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Biomedical subjects

T T Hansel

Publications and source records attributed to T T Hansel.

At least 19 recordsLinked to original sources
PubMed2003

Sputum T lymphocytes in asthma, COPD and healthy subjects have the phenotype of activated intraepithelial T cells (CD69+ CD103+).

BACKGROUND: T cells of intraepithelial phenotype have previously been detected in bronchoalveolar lavage (BAL) fluid in a range of lung diseases; these cells express the adhesion molecule alpha(E)beta(7) integrin, CD103, the ligand for epithelial cell E-cadherin. In subjects with asthma CD4+ lymphocytes are the predominant T cell subtype found in bronchial biopsy specimens and in BAL fluid, whereas CD8+ lymphocytes have been shown to predominate in subjects with chronic obstructive pulmonary disease (COPD). The aim of this study was to analyse the expression of CD103, activation markers (CD25 and CD69), and chemokine receptors (CXCR3, CCR5 and CCR3) on CD4+ and CD8+ lymphocytes from sputum and peripheral blood of subjects with asthma, COPD, and healthy controls. METHODS: T cell surface markers were assessed by immunofluorescence labelling and flow cytometry of gated lymphocytes among CD45+ leucocytes in sputum cell suspensions. RESULTS: Sputum lymphocytes expressed higher levels of CD103 and CD69 than blood lymphocytes in all subject groups, with CD103 expressed at higher levels on CD8+ than on CD4+ cells. There were no detectable differences in numbers of CD4+ and CD8+ T cells between subjects with asthma, COPD and controls. The percentage of sputum lymphocytes expressing CXCR3 was lower in subjects with asthma or COPD than in healthy controls; CCR3 was not detectable on sputum or blood lymphocytes. CONCLUSIONS: Sputum T lymphocytes are predominantly of activated intraepithelial phenotype (CD103+ CD69+), and normal numbers of CD4+ and CD8+ T cell populations are found in the sputum of patients with asthma and COPD.

Adult↗
PubMed2001

Novel drugs for treating asthma.

The health burden of asthma is increasing globally at an alarming rate, providing a strong impetus for the development of new therapeutics, particularly drugs that may prevent development of the disease. Currently available inhaled bronchodilators and anti-inflammatory drugs are effective in most asthmatic patients, but this palliative therapy requires long-term daily administration. Despite considerable efforts by the pharmaceutical industry, it has been difficult to develop novel therapeutic agents, the leukotriene antagonists being the only new class of asthma treatments to be licensed in the past 30 years. It is clearly important to understand more about the underlying mechanisms of asthma and about how currently used drugs work before rational improvements in therapy can be expected. There are numerous therapies in clinical development that combat the inflammation found in asthma, specifically targeting eosinophils, IgE, adhesion molecules, cytokines (interleukin-4, -5, -13) and chemokines, inflammatory mediators, and cell signaling (kinase inhibitors). In particular, there is the obvious need for new therapy for severe asthma that is poorly controlled by high-dose corticosteroids as well as agents to counter acute emergency asthma. A long-term goal is to develop disease-modifying immunotherapy that could be introduced in childhood to alter the natural history of asthma. Thanks to the extensive efforts of the pharmaceutical industry, we can expect the introduction of a range of novel therapies for asthma in the near future.

Anti-Inflammatory Agents↗
PubMed2001

New treatments for asthma: current and future aspects.

Inhaled beta 2-agonists continue to be the mainstay of asthma therapy, along with inhaled corticosteroids (ICS). A recent advance has been the recognition that 'add-on' or adjunctive therapies to ICS, such as long-acting beta 2-agonists and leukotriene antagonists, are a superior option to increased doses of ICS. Traditionally, inhaled beta 2-agonists and ICS have been administered via separate devices, but combined administration of a long-acting inhaled beta 2-agonist and an ICS by a single inhaler has recently become available in clinical practice. For the future, biotechnology is providing a number of potential therapies for asthma that are directed against some of the inflammatory mediators, such as immunoglobulin E and interleukin-4 and -5, thought to be involved in the pathophysiology of the disease. These biotechnological therapies may eventually provide the opportunity to tailor treatment to the needs of individual patients, and to manipulate the immune system away from allergic responses.

Adrenergic beta-Agonists↗
PubMed2001

Smoking-related lung disease: prospects for new drug therapy.

The first 2001 meeting of the Society for Medicines Research, held in London on March 14, was devoted to emerging treatments for chronic obstructive pulmonary disease, commonly referred to as smoking-related lung disease or COPD. As COPD afflicts more and more people around the world, the dual need for preventative measures and therapeutic approaches will also continue to grow. During this sobering yet inspiring symposium, researchers looked at compounds that are currently in phase III clinical studies; reactive oxidant species, proteases and neutrophil chemotactics as therapeutic targets; and finally, the potential of monoclonal antibodies and retinoids.

Journal Article↗
PubMed2000

Automated quantitation of circulating neutrophil and eosinophil activation in asthmatic patients.

BACKGROUND: Asthma has been associated with eosinophil activation, measured in serum, sputum, bronchoalveolar lavage (BAL) fluid, and urine. A whole blood automated method was developed to assess eosinophil and neutrophil activity in terms of peroxidase content and cell morphology using the Bayer haematology analyser. The method was applied to an in vitro stimulation model when fMLP was added to whole blood and the samples were then analysed for changes in granularity and shape. In addition, cells stimulated with interleukin (IL)-8 were examined by electron microscopy. METHODS: A cross sectional analysis was performed on venous blood from non-atopic, non-asthmatic normal subjects (n = 37), mild (n = 46) and symptomatic (n = 22) asthmatic patients on inhaled beta(2) agonist only, and more severe asthmatic patients (n = 17) on inhaled and oral corticosteroid therapy. Samples were analysed by the haematology analyser and peroxidase leucograms gated using the WinMDI software program. RESULTS: There were significant differences in the amount of light scatter by the neutrophil populations in the symptomatic (p = 0.007) and severe asthmatic (p = 0.0001) groups compared with the control group. However, abnormalities in eosinophil populations were not observed. In vitro activation of whole blood with fMLP caused similar changes in neutrophil light scatter, suggesting that neutrophil activation is present in peripheral blood of symptomatic asthmatic patients. IL-8 caused a change in shape of the neutrophils seen using transmission electron microscopy. CONCLUSIONS: Evidence of neutrophil activation can be seen in whole blood from patients with asthma using a novel automated method. This may potentially be applied to other inflammatory diseases.

Adult↗
PubMed2000

Novel therapy for asthma.

The health burden of asthma is increasing globally at an alarming rate, providing a strong impetus for the development of new therapeutics. Currently available inhaled bronchodilators and anti-inflammatory drugs are effective in most asthmatics, but this palliative therapy requires long-term daily administration. Despite considerable efforts by the pharmaceutical industry, it has been difficult to develop novel therapeutic agents; the leukotriene antagonists and synthesis inhibitors being the only new class of asthma treatments to have been licensed in the last 30 years. It is clearly important to understand more about the underlying mechanisms of asthma and about how current drugs work before rational improvements in therapy can be expected. There are numerous therapies in clinical development that combat the inflammation found in asthma, specifically targeting eosinophils, IgE, adhesion molecules, cytokines and chemokines, inflammatory mediators and cell signalling. In particular, there is the obvious need for new therapy for severe asthma that is poorly controlled by high doses of corticosteroids, as well as agents to counter acute emergency asthma. A long-term goal is to develop disease-modifying immunotherapy, that could be introduced in childhood to alter the natural history of asthma. Thanks to the extensive efforts of the pharmaceutical industry, in the near future we can expect the introduction of a range of novel therapies for asthma.

Adjuvants, Immunologic↗
PubMed2000

Novel therapy for COPD.

The incidence of chronic obstructive pulmonary disease (COPD) is increasing throughout the world. Much less is known about the pathogenesis of COPD than that of asthma and there is little response to current therapy. Most patients with COPD have acquired their lung disease through smoking cigarettes, and the major step in management is to minimise further damage by stopping this habit. A number of therapies are being developed for the treatment of COPD; including new bronchodilators such as tiotropium bromide, agents to block inflammation induced by neutrophils and macrophages, as well as strategies to combat proteases and oxidants. The long-term goal is to provide therapy that retards the accelerated loss of lung function occurring in COPD. Development of novel therapies for COPD requires reliable Phase II decision making before entering large scale Phase III studies. The patient with COPD is often overlooked compared to their asthmatic counterpart, who benefit from an urgent need to identify novel targets and better therapy.

Adrenergic beta-Agonists↗
PubMed1995

Zaditen SRO permits once-daily dosing with superior efficacy in the prophylaxis of asthma.

This international, multicenter clinical trial was designed to compare the efficacy and safety of two different formulations of ketotifen: Zaditen SRO and Zaditen Standard Form. In a randomized double-blind study over a 12-week treatment period, 3 parallel groups of asthmatic subjects received Zaditen SRO (2 mg once daily), Zaditen SRO (4 mg once daily), or Zaditen Standard Form (1 mg twice daily). Asthmatic subjects (362 evaluable cases, aged 6-29 years) kept daily records of clinical symptoms, use of concomitant medication, and peak flow recordings and were examined at 2-week intervals up to the end of the study. Zaditen SRO 4 mg administered once a day at night showed a statistically significant faster onset of action and was more clinically effective than Zaditen Standard Form. The Zaditen SRO 4-mg and 2-mg formulations were at least as well tolerated as the standard form, with somnolence occurring equally after both formulations. In conclusion, Zaditen SRO (4 mg once daily) was found to be equally safe and more effective in the prophylactic treatment of mild and moderate bronchial asthma than Zaditen Standard Form (1 mg twice daily).

Adolescent↗
PubMed1994

Pulmonary function, activated T cells, peripheral blood eosinophilia, and serum activity for eosinophil survival in vitro: a longitudinal study in bronchial asthma.

A close correlation among the number of activated, peripheral blood T helper cells, eosinophilia, and airflow obstruction has been reported in patients with asthma. To test these cross-sectional data we performed a prospective, longitudinal study investigating the relationships among T-cell activation in peripheral blood, eosinophilia, forced expiratory volume in 1 second (FEV1), and serum activity toward eosinophil survival in 20 individuals with asthma over a period of 21 days after admission to a clinic located 1560 m above sea level. During the study, maintenance treatment with inhaled beta 2-agonists and theophylline was unchanged. Five patients had also been taking inhaled corticosteroids, and this was also not changed during the study period. According to the changes in pulmonary function observed at the end of the study, patients were divided into three groups: twelve patients whose pulmonary function improved by more than 10% from baseline (group I), four patients whose pulmonary function deteriorated by more than 10% from baseline necessitating therapeutic intervention (group II), and four patients with no change in FEV1 (< 10% from baseline) (group III). Activation of T cells as determined by interleukin-2 receptor expression, number of eosinophils, and serum activity toward eosinophil survival in vitro declined in group I; whereas FEV1 increased. The decrease in FEV1 in group II was associated with an increase in interleukin-2 receptor-positive T cells, number of eosinophils, and serum activity. In group III FEV1, interleukin-2 receptor expression on T cells, the number of peripheral blood eosinophils, and the measured serum activity for eosinophil survival in vitro did not change significantly from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia.

Increasing evidence suggests an important role for cytokines in the regulation of eosinophilic inflammation. In the present study we investigated the distribution of leukocytes, lymphocyte subsets, their activation state, and the cytokine profile present in BAL fluid from patients with various lung diseases associated with eosinophilia. For this purpose, we analyzed the levels of IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, GM-CSF, TNF-alpha, and IFN-gamma, as well as soluble IL-2 and TNF receptors, in concentrated bronchoalveolar lavage (BAL) fluid obtained from clearly defined patients with allergic and nonallergic asthma, eosinophilic pneumonia, allergic bronchopulmonary aspergillosis (ABPA), hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. BAL fluid from normal individuals and sarcoidosis patients was analyzed as noneosinophilic controls. BAL cytokine levels were compared with the cellular infiltrate and the activation state of CD4+ and CD8+ T cells as measured by the expression of IL-2 receptors (CD25), HLA-DR, and the very late activation antigen VLA-1. Beside the characteristic leukocyte infiltrate in the various lung diseases, all patients demonstrated significantly increased numbers of activated CD4 and CD8 T cells compared with normal individuals. The analysis of the cytokine profile present in BAL fluid revealed a T helper type 2 (Th2) cell cytokine pattern, with elevated IL-4 and IL-5 but normal levels of IL-2 or IFN-gamma in allergic asthma. ABPA patients demonstrated significantly increased levels of IL-4 and IL-5, with low but significantly elevated concentrations of IL-2 and IFN-gamma. In contrast, the analysis of the cytokine profile in sarcoidosis patients revealed a Th1 cell cytokine pattern characterized by increased concentrations of IL-2 and IFN-gamma but normal levels of IL-4 or IL-5. All other patient groups showed a cytokine pattern incompatible with a pure Th1 or Th2 cell response, because IL-5, IL-2, and IFN-gamma were found to be significantly increased. The BAL fluid analysis of the other, mainly non-T cell-derived cytokines and soluble receptors showed increased levels in all patients compared with normal individuals and may represent the ongoing inflammatory responses. In conclusion, whereas increased IL-4 levels were found only in diseases characterized by increased IgE production, IL-5 was elevated in all patients with increased numbers of eosinophils. The close correlation between IL-5 levels, number of eosinophils, and activated T cells further supports a role for IL-5 in causing tissue eosinophilia.

Adult↗
PubMed1993

Human peripheral blood eosinophils produce and release interleukin-8 on stimulation with calcium ionophore.

We present evidence that human blood eosinophils produce interleukin (IL)-8 when stimulated with calcium ionophore. Following in vitro culture of 99% pure eosinophils with calcium ionophore, released IL-8 was detectable by enzyme-linked immunosorbent assay in supernatants. Eosinophil IL-8 production was considerably greater than that of IL-3 or granulocyte macrophage colony-stimulating factor. Furthermore, eosinophil production of IL-8 in the presence of calcium ionophore could be inhibited with the immunomodulating agent cyclosporin A and the protein synthesis inhibitor cycloheximide. In addition, following stimulation of highly purified blood eosinophils with calcium ionophore, IL-8 mRNA was detectable after polymerase chain reaction amplification. In comparison with other cells on stimulation with calcium ionophore, eosinophils produce about half as much IL-8 as neutrophils but significantly more than purified T cells. In contrast to monocytes and neutrophils, IL-8 production was not inducible with IL-1 or tumor necrosis factor. Finally, following calcium ionophore stimulation blood eosinophils were shown to contain cytoplasmic IL-8 by employing a monoclonal antibody against IL-8 in conjunction with immunohistochemistry. These observations demonstrate that eosinophils are capable of IL-8 production and release, which may contribute to defense against parasites and to the pathophysiology of allergic and asthmatic disease.

Calcimycin↗
PubMed1993

Eosinophils and cytokines.

Cytokines act on eosinophils to regulate eosinophil function, with IL-5 recognised to be especially important in control of eosinopoiesis, eosinophil survival and eosinophil priming. In addition, eosinophils have the capacity to produce cytokines involved in acute and chronic inflammatory and repair processes, as well as to produce cytokines that stimulate eosinophils within an autocrine loop. This paper describes (A) an immunomagnetic selection technique for the purification of human blood eosinophils, and (B) a method that employs immunofluorescence with flow cytometry for measurement of blood and sputum eosinophil surface markers. Having demonstrated that sputum eosinophils express HLA-DR, highly purified blood eosinophils were used to analyse (C) the induction and function of eosinophil HLA-DR. Cytokines have the capacity to induce eosinophil HLA-DR, and are produced by eosinophils as an accessory function during antigen presentation. Finally, preliminary data on (D) eosinophil production of IL-8 is presented. Hence, eosinophils have the capacity to act as immunomodulatory cells within cells networks in allergic and asthmatic inflammation.

Antigens, Surface↗
PubMed1993

(+/-) isoprenaline revisited: adverse effects of sympathomimetics in asthma.

It is a matter of concern that regular, excessive use of contemporary sympathomimetics has been associated with morbidity and mortality from asthma. As a consequence, restrictions on sympathomimetic usage have recently been advocated in asthma management guidelines. he association between excessive use of inhaled (+/-)isoprenaline and an epidemic of asthma deaths in the 1960s provides a precedent; hence, we have reviewed the numerous clinical and experimental reports concerning (+/-) isoprenaline to provide insight into the present controversy.

Asthma↗
PubMed1993

Anomalous bronchospasm following inhalation of (+) isoprenaline by asthmatics.

Sympathomimetics (beta-adrenergic agonists) presently used in asthma therapy comprise racemic mixtures of bronchodilator and non-bronchodilator enantiomers. In a randomized, double-blind placebo-controlled study, asthmatic subjects inhaled a nebulized solution of the non-bronchodilator (+) enantiomer of isoprenaline. Substantial decreased forced expiratory volume (FEV1) was detected in 2 patients and of the remaining 8, a single subject had increased reactivity to histamine 7 h after inhalation of (+) isoprenaline. These effects of (+) isoprenaline may contribute to anomalous effects of (+/-) isoprenaline in asthma.

Administration, Inhalation↗