Cell-mediated immune response in asthma.
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Asthma↗
Biomedical subjects
A B Kay
Publications and source records attributed to A B Kay.
The activated eosinophil in allergy and asthma.
Our studies indicate that human eosinophils can be activated in terms of up-regulation of surface receptors, increased membrane lipid generation, and enhanced cytotoxicity by a variety of pharmacological mediators, through IgE-, IgG-, and complement-dependent pathways. PAF is an impressive activator of eosinophil function and is the most potent chemotactic mediator for eosinophils so far described. It is not selective in that neutrophils are also attracted by PAF. In our hands, IL-1, IL-2, granulocyte/macrophage-colony stimulating factor, tumor necrosis factor, interferon-gamma, and IL-5 tested over a wide concentration range gave very weak chemotaxis for eosinophils in vitro. Nevertheless, in vivo infiltration of eosinophils into the site of allergic tissue reactions is closely associated with the local accumulation of activated (CD4+, IL-2 rec+) T cells. We suggest, therefore, that the selective eosinophil infiltration seen in allergic inflammation may result from the initial recruitment and activation of granulocytes by lipid mediators and the subsequent selective activation of eosinophils by cytokines.
Asthma↗
The relationship between infiltrating CD4+ lymphocytes, activated eosinophils, and the magnitude of the allergen-induced late phase cutaneous reaction in man.
The phenotype and activation status of leukocytes infiltrating human late phase allergic skin reactions were investigated by immunocytochemistry using a panel of mAb. Late phase skin reactions were induced in atopic individuals by intradermal challenge with allergen extract (grass pollen or house dust mite) and skin biopsies were obtained 6, 24, or 48 h after challenge. Cryostat sections were examined for evidence of infiltration and activation of T cells and eosinophils. Biopsies from saline-challenged control sites were used for comparison. A substantial number of CD3+ cells were observed close to the dermal capillaries. The number of CD4+ cells showed a similar pattern but few CD8+ cells were seen. The ratio of CD4 and CD8 subsets in tissue did not relate to the CD4/CD8 ratio in the peripheral blood. Two observations suggested that T cells had become activated: first, a small number of infiltrating cells bore receptors for IL-2, and second, there was indirect evidence of IFN-gamma secretion, demonstrated by increased expression of HLA-DR on endothelial cells and de novo expression of CD4 Ag on epidermal Langerhans cells. Activated eosinophils were detected in most of the allergen-challenged biopsies. The late phase reaction diameter at 6 h correlated with the number of activated eosinophils at 48 h (r = 0.61, p = 0.05), but not with infiltration by T cells. There was a strong correlation between the numbers of CD4+ cells and activated eosinophils at 24 h (r = 0.94, p less than 0.001). These findings suggest that interactions between T lymphocytes and eosinophils in reactions to airborne allergens may be more important than has previously been recognized.
Adolescent↗
T lymphocyte activation in acute severe asthma.
T lymphocyte subsets and lymphocyte activation markers in the peripheral blood were assessed in patients admitted to hospital with acute severe asthma (status asthmaticus). Measurements were made on admission, day 3, and day 7 (or on discharge from hospital if this was sooner). The results were compared with 3 control groups (mild asthma, chronic obstructive airways disease, and normal individuals). The percentages of CD4-positive and CD8-positive T lymphocytes, and the CD4/CD8 ratios, were similar in the patients with acute severe asthma and the control groups, and were within the normal range. In contrast, patients with acute severe asthma had significant increases, compared with control subjects, of three surface proteins associated with T lymphocyte activation: interleukin-2 receptor (IL-2R); class II histocompatibility antigen (HLA-DR); and "very late activation" antigen (VLA-1). The IL-2R-positive T lymphocytes were exclusively of the CD4 "helper-inducer" phenotype. The percentages of IL-2R-positive and HLA-DR-positive (but not VLA-1-positive) lymphocytes tended to decrease as the patients were treated and clinically improved, although these values remained raised above control values for the observation period. Cell-mediated immunity may be causally related to the pathogenesis of acute severe asthma.
Acute Disease↗
The pattern of human late-phase skin reactions to extracts of aeroallergens.
The kinetics and dose response of cutaneous late phase reactions (LPR) (defined as greater than 5 mm induration 6 hours after intradermal challenge with allergen) were studied in 20 randomly selected subjects with atopic rhinitis. When subjects were challenged intradermally with 0.2 biologic unit (BU) of Dermatophagoides pteronyssinus or grass pollen, wheal-and-flare reactions were elicited without subsequent LPRs. With 30 BU, all subjects developed LPRs, whereas 1 and 10 BU provoked LPRs in 28% and 64%, respectively. No biphasic responses were detected. At all concentrations which progressed to form an LPR, a palpable skin reaction was continuously present and either remained constant or increased steadily in magnitude during 6 hours. Skin reactions of similar diameter provoked by histamine resolved fully within 2 hours. Thus, we confirm that the development of a macroscopic cutaneous LPR requires a higher concentration of allergen than the wheal-and-flare reaction. Together with our other findings, these results suggest that all untreated atopic individuals are capable of mounting an LPR if they are challenged with sufficient allergen. In contrast to the asthmatic response to inhaled allergen, the cutaneous wheal and LPR are not biphasic.
Adult↗
Leukotriene C4 generation from human eosinophils stimulated with IgG-Aspergillus fumigatus antigen immune complexes.
Sepharose beads coated with IgG stimulate eosinophils to produce leukotriene C4 (LTC4). This observation has been extended with specific immobilized IgG/antigen immune complexes to elicit mediator generation. An extract of Aspergillus fumigatus was covalently coupled to Sepharose beads and incubated with the IgG fraction of immune serum from patients with allergic bronchopulmonary aspergillosis. These beads elicited generation of 7.72 +/- 1.7 pmol of LTC4 immunoreactive material (n = 5) from 1 X 10(6) normal eosinophils of greater than 86% purity, and significantly less LTC4 (0.73 +/- 0.19 pmol per 10(6) cells; n = 3) was produced by eosinophils after incubation with beads treated with IgG from normal nonimmune serum. The maximum antibody-dependent release achieved represented approximately 20% of that induced by the calcium ionophore (A23187). LTC4 was measured by radioimmunoassay and validated by reverse-phase high-performance liquid chromatography. The amount of LTC4 generated was dependent on the concentration of A. fumigatus-specific IgG, and mediator release was completely abolished by prior adsorption of the IgG fraction onto Sepharose-protein A (Staphylococcus aureus). Grass pollen-specific IgG antibody/antigen complexes, in combination with Sepharose beads, also triggered generation of LTC4 immunoreactive material. There was no evidence to suggest that IgE/A. fumigatus immune complexes triggered LTC4 generation, although IgE myeloma protein, in association with Sepharose beads, was a weak stimulus. The efficacy of the IgG immune complex-dependent stimulation of eosinophils suggests a possible physiologic mechanism whereby these cells could participate in the inflammatory changes associated with allergic bronchopulmonary aspergillosis and similar allergic disorders.
Antigen-Antibody Complex↗
Influence of atopy on the clinical manifestations of coronavirus infection in adult volunteers.
In an attempt to understand the relationship between viral upper respiratory tract infection and the underlying virological and immunological mechanisms, thirty-four volunteers were inoculated intranasally with coronavirus 229E; subsequent virus shedding and/or antibody rises, indicating active infection, were observed in twenty-nine. There was a greater increase in independently measured scores of clinical severity, e.g. cold symptoms, in those with detectable IgE in nasal secretions (P less than 0.01). A similar association was found between clinical scores and serum IgE concentrations greater than or equal to 150 IU/ml, but the relationship with systemic atopy, as assessed by skin-prick tests to common allergens, was less marked. A more detailed study of twelve of the infected volunteers failed to explain these findings on the basis of mast cell mediator release, as concentrations of leukotriene B4, the sulphidopeptide leukotriene C4, and histamine, were not appreciably elevated in the nasal secretions following virus inoculation. Similarly, there was no evidence that circulating coronavirus specific IgE was produced. Thus, this study suggest that atopy may be related to the severity of cold symptoms produced by coronavirus 229E, although the exact connection has yet to be determined.
Adolescent↗
Effects of nedocromil sodium (Tilade) on the activation of human eosinophils and neutrophils and the release of histamine from mast cells.
The ability of nedocromil sodium, a new anti-inflammatory agent for the treatment of asthma, to inhibit activation of human eosinophils and neutrophils in vitro, has been studied using an adherence reaction (the "rosette" technique) as well as a cytotoxicity assay. We have also investigated the capacity of nedocromil sodium to inhibit IgE-dependent histamine release from human lung mast cells. The drug was a potent inhibitor (IC50 approx 5 x 10(-9)M) of fMLP-induced enhancement of eosinophil and neutrophil complement (C3b) and IgG (Fc) rosettes. There was also a comparable inhibition of enhancement, by fMLP, of eosinophil and neutrophil cytotoxicity (for complement-coated schistosomula of Schistosoma mansoni). Although nedocromil sodium also inhibited histamine release from human lung mast cells in a dose-dependent fashion its activity was relatively weak (IC30 5 x 10(-6)M) compared to its effect on granulocytes. These experiments support the view that the principal mode of action of nedocromil sodium is its capacity to inhibit the activation of inflammatory cells.
Anti-Inflammatory Agents, Non-Steroidal↗
Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity.
We have performed bronchoalveolar lavage (BAL) on 17 subjects with mild atopic asthma (9 symptomatic, 8 asymptomatic) and 14 nonasthmatic control subjects (6 hay fever, 8 nonatopic). There was a significant increase in the percentage of mast cells in both groups of asthmatics although the counts were no different from those previously reported for a number of other respiratory diseases. Asthmatics with airway hyperreactivity (PC20 less than 4 mg/ml) had significant increases in spontaneous histamine release. There was a significant elevation in the eosinophil count and the concentration of major basic protein (MBP) in BAL fluid in the symptomatic asthmatics. Furthermore, there was a significant correlation between the amounts of MBP recovered and the percentage of eosinophils in the BAL. These changes were even more marked when asthmatics with airway hyperreactivity were compared with subjects with normoreactive airways. In addition, there was a significant increase in the percentage of epithelial cells in the hyperreactive asthmatics. There was an inverse correlation between the PC20 and the percentage of mast cells (p less than 0.01), eosinophils (p less than 0.05), and epithelial cells (p less than 0.05) and amount of MBP in BAL (p less than 0.01). This study supports the hypothesis that bronchial hyperresponsiveness is secondary to epithelial cell damage mediated through eosinophil-derived granule products.
Adult↗
MHC class II restriction specificity of cloned human T lymphocytes reactive with Dermatophagoides farinae (house dust mite).
In this report the antigen and restriction specificity of human T-cell clones induced with Dermatophagoides farinae (D. farinae) and isolated from an atopic individual with perennial rhinitis has been investigated. Of the six clones analysed, four were species specific and two showed cross-reactivity for the closely related Dermatophagoides pteronyssinus (D. pteronyssinus). Inhibition of antigen-dependent proliferation by murine monoclonal antibodies directed against HLA-D-region gene products revealed that all the clones were restricted by HLA-DR molecules. The restriction specificity was investigated further using a panel of histocompatible and allogeneic-presenting cells. Of the clones tested, one appeared to be DR5 restricted while the remainder showed complex patterns suggesting that DRw52 and DRw53 supertypic specificities may be the restriction elements presenting antigen.
Allergens↗
A T-lymphocyte-derived factor that enhances IgG-dependent release of leukotriene B4 (LTB4) from human neutrophils.
We describe a human blood mononuclear cell (MNC)-derived leukotriene release enhancing factor (LREF) which significantly increased IgG-dependent leukotriene B4 (LTB4) generation by neutrophils. MNCs incubated with phytohaemagglutinin (PHA) or anti-CD3 monoclonal antibody and PHA-stimulated ER+ lymphocytes produced a 150-350% increase in LTB4 generation from IgG-stimulated neutrophils. With PHA, maximal activity was observed 48 hr after culture in serum-free medium. LREF was relatively stable when exposed to low pH (pH 2) or heat (56 degrees, 60 min). Following progressive purification by gel filtration (FPLC, Superose 12) and chromatofocusing (FPLC, Mono P) LREF was associated with proteins of molecular weight of 35-40 kD and a pI of 5.1-5.5. Partially purified LREF did not contain detectable amounts of interleukin 2 (IL-2) or interferon-gamma (IFN-gamma). Although high concentrations of recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF) (greater than 2 ng/ml) and recombinant tumour necrosis factor (rTNF) (greater than 100 U/ml) gave a slight (60%) enhancement of LTB4 generation, this was considerably less than that of partially purified LREF (350%). Our results suggest that human lymphocyte-derived LREF may play a role in the amplification of inflammatory reactions involving sensitized lymphocytes, neutrophils and lipid mediators.
Humans↗
Antigen-induced neutrophil chemotactic factor from cloned human T lymphocytes.
Here we report the presence of a low molecular weight (10,000 neutrophil chemotactic factor (NCF) in the supernatants of activated human T lymphocytes. Appreciable amounts of the 10,000 MW NCF were generated by peripheral blood mononuclear cells (PBMC) stimulated with anti-CD3 antibody, and comparable NCF was secreted by both long-term human T-helper (CD4+) cell lines reactive with house dust mite (Dermatophagoides farinae) and influenza A virus-immune T-cell clones. When the cloned T cells were stimulated with specific antigen in the presence of irradiated accessory cells (AC) or insolubilized anti-CD3 antibody the 10,000 MW NCF was readily identifiable in 24-hr culture supernatants. Cultures of AC and antigen alone produced negligible neutrophil chemotactic activity, as did control cultures using an irrelevant allergen (mixed grass pollen). These findings indicate that the 10,000 MW NCF may be T-lymphocyte derived and that formation and release are dependent upon stimulation via the antigen receptor.
Antigens↗
The identification and partial characterization of a human mononuclear cell-derived neutrophil chemotactic factor apparently distinct from IL-1, IL-2, GM-CSF, TNF and IFN-gamma.
We have identified a neutrophil chemotactic factor (NCF) in supernatants from human blood mononuclear cells (MNC) cultured in the presence of phytohaemagglutinin (PHA). Maximal activity was observed 48 hr after culture. Following gel filtration, NCF eluted as a single major peak, together with proteins, having a molecular size of approximately 10,000 MW. The material gave a single band on SDS-PAGE but was heterogeneous following chromatofocusing (pIs approximately 6.8-7.0, 5.5-6.0 and 5.0). The biological activity of the partially purified material was abolished by trypsin and chymotrypsin treatment. NCF was heat stable (70 degrees, 60 min) and promoted both directional migration (chemotaxis) of neutrophils and, to a lesser extent, stimulated random locomotion (chemokinesis). The factor was not associated with detectable amounts of IL-1, IL-2 or interferon-gamma (IFN-gamma). MNC-derived NCF had a molecular size lower than recombinant granulocyte-monocyte colony-stimulating factor (rGM-CSF) and recombinant tumour necrosis factor (rTNF), and was considerably more active in chemotaxis. Optimal chemotactic concentrations of partially purified MNC-derived NCF were of comparable potency to FMLP and LTB4 and had about 60% of the activity of optimal concentrations of C5a, C5a-des-Arg and platelet-activating factor (PAF). These experiments indicate that the human MNC-derived NCF is a potent chemo-attractant distinct from other cytokines previously reported to promote neutrophil locomotion.
Cell Movement↗
The relationship between mast cell-mediator release and bronchial reactivity in allergic asthma.
The relationship between mast cell-mediator release and nonspecific bronchial reactivity was investigated in allergen-induced asthma. Two groups of subjects with asthma, one group with markedly reactive airways (provocative concentration of methacholine causing a 20% fall in FEV1, 0.07 mg/ml) and the other group with less reactive airways (provocative concentration of methacholine causing a 20% fall in FEV1, 3.83 mg/ml), had allergen bronchoprovocation. After challenge, bronchoconstriction was measured as change in specific airway conductance (SGaw), and mast cell-mediator release was measured as change in both plasma histamine and serum neutrophil chemotactic activity (NCA). In the group with more reactive airways, allergen challenge, while it produced a mean fall in SGaw of 58.1%, was not associated with any significant increase in plasma histamine from a mean resting level of 3.69 nmol/L-1. In contrast, a comparable mean fall in SGaw of 52.4% in the group with less reactive airways was associated with a significant (p less than 0.005) increase in plasma histamine from 1.17 to 3.60 nmol/L-1, maximal 5 minutes after allergen challenge. There were, however, significant increments in serum NCA in both groups with asthma after allergen challenge. The changes in NCA in the group with less reactive airways (136.7 +/- 38.1% above baseline; p less than 0.01; 1% sera dilution) were significantly greater (p less than 0.05) than changes identified in the group with more reactive airways (68.3% above baseline; p less than 0.01; 20% sera dilution). These findings directly support the concept that both mast cell-mediator release and nonspecific bronchial reactivity are separate factors that influence the airway response to inhaled allergen in asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Disodium cromoglycate inhibits activation of human inflammatory cells in vitro.
Recent clinical studies indicate that disodium cromoglycate (DSCG) may have a direct effect on inflammatory cells because the drug reversed various changes in leukocyte function, such as increased membrane-receptor expression and enhanced cytotoxic capacity observed in peripheral white blood cells from subjects with asthma undergoing allergen-inhalation challenge. In the present study, we have demonstrated that DSCG, at low concentrations (a concentration of drug required to produce 50% inhibition, approximately 10(-8) mol/L) and in a time-dependent fashion, directly inhibited the activation in vitro of human neutrophils, eosinophils, and monocytes. Peripheral blood leukocytes were incubated with the synthetic chemoattractant, formyl-methionyl-leucyl-phenylalanine (at an optimal concentration of 10(-8) mol/L), and activation was assessed by measuring increases in the percentages of complement and IgG (Fc) rosettes as well as the enhanced capacity of these cells to kill target organisms (schistosomula of Schistosoma mansoni). DSCG at a concentration of 10(-7) mol/L totally inhibited both the formyl-methionyl-leucyl-phenylalanine-induced enhancement of complement and IgG rosettes, as well as increased schistosomular killing. These observations indicate that DSCG directly inhibits the secretory properties of inflammatory cells and that in turn might have important implications in modulating mechanisms contributing to the inflammatory component of asthma and allergic disease. It may also help to explain why compounds with considerably greater mast cell stabilizing properties than DSCG have been so disappointing when they are evaluated clinically.
Cromolyn Sodium↗
Further characterisation of allergens associated with hypersensitivity to the "green nimitti" midge (Cladotanytarsus lewisi, Diptera: Chironomidae).
Chironomid midges are small (2-15 mm) non-biting flies, characteristically seen swarming by water at dusk. Allergens of the "green nimitti" midge, Cladotanytarsus lewisi (Freeman) (Diptera: Chironomidae), a cause of widespread hypersensitivity in the Sudan, were isolated and partially characterized by Sephacryl S200 chromatography. The allergenicity of the fractions was identified by "rocket" autoradiography, RAST inhibition, skin "prick" tests, and the immunoblot technique. The fractions were further analysed by isoelectric focusing and SDS-PAGE. Two major allergens with pI's ranging from 4.3 to 6.0 were identified and had molecular weights of approximately 17,000 and 32,000 daltons, sizes compatible with their being monomeric and dimeric haemoglobins. Since chironomids occur in nuisance numbers worldwide and their haemoglobins have been shown to produce severe hypersensitivity reactions in man, they should be seen as an important potential cause of environmental and occupational allergy.
Allergens↗
The role of the eosinophil in the pathogenesis of asthma.
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Adrenal Cortex Hormones↗
In vitro effects of chemotactic factors on eosinophil Fc and complement receptor expression.
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Chemotactic Factors↗