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Biomedical subjects

A B Kay

Publications and source records attributed to A B Kay.

428 records · Page 24Linked to original sources
PubMedDate not supplied

Eosinophil development and bone marrow and tissue eosinophils in atopic asthma.

BACKGROUND: Eosinophils develop from bone marrow (BM) progenitors, and interleukin-5 (IL-5) and eotaxin may act in expansion and mobilisation of BM eosinophils in asthma. METHODS: We have examined phenotypic changes as CD34+ cells develop to the eosinophil lineage in vitro, and have evaluated BM eosinophils from asthmatic and control subjects for expression of the eotaxin receptor, CCR3. RESULTS: Acquisition of receptors for IL-5 and CCR3 was an early event in eosinophil development. There were increased CD34+ cells, and mature and immature CCR3+ eosinophils in BM from asthmatics. CONCLUSION: These data suggest that IL-5 may act early in eosinophil development, and that eotaxin has the capacity to mobilise a BM eosinophil pool in asthma.

Antigens, CD34↗
PubMedDate not supplied

T cells and chronic asthma.

There is increasing evidence that the asthma process is 'driven' and maintained by persistence of a subset of chronically activated T memory cells, sensitized against allergenic, occupational or viral antigens which 'home' to the lung after antigen exposure or viral infection. In general, allergens induce a CD4 T helper (Th) cell response, whereas viruses recognize CD8+ cytotoxic (Tc) T cells. In the asthmatic airways, there are CD4+ and, to a lesser number CD8+ cells with a type 2 cytokine phenotype (i.e., Th-2 and Tc-2 type). These cells produce interleukin (IL) 3 and 5 and granulocyte-macrophage colony-stimulating factor which recruit, mobilize and activate eosinophils for subsequent mucosal damage, as well as IL-4, an essential cofactor for local or generalized IgE production. This leads to epithelial shedding, mucus hypersecretion and bronchial muscle contraction. Thus, although the eosinophil may damage the mucosal surfaces in asthma, its function appears to be under T cell control. Support for this hypothesis includes: (1) activated T cells and their products can be identified in biopsies from the major variants of the disease (atopic, non-atopic and occupational asthma); (2) colocalization of mRNA for type 2 cytokines to CD4+ and CD8+ cells in atopic and non-atopic asthma; (3) the presence of activated cytokine-producing T cells in corticosteroid-resistant asthma; (4) the association of disease severity with type 2 cytokines, especially IL-5; and (5) the efficacy of cyclosporin A and a monoclonal anti-CD4 in chronic steroid-dependent disease. Inhibitors and/or antagonists directed against more precise T cell associated molecular targets hold promise for the future treatment of chronic asthma.

Antibodies, Monoclonal↗
PubMedDate not supplied

Mechanisms of T cell peptide epitope-dependent late asthmatic reactions.

Short peptide sequences corresponding to T cell epitopes have been identified in the major cat allergen Fel d 1. In order to directly activate allergen-specific T cells in cat-allergic asthmatic individuals, peptides were administered by intradermal injection. Subsequently, a proportion of subjects experienced a delayed reduction of airway calibre manifested as a decrease in FEV(1). Changes in lung function occurred approximately 3 h after peptide injection, peaked at 6 h and resembled an isolated late asthmatic reaction (LAR). Using molecular tissue typing techniques, it was determined that many of the individuals experiencing isolated LAR expressed particular HLA-DR molecules. These molecules were shown in subsequent experiments to bind individual peptides within the preparation and thus to activate T cells in a major histocompatibility complex (MHC)-restricted fashion. The precise mechanisms whereby MHC-restricted activation of allergen-specific T cells gives rise to bronchoconstriction are currently under investigation.

Animals↗
PubMedDate not supplied

Phenotype of cells positive for interleukin-4 and interleukin-5 mRNA in allergic tissue reactions.

We have investigated the phenotype of cells positive for IL-4 and IL-5 mRNA in the nasal mucosa of subjects with allergic rhinitis and in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic subjects. The method employed was immunochemistry followed by in situ hybridization using either 35S- or digoxigenin-labelled riboprobes. With nasal and bronchial tissue, this double ICC/ISH method revealed that more than 70% of IL-4 and IL-5 mRNA+ cells were T cells. The remaining IL-4 and IL-5 signals were co-localized to tryptase-positive mast cells and EG2+ eosinophils. Occasional IL-4 and IL-5 mRNA cells were observed in non-asthmatic control subjects, the large majority being CD3+ cells. These results indicate that CD3+ cells are the principal cellular source of IL-4 and IL-5 transcripts in atopic asthma and allergic rhinitis.

Antigens, CD↗
PubMedDate not supplied

Changes in allergic inflammation associated with successful immunotherapy.

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.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Eosinophils and eosinophil-associated cytokines in allergic inflammation.

Eosinophils are major effector cells in allergic tissue reactions. Their capacity to synthesize and store cytokines, particularly Th2-type cytokines, which may have autocrine effects such as increased cell survival in tissues, is of particular current interest. We have shown that eosinophils infiltrating the site of human cutaneous late-phase reactions (LPR) express mRNA and protein product for IL-4 and IL-5. Stimulation of peripheral blood eosinophils in vitro with either IgG or sIgA produces time-dependent induction of IL-4 and IL-5 transcription, indicating that mature cells may undergo local cytokine synthesis. We also demonstrated that bronchial biopsies from patients with both atopic and non-atopic (intrinsic) asthma express IL-4 and IL-5 mRNA which mainly co-localized to T cells, although clear hybridization signals were also obtained with eosinophils and mast cells. On the other hand, immunoreactivity for the corresponding protein was detectable predominantly in eosinophils and mast cells; a finding believed to reflect granule storage of cytokines. We also studied the resolution of the cutaneous LPR. Apoptosis of eosinophils persisted slightly longer than neutrophils in the tissues. The eventual decline in both neutrophil and eosinophil numbers followed on from the peak of the LPR. This was associated with terminal-deoxynucteotidyl-transferase-mediated nick and labelling positive (TUNEL+) (apoptotic) cells with the subsequent removal of apoptotic neutrophils and eosinophils by tissue macrophages. Thus, IL-4 and IL-5 production by eosinophils may amplify local allergic inflammatory responses and, in the case of IL-5, may prolong local tissue survival. However, in the allergen-induced LPR, inflammation rapidly resolves, possibly through the initiation of programmed cell death and phagocytosis of apoptotic cells by macrophages.

Asthma↗
PubMedDate not supplied

Immunological aspects of chronic asthma.

The demonstration of leucocyte activation in the peripheral blood of patients with chronic asthma together with elevated levels of neutrophil chemotactic activity provides evidence for an underlying inflammatory process in asthma and confirms that bronchial inflammation is an important cause of airways obstruction. Corticosteroids may act through a variety of mechanisms but their anti-inflammatory action is probably mediated, at least in part, through the inhibition of phospholipase A2. Corticosteroids suppress leucocyte activation in asthma and this is associated with an improvement in lung function, thus supporting the view that their anti-inflammatory mode of action is of essential importance. However, a small group of chronic asthmatics do not respond to corticosteroids, even when given in large doses and the nature of the cellular defect in these "corticosteroid-resistant" individuals is thought to be the monocyte. The cells of the monocyte/macrophage series may play a central role in the pathogenesis of chronic asthma.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Drug effects on exercise-induced late asthmatic responses.

Disodium cromoglycate, prednisolone, beclomethasone and salbutamol were administered prior to the cycle ergometer exercise task separately to different groups of children with exercise-induced dual asthmatic reaction. Pre-treatment with disodium cromoglycate of ten asthmatics totally inhibited the dual reaction. Prednisolone treatment of eleven asthmatics and beclomethasone treatment of five asthmatics did not inhibit the early response but only the late response. Salbutamol treatment of ten asthmatics mainly inhibited the early phase reaction. Changes in neutrophil chemotactic activity correlated with airflow limitation in the disodium cromoglycate and prednisolone study, however, there were some discrepancies between the changes in FEV1 and neutrophil chemotactic activity in the beclomethasone and salbutamol studies. These findings suggest that exercise-induced dual asthmatic reaction are modified by disodium cromoglycate, prednisolone, beclomethasone or salbutamol in a mechanism which may be different in each drug and that there are similarities in the inflammatory responses in antigen- and exercise-induced dual asthmatic responses.

Albuterol↗
PubMedDate not supplied

Immunosuppressive agents in chronic severe asthma.

Previous immunosuppressive agents utilized as therapies for immune system mediated diseases such as chronic allergic asthma, and rheumatoid arthritis include purine antagonists, methotrexate, and gold salts. These treatment modalities have been shown to elicit either limited treatment efficacy or to produce undesirable side effects in many individuals. Cyclosporin A is a potent immunosuppressive agent which appears to arrest division of T lymphocytes and inhibit mediator release from mast cells. However, like other immunosuppressive agents, cyclosporin A may also produce many potentially serious side effects; among these is the possibility of irreversible renal damage. Nephrotoxicity can be attenuated, because renal pathological changes seem to be high cumulative dose-related. If whole blood levels of cyclosporin A are maintained between 200 and 500 ng/mL, serious renal toxicity is unusual. Investigation of cyclosporin A in individuals who have severe long-term corticosteroid-dependent chronic asthma has demonstrated the efficacy of this agent, resulting in clinically significant improvement in pulmonary function. Therefore, it can be hypothesized that T lymphocytes may act as effector cells in cell-mediated hypersensitivity reactions in atopic allergic inflammation.

Asthma↗
PubMedDate not supplied

Leucocytes in asthma.

A diagrammatic representation of the interactions between mediators of hypersensitivity and leucocytes in early-, late-phase, and ongoing asthma is shown in Fig. 1. Early-phase or immediate reactions are largely the result of bronchoconstriction consequent to the release of mediators such as histamine, PGD2, LTC4/D4 and PAF. The principal mediator cell (MC) is the mast cell (although other IgE receptor-bearing cells such as the macrophage, eosinophil and platelet might also be involved in this immediate response). The stimulus for mediator cell activation may be either immunologic (IgE-dependent) or non-immunologic (i.e. changes in osmolarity as a result of the respiratory water loss associated with exercise-induced asthma). Late-phase reactions appear to be a consequence of infiltration with neutrophils (N), eosinophils (E) and macrophages (MO). These cells are recruited and activated either by mast cell-associated chemotactic factors [such as LTB4, PAF, the eosinophil chemotactic factor of anaphylaxis (ECF-A) or high molecular weight neutrophil chemotactic activity (NCA (HMW]] and/or "lymphokines" derived from T helper cells (TH) which have been stimulated by antigen processed by the antigen processing cells (APC). These mononuclear cell interactions are under the control of regulatory T cells [T suppressor (TS) cells] and it is speculated that the availability of these subsets may determine the magnitude of the late-phase response. Lymphokines and monokines which selectively activate neutrophils, eosinophils and monocytes include LIF, EAF and INF-gamma respectively. Macrophage-derived tumour necrosis factor (TNF) also amplifies the inflammatory response by its capacity to enhance eosinophil cytotoxicity. Eosinophil-derived agents such as PAF, LTC4, MBP and ECP might be responsible for submucosal oedema and non-specific bronchial hyperreactivity which are characteristic features of late-phase reactions. T cell-derived lymphokines such as EDF (IL-5), together with GM-CSF, might lead to eosinophilopoiesis and account for the prolonged eosinophilia of ongoing chronic asthma. The T cell is prominent in the pathology of chronic asthma and is possibly "chronically activated". Thus lymphocytes, driven by as yet undetermined "antigens" (possibly viral), may perpetuate the inflammatory response in and around the bronchi. IL-5-like products from these putative activated lymphocytes might perpetuate (a) eosinophil production by the bone marrow, (b) its release into the circulation, (c) its migration into bronchial tissue and (d) activation to release PAF, LTC4, MBP, etc.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Comparison of the immunopathology of extrinsic, intrinsic and occupational asthma.

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 than control subjects (p < 0.05). These results suggest that T cell activation and eosinophil infiltration are features common to asthma of diverse etiology. There appears to be a complex pattern in in vivo of regulation for ICAM-1, E-selectin and VCAM-1, where they may reflect the degree of ongoing inflammation in asthma.

Adult↗