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Corrigan CJ, Hamid Q, North J, et al., 1995, 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., Am J Respir Cell Mol Biol, Vol: 12, Pages: 567-578, ISSN: 1044-1549
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 secr
Lund VJ, Aaronson D, Bousquet J, et al., 1995, International consensus report on the diagnosis and management of rhinitis, Revue Francaise d'Allergologie et d'Immunologie Clinique, Vol: 35, Pages: 189-228, ISSN: 0335-7457
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Caplen NJ, Alton EWFW, Middleton PG, et al., 1995, Erratum: Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis (Nature Medicine (January 1995) 1 (39-46)), Nature Medicine, Vol: 1, ISSN: 1078-8956
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- Citations: 1
CAPLEN NJ, ALTON E, MIDDLETON PG, et al., 1995, LIPOSOME-MEDIATED CFTR GENE-TRANSFER TO THE NASAL EPITHELIUM OF PATIENTS WITH CYSTIC-FIBROSIS, NATURE MEDICINE, Vol: 1, Pages: 39-46, ISSN: 1078-8956
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- Citations: 653
Durham SR, Kay AB, Hamid Q, 1995, Changes in allergic inflammation associated with successful immunotherapy., Int Arch Allergy Immunol, Vol: 107, Pages: 282-284, ISSN: 1018-2438
Allergen injection immunotherapy in selected patients is effective and has wide ranging anti-inflammatory effects. These include modulation of serum (and presumably local) IgE and IgG antibody responses, a reduction in mast cell numbers in the target organ and inhibition of mast cell mediator release. Tissue eosinophilia and eosinophil activation are also reduced. We have compared and contrasted the effects of immunotherapy and topical corticosteroids on allergen-induced late nasal responses. Both treatments inhibit allergen-induced late nasal symptoms and associated CD4+ T cell and eosinophil recruitment, possibly by distinct mechanisms. Whereas topical corticosteroids may act by suppressing cytokine mRNA expression for Th2-type cytokines, particularly interleukin-4, immunotherapy induces a local Th1 response with an increase in interferon-gamma.
Durham SR, 1995, New insights into the mechanisms of immunotherapy., Eur Arch Otorhinolaryngol, Vol: 252 Suppl 1, Pages: S64-S67, ISSN: 0937-4477
Allergen-specific immunotherapy retains a place in treatment in patients with allergic rhinitis who fail to respond to conventional treatment with antihistamines and topical corticosteroids. Studies on mechanisms of immunotherapy have previously focussed on changes in serum antibodies, including blunting of seasonal rises in specific IgE and increase in "blocking" specific IgG antibodies. Immunotherapy in patients with rhinitis has also been shown to inhibit effector cells with a decrease in nasal mucosal eosinophils and epithelial mast cells. Recent evidence suggests that these events may be orchestrated by an effect of immunotherapy on T lymphocytes with alteration from a predominant "Th2" response (interleukin 4 and 5) in favour of an additional "Th1" response (gamma interferon) which may decrease tissue eosinophilia and local IgE production. Novel therapeutic approaches to allergic diseases might include use of topical gamma interferon, immunosuppressive agents, anti-CD4 antibodies or strategies directed specifically against IL-4 or IL-5.
TSICOPOULOS A, HAMID Q, HACZKU A, et al., 1994, KINETICS OF CELL INFILTRATION AND CYTOKINE MESSENGER-RNA EXPRESSION AFTER INTRADERMAL CHALLENGE WITH ALLERGEN AND TUBERCULIN IN THE SAME ATOPIC INDIVIDUALS, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 94, Pages: 764-772, ISSN: 0091-6749
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- Citations: 90
Rak S, Jacobson MR, Sudderick RM, et al., 1994, 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., Clin Exp Allergy, Vol: 24, Pages: 930-939, ISSN: 0954-7894
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.
Ying S, Durham SR, Jacobson MR, et al., 1994, T lymphocytes and mast cells express messenger RNA for interleukin-4 in the nasal mucosa in allergen-induced rhinitis., Immunology, Vol: 82, Pages: 200-206, ISSN: 0019-2805
We have investigated the phenotype of interleukin-4 (IL-4) mRNA+ cells in the nasal mucosa of six subjects with allergic rhinitis before and 24 hr after local allergen provocation with grass pollen extract. Serial cryostat sections were cut from paraformaldehyde-fixed snap-frozen nasal biopsies, and immunocytochemistry (APAAP) followed by in situ hybridization performed on the same sections. For immunocytochemistry, antibodies against CD3, tryptase, major basic protein (MBP) and CD68 were used to identify T cells, mast cells, eosinophils and macrophages, respectively. Hybridization studies were performed using a digoxigenin-labelled IL-4 riboprobe. Nitroblue tetrazolium (NBT) and X-phosphate-5-bromo-4-chloro-3-indoly phosphate (BCIP) served as chromogens to detect hybridization IL-4 mRNA signals. Significant increases in T lymphocytes and eosinophils and in the number of IL-4 mRNA+ cells were observed after allergen challenge. Double immunocytochemistry/in situ hybridization demonstrated that the majority of IL-4 mRNA+ cells after allergen challenge were CD3+ (73.7% +/- 1.6). Lower numbers of IL-4 mRNA hybridization signals were co-localized to tryptase+ cells (26.0% +/- 1.6). In contrast, no IL-4 mRNA hybridization signals were co-localized to either eosinophils or macrophages. These results indicate that after allergen challenge T cells are the principal cellular source of IL-4 mRNA transcripts during human late nasal responses, with a lesser contribution from mast cells.
Masuyama K, Jacobson MR, Rak S, et al., 1994, Topical glucocorticosteroid (fluticasone propionate) inhibits cells expressing cytokine mRNA for interleukin-4 in the nasal mucosa in allergen-induced rhinitis., Immunology, Vol: 82, Pages: 192-199, ISSN: 0019-2805
Allergen-induced late nasal responses are associated with recruitment and activation of T lymphocytes and eosinophils and preferential mRNA expression for T-helper type 2 (Th2) cytokines. We tested the hypothesis that topical corticosteroids may inhibit late responses by inhibiting cells expressing mRNA for Th2 cytokines. A randomized double-blind placebo-controlled trial of topical corticosteroid (fluticasone propionate) was performed in 48 adult grass pollen-sensitive patients. Nasal biopsies were taken at baseline and repeated 24 hr after local nasal allergen provocation following 6 weeks treatment with either fluticasone propionate 200 micrograms or placebo nasal spray twice daily. Baseline mRNA expression for interleukin-4 (IL-4) (P = 0.01) and IL-5 (P = 0.002) was higher in the patients than in normal controls. Topical corticosteroid treatment significantly inhibited immediate nasal symptoms, with almost complete inhibition of the late response following allergen challenge. This was associated with a marked decrease in the allergen-induced increases in cells expressing mRNA for IL-4 (P = 0.002) but not for IL-5. Inhibition of the late response was also accompanied by decreases in CD25+ cells, presumed T lymphocytes and eosinophils. A significant correlation was observed between the decreases in IL-4 mRNA+ cells and in eosinophils after treatment (r = 0.46, P < 0.05). These results suggest that prolonged treatment with topical corticosteroid inhibits allergen-induced early and late nasal responses and the associated tissue eosinophilia, and that, at least in part, this may result from inhibition of cells expressing mRNA for IL-4.
VARNEY VA, CUMBERWORTH V, SUDDERICK R, et al., 1994, RHINITIS, SINUSITIS AND THE YELLOW NAIL SYNDROME - A REVIEW OF SYMPTOMS AND RESPONSE TO TREATMENT IN 17 PATIENTS, CLINICAL OTOLARYNGOLOGY, Vol: 19, Pages: 237-240, ISSN: 1749-4478
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- Citations: 25
Masuyama K, Rak S, Jacobson MR, et al., 1994, Rhinitis at the cellular level, Pages: 252-255, ISSN: 0905-9180
Allergic rhinitis is characterized by tissue eosinophilia, although the mechanism is largely unknown. Recent work has focused on the role of cytokines derived from T-lymphocytes and possibly alternative cells, including mast cells, in promoting the recruitment, activation and persistence of eosinophils at allergic tissue sites. We have used the nasal late response as a clinical model of allergic inflammation. In order to assess the influence of topical corticosteroids, we performed a double-blind, placebo-controlled clinical trial of fluticasone propionate aqueous nasal spray (FPANS), 200 μg twice daily, on allergen-induced early and late nasal responses. The study group comprised of 48 adults with seasonal allergic rhinitis. Associated cellular infiltration and cytokine messenger ribonucleic acid (mRNA) expression in the nasal mucosa was also assessed in 40 of these patients. FPANS pretreatment resulted in approximately 50% reduction in the size of the early response and almost complete inhibition of late nasal symptoms following allergen challenge. Immunostaining of nasal biopsies obtained 24 h after allergen challenge revealed a marked reduction in T-lymphocytes and CD25+ (interleukin-2 receptor bearing) cells (presumed activated T-lymphocytes) in both the epithelium and submucosa. Significant decreases were observed in both total and activated eosinophils, particularly within the nasal epithelium. Submucosal mast cell counts were also reduced. In situ hybridization studies demonstrated highly significant inhibition of the number of cells expressing mRNA for interleukin-4 (IL-4). Thus, topical FPANS inhibited both early and late nasal responses, possibly by decreasing the number of T-lymphocytes and/or mast cells and IL-4 production, with a consequent reduction in tissue eosinophilia.
Bentley AM, Durham SR, Kay AB, 1994, Comparison of the immunopathology of extrinsic, intrinsic and occupational asthma., J Investig Allergol Clin Immunol, Vol: 4, Pages: 222-232, ISSN: 1018-9068
Using immunohistochemistry and a panel of monoclonal antibodies we have compared T lymphocyte, eosinophil, macrophage and neutrophil infiltration and expression of adhesion receptors (ICAM-1, E-selectin and VCAM-1) in bronchial biopsies from 10 intrinsic asthmatics, 9 isocyanate-induced asthmatics, 10 extrinsic asthmatics and 12 normal healthy nonatopic controls. There was a significant increase in the number of CD25+ (interleukin-2 receptor [IL-2R]-bearing) cells (p < 0.01) in isocyanate-induced asthma compared with that of controls. There were also significant increases in MBP+ cells (p < 0.02) and EG2+ cells (p < 0.01), which represent total and activated eosinophils. CD25+ (p < 0.01), MBP+ (p < 0.03) and EG2+ (p < 0.01) cells were also elevated in extrinsic asthma. An intense mononuclear cell infiltrate was identified in intrinsic asthmatics with an increase in the number of CD45+ cells (total leukocytes), CD3+ and CD4+ T lymphocytes and CD68+ macrophages (p < 0.03, p < 0.01, p < 0.03 and p < 0.03, respectively), compared with normal controls. CD25+ cells (IL-2R+) and the number of MBP+ and actively secreting eosinophils were also increased in intrinsic asthmatics compared with normal controls (p < 0.01, p < 0.01 and p < 0.01, respectively). EG2+ cell numbers in intrinsic asthma correlated with the Aas symptom score (r = 0.65, p < 0.05), where EG2+ cell numbers in intrinsic and extrinsic asthmatics correlated with airways methacholine responsiveness (r = -0.5, p < 0.03) and the Aas symptom score (r = 0.54, p < 0.03). There was constitutive expression of ICAM-1, E-selectin and VCAM-1 in patients with asthma (intrinsic and extrinsic) and normal controls. Compared with controls, ICAM-1 and E-selectin staining in the submucosa was increased in intrinsic asthma both for intensity (p < 0.02, p < 0.05) and extent of staining (p < 0.01, p < 0.05). Epithelial expression of ICAM-1 was more frequent in asthmatics
, 1994, International Consensus Report on the diagnosis and management of rhinitis. International Rhinitis Management Working Group., Allergy, Vol: 49, Pages: 1-34, ISSN: 0105-4538
Bentley AM, Durham SR, Robinson DS, et al., 1993, Expression of endothelial and leukocyte adhesion molecules interacellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 in the bronchial mucosa in steady-state and allergen-induced asthma., J Allergy Clin Immunol, Vol: 92, Pages: 857-868, ISSN: 0091-6749
BACKGROUND: Interactions between cell adhesion molecules and their ligands are an integral part of inflammatory processes and may have direct relevance to the pathology of asthma. METHODS: Immunostaining with antibodies to cell adhesion molecules was performed on bronchial biopsy specimens from persons with intrinsic and extrinsic asthma, normal nonasthmatic control subjects, and patients with asthma after allergen challenge. RESULTS: There was constitutive expression of intercellular adhesion molecule-1 (ICAM-1), E-selectin and vascular cell adhesion molecule-1 (VCAM-1) in patients with intrinsic and extrinsic asthma and in control subjects. Compared with control subjects, ICAM-1 and E-selectin staining in the submucosa was greater in the intrinsic asthmatic group for intensity (p < 0.02, p < 0.05) and extent (p < 0.01, p < 0.05) of staining, respectively. No differences were observed between patients with extrinsic asthma and normal control subjects, and VCAM-1 expression did not differ among the groups. Epithelial expression of ICAM-1 was more frequent in patients with asthma compared with normal control subjects (p < 0.05). Compared with diluent challenge, bronchial biopsy specimens obtained 24 hours after allergen challenge revealed no significant differences in intensity or extent of staining for ICAM-1, E-selectin, or VCAM-1. After allergen challenge, the intensity and extent of both VCAM-1 and ICAM-1 expression correlated significantly with the number of eosinophils (cells positive for major basic protein). Epithelial ICAM-1 expression was more frequently observed after allergen challenge than after diluent challenge (p < 0.02). CONCLUSIONS: The data suggest a complex pattern of regulation for ICAM-1, E-selectin, and VCAM-1 in vivo, where they may reflect the degree of ongoing inflammation in asthma.
DURHAM SR, 1993, MEDICAL APPROACH TO RHINITIS, BRITISH JOURNAL OF HOSPITAL MEDICINE, Vol: 50, Pages: 458-&, ISSN: 0007-1064
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- Citations: 2
YING S, DURHAM SR, BARKANS J, et al., 1993, T-CELLS ARE THE PRINCIPAL SOURCE OF INTERLEUKIN-5 MESSENGER-RNA IN ALLERGEN-INDUCED RHINITIS, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 9, Pages: 356-360, ISSN: 1044-1549
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- Citations: 131
Robinson DS, Ying S, Bentley AM, et al., 1993, Relationships among numbers of bronchoalveolar lavage cells expressing messenger ribonucleic acid for cytokines, asthma symptoms, and airway methacholine responsiveness in atopic asthma., J Allergy Clin Immunol, Vol: 92, Pages: 397-403, ISSN: 0091-6749
BACKGROUND: We recently demonstrated that T lymphocytes in bronchoalveolar lavage (BAL) fluid from atopic asthmatic patients were activated and expressed increased cytokine messenger ribonucleic acid (mRNA) for "TH2-type" cytokines, particularly IL-4 and IL-5, when compared with those in normal control subjects. This pattern of cytokines may determine the nature of the cellular infiltrate in the bronchial mucosa in asthma and hence the bronchial hyperresponsive (BHR) and symptoms that characterize this condition. METHODS: To examine the association between these cytokines and clinical measures of asthma severity we have extended our studies of BAL cells from subjects with atopic asthma. Numbers of BAL cells with positive in situ hybridization signals for IL-2, IL-3, IL-4, IL-5, granulocyte macrophage colony-stimulating factor (GM-CSF), and interferon-gamma were counted on cytocentrifuge preparations. Results were compared between patients with symptomatic (n = 19) and asymptomatic asthma (n = 10), and associations were sought with airway methacholine responsiveness, resting airway caliber, and asthma symptom scores. RESULTS: There were increased proportions of cells positive for IL-3 (p < 0.05), IL-4 (p < 0.005), IL-5 (p < 0.005), and GM-CSF (p < 0.005) mRNA in BAL fluid from patients with symptomatic asthma when compared with that from subjects free of symptoms, but no difference between the groups in numbers of cells expressing IL-2 and interferon-gamma mRNA. There were significant associations among numbers of cells expressing mRNA for IL-4, IL-5, and GM-CSF, and airflow restriction, BHR, and Aas asthma score. CONCLUSIONS: These findings support the hypothesis that cytokines contribute to airway events that determine asthma symptoms and BHR.
VARNEY VA, HAMID QA, GAGA M, et al., 1993, INFLUENCE OF GRASS-POLLEN IMMUNOTHERAPY ON CELLULAR INFILTRATION AND CYTOKINE MESSENGER-RNA EXPRESSION DURING ALLERGEN-INDUCED LATE-PHASE CUTANEOUS RESPONSES, JOURNAL OF CLINICAL INVESTIGATION, Vol: 92, Pages: 644-651, ISSN: 0021-9738
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- Citations: 431
Robinson D, Hamid Q, Bentley A, et al., 1993, Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma., J Allergy Clin Immunol, Vol: 92, Pages: 313-324, ISSN: 0091-6749
BACKGROUND: We have examined whether the local eosinophilia provoked by inhalational allergen challenge of patients with atopic asthma is associated with the appearance, in vivo, of activated TH2-type T helper lymphocytes. METHODS: Fifteen patients with atopic asthma had bronchial wash and bronchoalveolar lavage (BAL) 24 hours after allergen or diluent challenge separated by at least 21 days. RESULTS: There was an increase in eosinophils in both bronchial wash (p = 0.01) and BAL (p = 0.02) after allergen challenge but not after diluent challenge. Activation of CD4+ BAL T cells was suggested by an increase in the expression of CD25 shown by flow cytometry after allergen challenge, when compared with diluent (p = 0.02). There was no evidence of activation of CD8 T cells. By in situ hybridization after allergen challenge as compared with diluent, increases were shown in the numbers of cells expressing mRNA for interleukin-4 (IL-4) (p = 0.005), IL-5 (p = 0.01), and granulocyte-macrophage colony-stimulating factor (p = 0.03) but not IL-3, IL-2, or interferon-gamma. In situ hybridization of BAL cells after immunomagnetic separation of CD2-positive and CD2-negative cell populations showed that IL-4 and IL-5 mRNAs were associated with T lymphocytes after allergen challenge. BAL and bronchial wash eosinophilia closely correlated with maximal late fall in forced expiratory volume in 1 second after allergen challenge. CONCLUSION: Cytokines produced by activated TH2-type CD4+ T cells in the airway may contribute to late asthmatic responses by mechanisms that include eosinophil accumulation.
Robinson D, Hamid Q, Ying S, et al., 1993, Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon-gamma cytokine gene expression., Am Rev Respir Dis, Vol: 148, Pages: 401-406, ISSN: 0003-0805
Although corticosteroids are effective in improving asthma symptoms and bronchial responsiveness, their mechanism of action is unknown. We examined whether changes in bronchial responsiveness with corticosteroid therapy of asthma are accompanied by a reduction in cytokine gene expression and eosinophil infiltration in the airways. Bronchoalveolar lavage (BAL) was performed in 18 patients with moderate asthma before and after 2 wk of treatment with prednisolone, 0.6 mg/kg/day, or matched placebo in a randomized double-blind parallel group study. Cells were counted in BAL cytocentrifuge preparations, and the numbers of cells expressing cytokine mRNA were assessed by in situ hybridization using 35S-labeled RNA probes. When the actively treated and placebo groups were compared, there was a decrease in airway methacholine responsiveness (p < 0.01) after prednisolone. This was accompanied by a decrease in bronchoalveolar lavage eosinophils (p < 0.05), a reduction in the numbers of BAL cells per 1,000 expressing mRNA for interleukin-4 (IL-4, p < 0.01) and interleukin-5 (IL-5, p < 0.005), and an increase in numbers of cells expressing mRNA for interferon-gamma (p < 0.005). These results are compatible with the hypothesis that the beneficial effects of corticosteroids in asthma may result from modulation of cytokine production, with consequent inhibition of local bronchial eosinophilia.
Robinson DS, Durham SR, Kay AB, 1993, Cytokines. 3. Cytokines in asthma., Thorax, Vol: 48, Pages: 845-853, ISSN: 0040-6376
, 1993, Guidelines for the management of asthma: a summary. British Thoracic Society and others., BMJ, Vol: 306, Pages: 776-782, ISSN: 0959-8138
Corrigan CJ, Haczku A, Gemou-Engesaeth V, et al., 1993, CD4 T-lymphocyte activation in asthma is accompanied by increased serum concentrations of interleukin-5. Effect of glucocorticoid therapy., Am Rev Respir Dis, Vol: 147, Pages: 540-547, ISSN: 0003-0805
Peripheral blood mononuclear cells (PBMC) and serum were obtained, on two occasions, from 15 asthmatic patients who required oral glucocorticoid therapy for moderate to severe disease exacerbations. Samples were obtained immediately before commencement of oral glucocorticoids (Day 1) and again after 7 days of treatment (Day 7), when lung function had significantly improved. Samples were also isolated on two occasions 7 days apart from a group of seven untreated volunteers. Expression of CD25, human lymphocyte antigen (HLA-)DR, CD45RA, and CD45RO on CD4 and CD8 T lymphocytes was measured by flow cytometry, and serum concentrations of interleukin-5 (IL-5) were measured using an enzyme-linked immunosorbent assay technique. On Day 1 the asthmatic patients showed significantly higher percentages, as compared with the control subjects of CD4 T lymphocytes expressing the markers CD25, HLA-DR, and CD45RO and significantly lower percentages of CD4 T cells expressing CD45RA. After glucocorticoid therapy, the percentages of CD4 T cells expressing CD25, HLA-DR, and CD45RO were significantly reduced in the asthmatic patients, and the percentages of those expressing CD45RA significantly increased so that by Day 7 expression of all four markers was no longer significantly different from that of the control subjects. By contrast, the percentages of CD8 T cells expressing HLA-DR, CD45RA, and CD45RO in the PBMC of the asthmatic patients on Day 1 were not significantly different from those in control subjects, whereas the percentages of CD25 expressing CD8 T cells were only marginally elevated. Glucocorticoid therapy resulted in no significant change in the expression of all four markers on CD T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Durham SR, 1993, Immunotherapy: Mechanisms of action, Pages: 57-59, ISSN: 0108-1675
BARANIUK JN, OHKUBO K, KWON OJ, et al., 1993, IDENTIFICATION OF NEUTRAL ENDOPEPTIDASE MESSENGER-RNA IN HUMAN NASAL-MUCOSA, JOURNAL OF APPLIED PHYSIOLOGY, Vol: 74, Pages: 272-279, ISSN: 8750-7587
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- Citations: 17
Bentley AM, Meng Q, Robinson DS, et al., 1993, Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics., Am J Respir Cell Mol Biol, Vol: 8, Pages: 35-42, ISSN: 1044-1549
Immunohistology and in situ hybridization were used to evaluate the presence, activation status, and cytokine mRNA profile of cells in the bronchial mucosa during human allergen-induced asthma. Fifteen atopic asthmatic subjects underwent inhalation challenge with allergen and with allergen diluent, performed in random order separated by an interval of at least 3 wk. Bronchial biopsies were obtained 24 h after challenge. Immunostaining revealed increases in the numbers of secreting eosinophils (EG2+; P < 0.05) and in interleukin-2 receptor (IL-2R)-positive cells (CD25+; P < 0.01) after allergen compared with diluent challenge. No differences were observed in the numbers of total leukocytes (CD45+), T lymphocytes (CD3+, CD4+, and CD8+), elastase-positive neutrophils, macrophages (CD68+), or mast cell subtypes (MCT+ or MCTC+). In situ hybridization revealed significant increases in the numbers of cells expressing mRNA for IL-5 (P < 0.02) and granulocyte/macrophage colony-stimulating factor (P < 0.01) after allergen compared with diluent challenge. A significant inverse relationship was observed between the number of cells expressing mRNA for IL-4 and for interferon-gamma (r = -0.75, P < 0.02). The results support the view that cytokines possibly from activated T lymphocytes may contribute to local eosinophil accumulation during allergen-induced asthma.
Robinson DS, Bentley AM, Hartnell A, et al., 1993, Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness., Thorax, Vol: 48, Pages: 26-32, ISSN: 0040-6376
BACKGROUND: Bronchial mucosal inflammation and epithelial damage are characteristic features of asthma. Activation of T helper lymphocytes may contribute to this process by mechanisms including the release of cytokines promoting eosinophil infiltration and activation. METHODS: Bronchial washings and bronchoalveolar lavage fluid were obtained from 29 atopic asthmatic patients (19 with current symptoms and 10 symptom free) and 13 normal volunteers. Flow cytometry was used to assess T cell phenotype and activation status in bronchoalveolar lavage fluid and peripheral blood, and differential cell counts were made on bronchial washings and bronchoalveolar lavage fluid. Findings were related to severity of disease as reflected by symptom scores, baseline lung function, and airway responsiveness. RESULTS: CD4 T lymphocytes in bronchoalveolar lavage fluid and blood from asthmatic patients were activated by comparison with controls (CD4 CD25, median 16.8% v 8.7% for bronchoalveolar lavage fluid, and 15.3% v 8.7% in blood). Bronchoalveolar lavage fluid CD4 T cells from both asthmatic patients and controls were of memory phenotype (95.8% and 96.8% CD45RO and 1.7% and 0.4% CD45RA respectively), whereas both CD45RO and CD45RA T cells were present in blood. Patients with asthma and current symptoms showed increased bronchoalveolar T cell activation compared with patients without symptoms (CD4 CD25 18.7% v 12.3%). Within the asthmatic group there was a significant association between CD4 CD25 lymphocytes and asthma symptom scores (rs = 0.75), airway methacholine responsiveness (log PC20, rs = -0.43) and baseline FEV1 (rs = -0.39). A correlation was also found between CD4 CD25 lymphocytes and eosinophils in bronchoalveolar lavage fluid (rs = 0.48). Eosinophils in bronchoalveolar lavage fluid were increased in asthmatic patients compared with controls and the percentage of eosinophils in bronchoalveolar lavage fluid correlated with asthma symptom score. A relation was found between
Robinson DS, Hamid Q, Jacobson M, et al., 1993, Evidence for Th2-type T helper cell control of allergic disease in vivo., Springer Semin Immunopathol, Vol: 15, Pages: 17-27, ISSN: 0344-4325
Durham SR, 1993, Allergic inflammation., Pediatr Allergy Immunol, Vol: 4, Pages: 7-12, ISSN: 0905-6157
A greater understanding of the basic mechanisms of allergic inflammation is pertinent to the development of new treatments. Previous studies have focused on the role of mediators of hypersensitivity and effector cells, including mast cells and eosinophils. Recent evidence suggests that IgE-dependent activation and tissue eosinophilia are under the local regulation of distinct cytokines. Originally described as products from T lymphocytes, these peptide messengers are produced by alternative cells, including mast cells, eosinophils and the respiratory epithelium. In vitro studies in murine models and using cloned human T lymphocytes indicate the preferential production of "Th2-type" cytokines, including interleukin-4 (IL-4) and IL-5. This review considers the evidence from in vivo studies in humans that "Th2-type" cytokines have a primary role in orchestrating both IgE-dependent events and local tissue eosinophilia. Novel therapeutic approaches might include a broad strategy directed against T lymphocytes, including the use of immunosuppressive agents or anti CD4 antibodies or more precise targeting of IL-4 and/or IL-5.
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