtained simultaneously from the peripheral blood. Antigen site cells were as capable of serum-dependent phagocytosis as peripheral blood neutrophils. There was no significant difference in the migratory response to buffer, the chemoattractant N-formyl-methionyl-leucyl-phenylalanine, or leukotriene B4, but there was a significantly decreased response to platelet-activating factor when the cells recovered from antigen sites were compared to autologous blood neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)     

Release of high-molecular-weight neutrophil chemotactic activity from resected human nasal turbinate after antigen challenge

Eleven patients with allergic rhinitis were studied. All subjects were sensitive to house dust mite documented by skin test, RAST score, and nasal provocation test. The patients needed lower turbinectomy because of chronic hypertrophic rhinitis. Tissues of the lower turbinate were obtained at the time of surgery, fragmented, and subsequently challenged with house dust mite in vitro. Diffusates were collected for measurement of neutrophil chemotactic activity (NCA) and histamine. NCA and histamine were released in a dose-dependent manner, and the time course of release of these mediators was identical. Release of NCA and histamine correlated significantly (p less than 0.001). The prior administration of the antiallergic drugs, disodium cromoglycate or tranilast, significantly blocked the release of NCA and histamine from antigen-challenged tissues. NCA released from nasal tissues eluted as a single peak with estimated molecular size of between 669 kd and 440 kd in three subjects and as two or three peaks in two patients. These results provide evidence that NCA might be involved in the pathogenesis of allergic rhinitis.     

Correlations of in vivo mediator release with late cutaneous allergic responses in humans : I. Kinetics of histamine release

To evaluate the contribution of mast cell-derived mediators in the late cutaneous allergic response, the duration and quantity of antigen-induced histamine release was compared to the intensity of the antigen-induced skin reactions in atopic volunteers. Chambers containing either pollen extract or buffer were appended to denuded bases for 1 hr and were replaced hourly with buffer for 3 additional hr. These were compared to the extinction dilution skin test titer and to the mean diameters of the 20-minute wheal and induration at 6 and 8 hr after intradermal injection of antigen. Chamber-fluid histamine levels were significantly higher at antigen than at buffer sites throughout the 4 hr. The hourly histamine levels correlated with the size of the induration at 6 and 8 hr but not with the wheal size or skin test titer. We conclude that (1) histamine is released for at least 4 hr at skin sites of antigen challenge as a consequence of prolonged release either from individual or sequentially activated mast cells, and (2) the quantity of histamine released correlates with the intensity of the late-phase skin response. We hypothesize that histamine might be a marker for prolonged release from the mast cell of other mediators that are responsible for the late-phase response.     

Further studies on the role of neutrophils in passive cutaneous anaphylaxis of the guinea-pig

Passive cutaneous anaphylaxis (PCA) was studied in guinea-pigs sensitized with rabbit antisera to bovine serum albumin or horse spleen ferritin and challenged 4–5 hours later with antigen. Ultrastructural studies of lesions obtained after sensitization or challenge indicated that substantial numbers of neutrophils had infiltrated into the skin. Following challenge these elements exhibited phagocytic activity, presumably representing the uptake of immune precipitates formed in the interstitial spaces. This was associated with degranulative and degenerative phenomena, suggesting that lysosomes were discharged extracellularly. A significant suppression of the intensity of the hyperpermeability response in PCA was noted when animals were pretreated with an antiserum to guinea-pig neutrophils. Antihistamines also suppressed PCA, and the combined effect of neutrophil depletion and antihistamine therapy was additive. It was concluded that a combination of anaphylactic (histamine release) and Arthus-like (neutrophil lysosome release) mechanisms mediated the vascular response in this type of PCA.     

Platelet-activating factor- and leukotriene B4-induced release of lactoferrin from blood neutrophils of atopic and nonatopic individuals

We found increased accumulation of neutrophils and their components, lactoferrin (Lf) and elastase, as well as platelet-activating factor (PAF) and leukotriene B4 (LTB4) at sites of ongoing human allergic reactions. To determine whether PAF or LTB4, could be the stimulus for in vivo Lf release, blood neutrophils of 17 subjects were incubated with PAF, LTB4, or the phorbol ester, phorbol myristate acetate (PMA), and the released Lf (ELISA assay) was compared with spontaneous release. Significantly increased Lf release was induced by PAF, 10(-5) to 10(-8) mol/L (p less than 0.002); LTB4, 10(-7) to 10(-8) mol/L (p less than 0.004); and PMA (0.05 micrograms/ml) in a dose-dependent reaction. Cytochalasin was not required for Lf secretion but did enhance such responses. PAF-induced Lf secretion was inhibited by the specific PAF antagonist, BN 52063. More Lf was released from neutrophils of atopic than from nonatopic subjects in response to PAF, 10(-6) mol/L (4.2 micrograms/ml +/- 0.2 versus 2.6 micrograms/ml +/- 0.2; p less than 0.001) but not to LTB4, PMA, or buffer (p, not significant). We conclude that (1) PAF and LTB4 released in vivo could stimulate local neutrophils to release Lf with possible pathogenic effects and (2) neutrophils of atopic subjects are more responsive to PAF than neutrophils of nonatopic subjects in this regard.     

Effect of Cimetidine on Exogenous Histamine Inhibition of Histamine Release in Vivo

We previously reported that exogenous histamine inhibits in vivo histamine release and eosinophil accumulation in ragweed-challenged skin sites of sensitive human subjects. The mechanism(s) involved were unclear. In this study, we repeated similar approaches in four of the same subjects pretreated for 3 days with cimetidine, an H2 receptor antagonist. The pattern of exogenous histamine effects was now different in that local exogenous histamine (50 ng/ml) did not significantly alter ragweed-induced mast cell alteration, histamine release, or the degree of eosinophil accumulation in skin challenge sites. These findings suggest that the observed exogenous histamine inhibitory effects may be mediated through the H2 receptor.     

Increased antigen-induced local and systemic mediator release in rhinitis subjects with pulmonary symptoms in the pollen season

In order to delineate parameters that might discriminate between allergic subjects who develop R or R-P symptoms during natural antigen exposure, 26 subjects allergic to grass or ragweed pollen were classified into R or R-P groups, and then the antigen sensitivity and degree of in vivo mediator release were compared. Antigen-skin sensitivity was quantitated by dilutional skin-test titration, and bronchial sensitivity was quantitated by the amount of inhaled antigen required to receive the FEV1 by 20%. Mediator release was determined by measuring the amount of histamine that was released into skin chambers during antigen incubation and the rise in plasma histamine and serum NCA during antigen-induced bronchospasm. Compared to the 13 R subjects, the 13 R-P subjects were: (1) more sensitive to antigen by both skin-test and inhalation challenge, (2) responded to inhalation of antigen with a greater fall in FEV1 and a greater rise in serum NCA and plasma histamine, and (3) released more histamine into skin chambers after antigen incubation. Even when R and R-P subjects were matched by comparing only subjects with equal skin sensitivity to antigen, greater increases in serum NCA and plasma histamine occurred after inhalation of antigen in the R-P subjects. These data are consistent with the hypothesis that allergic rhinitis subjects who develop pulmonary symptoms during natural pollen exposure are more sensitive to antigen and release more mediators in response to antigen administration. It is therefore possible that the degree of mediator release may be an important factor in determining the pattern of clinical responses to antigen exposure.     

Nasal response to a single antigen challenge in patients with allergic rhinitis — inflammatory cell recruitment persists up to 48 hours

BACKGROUND: Allergen challenge in some patients with respiratory allergy is followed by an early and a late reaction. OBJECTIVE: To evaluate the duration of mediator release and inflammatory cell recruitment during the late antigen-induced nasal response. METHODS: Eight patients with seasonal allergic rhinitis due to grass pollen underwent local challenge with the relevant allergen, a non-relevant allergen (Parietaria judaica), and nebulized saline solution. Nasal lavages were performed at baseline and 6, 24, 48, 72 h after challenge. Eosinophil cationic protein (ECP), leukotriene C4 (LTC4), leukotriene B4 (LTB4) myeloperoxidase (MPO) and prostaglandin D2 (PGD2) levels were radioimmunoassayed and histamine concentration was measured by an automated fluorometric method. RESULTS: Nasal challenge with the relevant antigen induced a response 6 h after stimulation, which subsided within 24 h. Eosinophilia, observed in the nasal lavages collected from 6 to 24 h after this challenge, was accompanied by ECP release. Neutrophilia were found in the nasal lavages collected from 6 to 24 h after challenge. The increase in neutrophil number correlated with MPO levels and LTB4 concentrations, but not with the intensity of nasal obstruction. Antigen challenge also induced significant recruitment of mononuclear cells 48 h after provocation. The challenge significantly raised histamine, but not PGD2, levels in the nasal lavages collected 6 h after provocation. A trend towards an increase in LTC4 levels in the nasal lavages collected 6 h after specific antigen challenge was also found. Nasal challenge with a non-relevant allergen or with saline solution did not cause either inflammatory cell recruitment or mediator release. CONCLUSION: Nasal challenge with the relevant antigen can induce a late response characterized by local accumulation of eosinophils, neutrophils and mononuclear cells persisting for 48 h and accompanied by release of ECP, MPO, LTB4 and histamine. These results indicate that a single antigen challenge in patients with allergic rhinitis causes prolonged inflammatory alterations which may contribute to the development of airway hyperreactivity.     

Interleukin-6 is released in the cutaneous response to allergen challenge in atopic individuals.

The mechanisms responsible for cutaneous response to antigen are complex. Interleukin-1 (IL-1) and interleukin-6 (IL-6) are proinflammatory cytokines that share many properties. Previous studies with a blister-chamber model have demonstrated IL-1 to be produced in the cutaneous response to antigen. Since IL-2 production by activated T cells and IL-6 production by macrophages are both stimulated by IL-1, we hypothesized that IL-2 and IL-6 may be involved in the cutaneous late-phase response (LPR) to antigen. We examined antigen-challenged sites for IL-2 immunoreactivity (ELISA) but found no difference between antigen- and diluent-challenged skin sites (N = 4). Since IL-2 has been demonstrated to be produced in response to IL-1 and IL-1 activity has been demonstrated to be greatest between hours 10 and 12, we speculated that IL-2 might not be detected until after hour 12. We were unable to demonstrate any increase in IL-2 production, even by extending our studies to 24 hours in two subjects. Antigen-challenged, skin blister-chamber fluids from atopic subjects demonstrated the appearance of IL-6 (ELISA) in pooled samples representing hours 1 1/2, 3 1/2, 5 1/2, and 7, but not at diluent control sites (p less than 0.05; N = 6). IL-6 reached a median peak of 0.66 ng/ml at 3 1/2 hours. Median levels of IL-6 fell to baseline at 8 hours, followed by a second peak of 0.25 ng/ml at hour 10. Three distinct patterns of IL-6 release were noted: early release of IL-6 followed by a sustained slower rise that peaked at hour 9 before declining to baseline levels at 12 hours, early release of IL-6 followed by a fall to baseline levels at hours 7 to 9 with a second smaller peak at hours 9 to 11, and isolated early release of IL-6. Early IL-6 production correlated with late histamine production (R = 0.801; p = 0.06), and late IL-6 production correlated with eosinophil influx (R = 0.813; p = 0.05). The area of the LPR at skin test sites correlated with early IL-6 peak levels (R = 0.977; p = 0.004) and with total early IL-6 production (R = 0.885; p = 0.05), but not with late IL-6 production.(ABSTRACT TRUNCATED AT 400 WORDS)     

In vivo effects of corticosteroids on human allergic responses. I. Effects of systemic administrations of steroids

In order to better understand the effects of corticosteroids in allergic disease, the relative degrees of allergen-induced cutaneous histamine release and granulocyte accumulation were evaluated in atopic volunteers following intravenous placebo or methylprednisolone administration. In nine subjects, a single intravenous dose of methylprednisolone (1 mg/kg) did not inhibit histamine release but did significantly reduce granulocyte accumulation at both allergen and buffer-challenged sites during five and one-half to six and one-half hours following steroid injection. These findings suggest that the corticosteroid-induced anti-inflammatory effects at allergic reaction sites do not include inhibition of local mediator release. Furthermore, the steroid-induced inhibition of inflammatory cell accumulation is not specific for the allergic reaction.     

Basophil influx occurs after nasal antigen challenge: effects of topical corticosteroid pretreatment

Both the pattern of mediator release during the late-phase response (LPR) and the reduction of the LPR with corticosteroid pretreatment have suggested that basophils, not mast cells, represent the main source of histamine in the late response to nasal antigen challenge. We tested this hypothesis by examining alcian blue-stained cytospin slides of nasal washings obtained before and for 11 hours after nasal antigen challenge in 11 asymptomatic subjects with seasonal allergic rhinitis. In a double-blind manner, subjects received placebo or topical flunisolide (50 micrograms, each nostril, twice daily) for 1 week before antigen challenge. One month later, the challenge was repeated with the alternate pretreatment. On placebo-treatment days, a twelve-fold increase occurred in the number and a threefold increase in the percentage of alcian blue-stained positive cells in nasal washings in the LPR compared to baseline. At least 68% of these alcian blue-stained positive cells were basophils, as determined by light microscopic criteria. Alcian blue-stained cell influx correlated with increases in histamine levels in nasal washes (p less than 0.001). Topical steroid pretreatment blocked the influx of alcian blue-stained positive cells, as well as other inflammatory cells, including eosinophils, neutrophils, and mononuclear cells. Symptoms and mediator release were also blocked. These data demonstrate an influx of basophils and suggest that these cells are responsible for the histamine release observed in the LPR. Our findings indicate that pharmacologic control of basophil histamine release may represent a strategy for the treatment of a variety of chronic allergic diseases that are believed to resemble the LPR.     

Exercise-induced release of histamine and neutrophil chemotactic factor in atopic asthmatics

Concentrations of plasma histamine and serum neutrophil chemotactic factor (NCF) were measured in seven atopic asthmatics who developed exercise-induced asthma (EIA) after a treadmill task. The results were compared with those obtained after inhalation of specific antigen or methacholine. Plasma histamine concentrations were measured with a novel double-isotope radiometric assay, and NCF was identified by its elution in the void volume fractions of Sephadex G-200 and as a single peak of activity at approximately 0.20 molar NaCl after anion exchange chromatography on diethylaminoethyl-Sephacel (pH 7.8). After exercise or antigen challenge, the time courses of appearance of both mediators were virtually identical and accompanied the increase in airways obstruction. There was a statistically significant correlation between the concentrations of histamine or NCF and the magnitude of airflow obstruction after exercise and antigen challenge. This suggested that there may be a direct association between mediator release and EIA or antigen-induced bronchoconstriction. In contrast, there were no significant elevations in circulating histamine and NCF after inhalation of methacholine, at concentrations giving a fall in FEV1 comparable to that induced by exercise or antigen. The prior administration of cromolyn to three asthmatics inhibited both their EIA and the release of histamine and NCF. When four asthmatics were exercised for periods of 1, 3, and 6 min, the release of NCF and fall in peak expiratory flow rate were directly related to the duration of the exercise. The rise of NCF activity in subjects with EIA was fivefold greater than that observed in asthmatics who did not experience airways obstruction when subjected to the same exercise task. These results provide further evidence that mediators of hypersensitivity are released during EIA.     

Histamine Secretion from Human Leucocytes Stimulated by Basophil-derived Platelet-activating Factor

Crude preparations of platelet-activating factors (PAF) derived by methanolic extraction of supernatants from antigen-challenged basophils generally stimulated the secretion of histamine from human peripheral blood leucocytes when co-incubated with these cells in the absence of an additional stimulator. When these crude preparations were analysed by a preparative thin-layer chromatography technique established for the isolation of purified native PAF, multiple lipid components were identified. The component that migrated in accordance with native PAF, and which activated platelets to aggregation/secretion, was responsible for the induction of histamine release previously seen with the crude PAF preparations and could augment histamine secretion from leucocytes undergoing stimulation with either the biologically active peptide F-Met-Leu-Phe or with antigen E. These data suggest that basophil-derived PAF may serve as an important endogenous feedback mechanism during basophil activation in addition to its modulatory role upon the platelet.     

Effects of drugs on the acute inflammation following intraperitoneal injection of antigen into actively sensitised rats.

When actively sensitised rats were injected intraperitoneally with antigen, the local reaction that ensued can be divided into two phases: an immediate reaction characterised by histamine and SRS-A release with an associated extravasation of plasma proteins, and a later reaction involving infiltration of neutrophilic polymorphonuclear leucocytes. When the immediate reaction was modified by BRL 10833 (which inhibits histamine release from rat mast cells and reduces extravasation of plasma proteins), there was no reduction in neutrophil infiltration. FPL 55712, an SRS-A antagonist, also failed to inhibit neutrophil infiltration. The beta-adrenoreceptor stimulants isoprenaline and salbutamol reduced neutrophil infiltration. Isoprenaline inhibited the extravasation of plasma proteins when given before antigen, but even when administered to rats after antigen, when extravasation was complete, it still inhibited neutrophil infiltration. Propranolol reversed isoprenaline-induced inhibition of neutrophil infiltration.     

Antigen-induced neutrophil chemotactic activity from sensitized lung

We have used the model of ovalbumin-sensitized guinea pigs to define the source of antigen-derived, high-molecular-weight neutrophil chemotactic activity (NCA). Incubating sensitized lung fragments with specific antigen (ovalbumin) but not irrelevant antigen (bovine serum albumin) or buffer resulted in the release of high-molecular-weight NCA and histamine, suggesting a lung mast cell origin for NCA. High-molecular-weight NCA accounted for greater than 90% of the NCA observed after antigen-lung incubation. The importance of high-molecular-weight NCA in recruitment of neutrophilic leukocytes to the site of allergic inflammatory reactions is emphasized.