Eosinophils: biology and role in disease.
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Animals↗
Biomedical subjects
A B Kay
Publications and source records attributed to A B Kay.
Are you TH-1 or TH-2?
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Granulomatous Disease, Chronic↗
Eosinophil cationic protein (ECP) and eosinophil protein X (EPX) concentrations in serum and bronchial lavage fluid in asthma. Effect of prednisolone treatment.
BACKGROUND: Eosinophil granule proteins may contribute to bronchial hyperresponsiveness in asthma. OBJECTIVE: To measure eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in serum and bronchial lavage fluid from 20 asthmatics and 16 control subjects. To assess the effect on these eosinophil proteins of corticosteroid treatment of asthma. To determine whether serum ECP and EPX measured weekly in a longitudinal study for 10 weeks reflected changes in lung function. METHODS: Eosinophil granule proteins were measured by radioimmunoassay of bronchial wash (BW), bronchoalveolar lavage (BAL) and serum. RESULTS: Eosinophils were elevated in BAL (P < 0.01), BW (P < 0.01) and blood (P < 0.01) from asthmatics compared with control subjects. Eosinophils cationic protein concentration was significantly elevated in BAL (P < 0.05) and BW from asthmatics (P < 0.01) and EPX was increased in BAL (P < 0.05) and BW (P < 0.01). These changes were also reflected in elevated serum ECP (P < 0.01) and EPX (P < 0.01) concentrations in asthmatic subjects. There was no significant difference between subjects receiving prednisolone and the placebo group, but there was a fall in ECP in BW (P < 0.05) and serum (P < 0.01) and in EPX in BW (P < 0.01) and serum (P < 0.01) within the group receiving prednisolone. In the longitudinal study there was only a significant difference between ECP values associated with highest and lowest peak expiratory flow rate (PEFR) (P < 0.05). CONCLUSIONS: These data confirm a role for eosinophil activation in the airway in asthma pathogenesis, and add some support to the hypothesis that corticosteroids may inhibit eosinophil activation in asthma.
Adult↗
Mechanisms of persistent airway inflammation in asthma. A role for T cells and T-cell products.
The role of T cells in human allergic inflammation is just beginning to be understood. However, the data presented indicate how the T cell may be a pivotal cell to direct features of allergic inflammation in asthma, how the T cell may be able to transfer hyperresponsiveness, which is a feature of bronchial asthma, what some of the genetic factors are that may determine this process, and how an important precipitant of asthma, viral respiratory infections, may participate in this process. Its cells are isolated from patients with asthma and studied for their ability to generate proinflammatory failure. An expanded understanding of the chronic, persistent nature of asthma will become apparent.
Animals↗
Phenotype of cells expressing mRNA for TH2-type (interleukin 4 and interleukin 5) and TH1-type (interleukin 2 and interferon gamma) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects.
We investigated the phenotype of cells expressing messenger RNA encoding interleukin 4 (IL-4), IL-5, IL-2, and interferon gamma (IFN-gamma) in bronchoalveolar lavage (BAL) and bronchial biopsies (BX) from seven mild atopic asthmatic patients and nine nonasthmatic controls. Immunocytochemistry followed by in situ hybridization using either 35S- or digoxigenin-labeled riboprobes was performed on cytospins from BAL and BX, respectively. With BAL or BX, in situ hybridization alone showed significant increases in percentages of IL-2, IL-4, and IL-5 mRNA+ cells when asthmatics were compared to nonasthmatic controls. Double immunocytochemistry-in situ hybridization revealed that > 70% of IL-4 and IL-5 mRNA+ cells were activated T cells (CD3+). The remaining IL-4 and IL-5 mRNA+ signals were colocalized to tryptase+ mast cells, and activated eosinophils (EG2+). Rare IL-4 and IL-5 mRNA+ cells were observed in nonasthmatic controls, the majority being CD3+ cells, as were IL-2 and IFN-gamma mRNA+ cells (in both asthmatics and controls). A few IL-4 (< 8%) and IL-5 (< 5%) mRNA+ signals did not colocalize with any of the cells identified by immunocytochemistry. Thus, we provide further evidence that CD3+ T cells are the most abundant cells expressing IL-4 and IL-5 mRNA in BAL and BX from allergic asthma. Fewer, but detectable, numbers of tryptase+ mast cells and EG2+ eosinophils also expressed these transcripts.
Adult↗
Peripheral blood CD4 but not CD8 t-lymphocytes in patients with exacerbation of asthma transcribe and translate messenger RNA encoding cytokines which prolong eosinophil survival in the context of a Th2-type pattern: effect of glucocorticoid therapy.
T-lymphocyte (T-LC)-derived cytokines have been implicated in asthma pathogenesis. Activation of peripheral blood CD4 but not CD8 T-LC and a Th2-type pattern of elevated cytokine mRNA expression in BAL fluid T-LC have been observed in asthmatics, but the principal source (CD4 or CD8 T-LC) of these cytokines is unknown. Our objective was to measure expression of Th1- and Th2-type cytokine mRNA and spontaneous secretion of IL-3, IL-5, and GM-CSF by peripheral blood CD4 and CD8 T-LC from asthmatics before and after oral glucocorticoid therapy and non-asthmatic controls. We used in situ hybridization to detect mRNA expression in isolated CD4 and CD8 T-LC, and an in vitro eosinophil survival assay to detect secretion of IL-3, IL-5, and GM-CSF in T-LC culture supernatants. Comparing the asthmatics with the controls, elevated percentages of CD4 T-LC expressed mRNA encoding IL-5, IL-4, and GM-CSF (P < 0.02) but not IL-3, IL-2, or IFN-gamma. In CD8 T-LC, mRNA expression was generally low with no significant differences between the groups. In the asthmatics, the percentages of CD4 T-LC expressing IL-5 mRNA correlated with disease severity and the numbers of peripheral blood eosinophils (P < 0.01). Culture supernatants of asthmatic CD4 but not CD8 T-LC exhibited significantly higher (P = 0.0003) eosinophil survival-prolonging activity compared with controls, in which low activity was detected. Inhibition with anti-cytokine antibodies suggested that GM-CSF, and to a lesser extent IL-5 and IL-3, could account for this activity. After oral glucocorticoid therapy of the asthmatics, lung function improved and the percentages of CD4 T-LC expressing mRNA encoding IL-3, IL-5, and GM-CSF but not IL-2, IL-4, or IFN-gamma were reduced (P < 0.04). Secretion of eosinophil survival-prolonging activity by the CD4 T-LC was also reduced (P = 0.004). We conclude that peripheral blood CD4 but not CD8 T-LC from asthmatics express cytokine mRNA in a Th2-type pattern and show elevated secretion of cytokines prolonging eosinophil survival. Glucocorticoid therapy of asthmatics is associated with a reduction in the percentages of CD4 T-LC expressing IL-3, IL-5, and GM-CSF mRNA and secretion of the corresponding proteins.
Adolescent↗
T-cells subsets and activation in bronchial mucosa of sensitized Brown-Norway rats after single allergen exposure.
We have investigated the relationship between changes in T-cell activation in the bronchial mucosa, airway responsiveness and eosinophilic inflammation in sensitized Brown-Norway rats exposed to ovalbumin (OVA). Rats sensitized intraperitoneally with OVA and exposed to OVA aerosol 21 days later showed an enhanced increase in lung resistance (RNL) to acetylcholine (P < 0.05), and a significant increase in the number of eosinophils, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BAL) (P < 0.05), compared with sensitized but saline-exposed controls. There was a significant increase in cells expressing the T-cell activation marker CD25 (P < 0.05) and the numbers of CD8+ T cells (P < 0.05), but not in the numbers of CD2+ and CD4+ cells. Eosinophil counts in airway submucosal tissue, as assessed by staining with BMK-13; a monoclonal antibody that binds to eosinophil major basic protein (MBP), were increased in rats receiving sensitization and exposure to OVA compared with naive controls (P < 0.002). There were significant positive correlations between the increase in RL to acetylcholine and the numbers of CD25+ (r = 0.92, P < 0.001), CD4+ (r = 0.77, P < 0.05), CD8+ (r = 0.71, P < 0.05) and MBP+ (r = 0.72, P < 0.03) cells in the OVA-sensitized and exposed group, but not in saline-exposed or naive animals. The number of MBP+ cells also correlated with CD25 expression (r = 0.71, P < 0.05). We conclude that airway hyper-responsiveness and inflammatory cell infiltration caused by OVA exposure of sensitized animals is associated with the presence of activated T cells in the airway mucosa. CD8+ T cells may play a role in the regulation of events leading to eosinophil inflammation and airway hyper-responsiveness.
Allergens↗
Airway hyperresponsiveness, elevation of serum-specific IgE and activation of T cells following allergen exposure in sensitized Brown-Norway rats.
T lymphocytes may play a regulatory role in the development of allergic airway hyperresponsiveness (AHR). We have studied the relationship between airway responsiveness and a number of immunological changes in Brown-Norway rats sensitized intraperitoneally and repeatedly exposed to ovalbumin (OVA) aerosol. Acetylcholine provocation concentration (PC)150 (the concentration of acetylcholine causing a 150% increase of base-line lung resistance) was measured and peripheral blood and bronchoalveolar lavage (BAL) cells were collected 18-24hr after the final exposure. Total and OVA-specific IgE in serum was measured by enzyme-linked immunosorbent assay (ELISA). Mononuclear cells were analysed by flow cytometry after labelling with monoclonal antibodies against CD2 (pan T-cell marker), CD4, CD8 (T-cell subsets) or CD25 (interleukin-2 receptor). There were significant differences in PC150 (P < 0.05) and in OVA-specific IgE levels in serum (P < 0.002); CD4+ T cells expressed a significantly increased level of CD25 immunoreactivity in BAL, but not in peripheral blood, of rats sensitized and exposed to OVA, compared with saline-exposed controls (P < 0.02). There was a significant correlation between CD25 expression and BAL eosinophil numbers (r = 0.74, P < 0.001), PC150 (r = 0.63, P < 0.003) and OVA-specific IgE (r = 0.77, P < 0.001). These data suggest that activated T cells may be involved in the regulation of allergen-induced AHR in a relevant animal model of allergic asthma.
Allergens↗
Clinical response to cyclosporin in chronic severe asthma is associated with reduction in serum soluble interleukin-2 receptor concentrations.
Activated T-lymphocytes play an important role in asthma pathogenesis and release soluble interleukin-2 receptor (sIL-2R), which can be detected in the serum. In a recent randomized, cross-over trial we showed that cyclosporin, an inhibitor of T-lymphocyte activation, improved lung function in patients with chronic severe asthma. To investigate whether changes in serum sIL-2R concentration could be related to clinical response we prospectively compared serum sIL-2R concentrations in patients during cyclosporin and placebo treatment. Peripheral venous blood was obtained from 22 patients during the last 4 weeks of both the cyclosporin and placebo treatment periods and serum stored at -80 degrees C pending measurement of sIL-2R concentration by enzyme immunoassay. Soluble IL-2R was detected in all samples at a concentration range of 191-2,297 U.ml-1. Mean serum concentrations of sIL-2R were significantly lower on cyclosporin therapy (560 U.ml-1) as compared with placebo (676 U.ml-1). The decreases in serum sIL-2R concentrations associated with cyclosporin therapy in these patients correlated with the percentage increases in their morning peak expiratory flow rate (PEFR) measurements on cyclosporin as compared with placebo. These data demonstrate that in patients with chronic severe asthma, cyclosporin therapy which results in clinical improvement is associated with a decrease in serum concentrations of sIL-2R. This is compatible with the hypothesis that cyclosporin ameliorates asthma, at least partly, by inhibition of T-lymphocyte activation.
Asthma↗
Origin of type 2 helper T cells.
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CD4-Positive T-Lymphocytes↗
Allergy testing in supermarkets. Misleads susceptible people.
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Humans↗
Cytokine generation by eosinophils.
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Chemokine CCL4↗
The effect of dexamethasone, cyclosporine, and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma.
Inhibition of T-lymphocyte activation may provide a useful approach to the treatment of chronic severe asthma. We compared rapamycin, a novel immunosuppressive drug, with cyclosporine and dexamethasone for its effects in inhibiting proliferation of T lymphocytes from patients with glucocorticoid-resistant and glucocorticoid-sensitive asthma. Phytohemagglutinin-stimulated peripheral blood T lymphocytes from 11 patients with clinically glucocorticoid-resistant and 8 patients with glucocorticoid-sensitive chronic asthma were tested for sensitivity to these drugs in a highly reproducible proliferation assay. All drugs inhibited proliferation in a dose-dependent manner (10(-6) to 10(-10) mol/L). T lymphocytes from the patients with glucocorticoid-resistant asthma were significantly less sensitive (p < 0.01) to dexamethasone than those of patients with glucocorticoid-sensitive asthma over a wide concentration range. In contrast, cyclosporine and rapamycin inhibited cells from both patient groups to an equivalent extent. The presence of exogenous interleukin-2 abrogated the inhibitory effect of dexamethasone but not that of cyclosporine or rapamycin, suggesting that dexamethasone may act principally by inhibition of interleukin-2 production, whereas the latter drugs exert distinct or additional inhibitory effects. Stimulation of peripheral blood T lymphocytes with phytohemagglutinin for 24 hours before addition of the drugs abolished the inhibitory effect of dexamethasone and significantly reduced that of cyclosporine. The inhibitory effect of rapamycin was, however, unaltered. These data suggest that dexamethasone and cyclosporine exert their effects only at an early stage of T-lymphocyte activation, whereas rapamycin is able to inhibit lymphoblasts. The fact that the inhibitory mechanisms of these drugs are different might explain why cyclosporine and rapamycin are effective in inhibiting T lymphocytes from both patients with glucocorticoid-sensitive and those with glucocorticoid-resistant asthma. The data further suggest that cyclosporine and rapamycin may be effective for the therapy of glucocorticoid-resistant asthma.
Adult↗
Polymerase chain reaction quantification of cytokine messenger RNA expression in peripheral blood mononuclear cells of patients with acute exacerbations of asthma: effect of glucocorticoid therapy.
We have measured the expression of messenger ribonucleic acid (RNA) (mRNA) encoding interleukin-5 (IL-5), IL-4, IL-2 and interferon-gamma (IFN gamma) in peripheral blood mononuclear cells (PBMC) from 10 patients with acute exacerbations of asthma and nine non-asthmatic controls. Measurements were repeated in seven of the asthmatics following 7 days of oral glucocorticoid therapy. Total RNA was extracted from the PBMC, reverse transcribed using oligo-(dT) primers and aliquots of the resulting complementary DNA (cDNA) amplified using the polymerase chain reaction (PCR) in the presence of cytokine-specific primers under non-saturating conditions. PCR products were quantified on a relative basis after Southern blotting and probing with radiolabelled internal oligonucleotide probes by computer assisted densitometry of blot autoradiographs. The relative amounts of IL-5 mRNA in PBMC from the asthmatic patients prior to glucocorticoid therapy were greater (P < 0.01) than those in PBMC from non-asthmatic controls. In contrast, there were no differences in the relative amounts of IL-4, IL-2 and IFN gamma mRNA. In the asthmatics, the relative amounts of IL-5 mRNA correlated with the peripheral blood eosinophil counts (P = 0.02). After oral glucocorticoid therapy of the asthmatics, lung function improved and the relative amounts of PBMC IL-5 mRNA were reduced (P = 0.04) and no longer differed from those in PBMC from non-asthmatic controls. Glucocorticoid therapy was not associated with significant changes in the relative amounts of PBMC IL-4, IL-2 and IFN gamma mRNA. PBMC from atopic subjects contained significantly greater quantities of IL-4 mRNA (P = 0.04) but not IL-5, IL-2 and IFN gamma mRNA compared with non-atopic subjects regardless of their asthmatic status. We conclude that PBMC of patients with acute exacerbations of asthma demonstrate elevated expression of mRNA encoding IL-5, but not IL-2, IL-4 and IFN gamma and that the clinical improvement associated with glucocorticoid therapy is associated with a reduction of IL-5 mRNA expression. We further conclude that elevated expression in PBMC of mRNA encoding IL-4 is a feature of atopy but not of asthma. These observations suggest that IL-5 synthesis by activated T-lymphocytes may be relevant to the pathogenesis of asthma, and that inhibition of this release by glucocorticoids may at least partly explain their therapeutic effect in this disease.
Actins↗
Influence of prolonged treatment with topical corticosteroid (fluticasone propionate) on early and late phase nasal responses and cellular infiltration in the nasal mucosa after allergen challenge.
We have examined the effect of prolonged treatment with topical corticosteroid on allergen-induced early and late nasal responses and the associated inflammatory cell infiltrate in grass pollen sensitive allergic rhinitics. Following a randomized double-blind 6 week treatment period with fluticasone propionate 200 micrograms aqueous nasal spray twice daily or matched placebo spray, nasal provocation was performed using Timothy grass pollen extract. Nasal symptoms were recorded at intervals from 0 to 24 h. Nasal biopsies were performed before treatment and at 24 h after allergen and processed for immunohistology. When corticosteroid-treated patients were compared with the placebo group there was an approximately 50% decrease in the size of the early (0-60 min) response and almost complete inhibition of late (1-24 h) nasal symptoms after allergen challenge. After allergen challenge markedly fewer T lymphocytes and CD25+ (interleukin-2 receptor bearing) cells were observed in both the epithelium and submucosa in fluticasone treated patients compared with the placebo group. Significantly less total and activated eosinophils were observed, particularly within the nasal epithelium. Submucosal mast cell counts were decreased, whereas increased numbers of submucosal neutrophils were observed. These results confirm that topical corticosteroid treatment inhibits allergen-induced early and late nasal responses. This may possibly occur following a decrease in T lymphocytes and/or mast cells and their products and a consequent reduction in tissue eosinophilia.
Administration, Topical↗
Activated peripheral blood CD4 and CD8 T-lymphocytes in child asthma: correlation with eosinophilia and disease severity.
There now exists compelling evidence of a role for cell-mediated immunity in the pathogenesis of adult asthma, but little information is available as to what extent this process participates in the pathogenesis of childhood asthma. We hypothesised that asthma in children is associated with the activation of T-lymphocytes whose products regulate, at least in part, the mobilisation and recruitment of eosinophils and thereby disease severity. Our aims, therefore, were to compare the expression of activation markers, including CD45 isoforms, on peripheral blood T-lymphocytes from asthmatic and non-asthmatic, allergic control children matched for age and atopic status, and to attempt to correlate the percentages of activated T-lymphocytes in the asthmatics with the numbers of peripheral blood eosinophils and with disease severity. Seventeen children with moderate to severe chronic asthma were compared with 8 non-asthmatic, allergic children matched for age and atopic status. Expression of the activation markers CD25, HLA-DR and VLA-1 and the CD45 isoforms CD45RA and CD45RO on peripheral blood CD4 and CD8 T-lymphocytes was measured using dual fluorescence flow cytometry. Peripheral blood eosinophils were measured using an automated laser cytometer. Asthma severity was assessed by a symptom score, spirometry and measurement of histamine PC20. The absolute numbers of eosinophils in the peripheral blood of the asthmatics were elevated as compared to the non-asthmatic, allergic controls (p < 0.01), whereas the absolute numbers of both CD4+ and CD8+ T-lymphocytes were not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Serum interleukin 5 concentrations in atopic and non-atopic patients with glucocorticoid-dependent chronic severe asthma.
BACKGROUND: Interleukin (IL)-5 is thought to play a part in asthmatic bronchial mucosal inflammation and is a potential therapeutic target. Detectable serum IL-5 concentrations have been found previously in a proportion of patients with acute severe asthma, but not in the same patients following oral glucocorticoid therapy or in normal controls. A study was undertaken to investigate whether or not IL-5 is detectable in the serum of patients with glucocorticoid-dependent chronic severe asthma. METHODS: Serum concentrations of IL-5 were measured in 29 patients with stable oral glucocorticoid-dependent chronic severe asthma (mean PEFR 59.7% predicted) and seven normal controls using a specific enzyme-linked immunoassay calibrated with recombinant human IL-5 standards (lower limit of sensitivity 40 pg/ml). RESULTS: Interleukin 5 was detectable in the serum of 15 of the 29 patients at a median concentration of 150 pg/ml (range 40-690), but was undetectable in the serum of all the control subjects. The patients with detectable serum IL-5 concentrations did not differ from those with undetectable concentrations in terms of atopic status, disease severity (percentage predicted PEFR or FEV1), prednisolone dosage, serum IgE concentrations, or peripheral eosinophil count. CONCLUSIONS: Interleukin 5 is detectable in the serum of a proportion of both atopic and non-atopic patients with chronic severe asthma, and concentrations in these patients were higher than in normal controls. These observations are compatible with the hypothesis that IL-5 release occurs in these patients during a period of stable asthma despite systemic glucocorticoid therapy.
Adult↗
Evidence for a Th1-like bronchoalveolar T-cell subset and predominance of interferon-gamma gene activation in pulmonary tuberculosis.
Mycobacterium-specific human helper T-cell clones produce a Th1 pattern of cytokines in vitro: interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), but little or no IL-4 or IL-5. To test the hypothesis that a similar Th1-like pattern of cytokine gene expression occurs in vivo in pulmonary tuberculosis we used in situ hybridization to detect cytokine mRNA expression by bronchoalveolar lavage cells from nine patients with microbiologically confirmed tuberculosis and nine control subjects. Because IFN-gamma may also originate from alveolar macrophages, simultaneous immunocytochemistry and in situ hybridization was applied to determine whether cytokine mRNA was localized to bronchoalveolar macrophages in addition to T-lymphocytes. When samples from patients with tuberculosis and control subjects were compared, there was a significant increase in numbers of IFN-gamma mRNA-positive BAL cells per 1,000 among patients with tuberculosis (p < 0.01). Differences between the two groups in the proportions of cells expressing IL-2, IL-4, or IL-5 mRNA were not significant. Expression of IFN-gamma mRNA by macrophages was detected (median, 14.3% of IFN-gamma mRNA-positive BAL cells). However, the majority of IFN-gamma mRNA expressing BAL cells were T-lymphocytes (median, 80.7%). Activation of Th1-like bronchoalveolar T-lymphocytes, together with production of IFN-gamma by alveolar macrophages, may contribute to the local cellular immune response in pulmonary tuberculosis.
Adolescent↗