TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis

Brightling, Christopher E.; Symon, F A; Birring, Surinder S.; Bradding, Peter; Pavord, Ian D.; Wardlaw, Andrew J.

doi:10.1067/mai.2002.129698

Cited by 205 publications

(168 citation statements)

References 26 publications

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“…It has been shown that similar chemokine receptor expression profiles are found on BAL T cells from healthy controls and asthmatic subjects (27)(28)(29)(30)(31), so the increased expression of specific chemokine receptors on BAL T cells as compared with PB T cells is likely to be related to both an increase in memory T cells in the BAL as compared with PB and to the requirement for specific chemoattractant receptors in trafficking to the BAL and other tissue sites. In addition to the skin-associated (CCR4 and CCR10) and gut-associated (CCR9) chemoattractant receptors, certain receptors are enriched on tissue-localized T cells as compared with PB T cells, including but not limited to CXCR3, CXCR6, CCR5, and CCR6.…”

Section: Discussionmentioning

confidence: 80%

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

Thomas

Banerji

Medoff

et al. 2007

The Journal of Immunology

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Human allergic asthma is a chronic inflammatory disease of the airways thought to be driven by allergen-specific Th2 cells, which are recruited into the lung in response to inhaled allergen. To identify chemoattractant receptors that control this homing pattern, we used endobronchial segmental allergen challenge in human atopic asthmatics to define the pattern of chemoattractant receptor expression on recruited T cells as well as the numbers of recruited CD1d-restricted NKT cells and levels of chemokines in the bronchoalveolar (BAL) fluid. CD1d-restricted NKT cells comprised only a small minority of BAL T cells before or after Ag challenge. BAL T cells were enriched in their expression of specific chemoattractant receptors compared with peripheral blood T cells prechallenge, including CCR5, CCR6, CXCR3, CXCR4, and BLT1. Surprisingly, following segmental allergen challenge, no chemoattractant receptor was specifically increased. However, CCR6 and CXCR3, which were expressed on virtually all CD4+ BAL T cells prechallenge, were markedly decreased on all recruited BAL T cells following Ag challenge, suggesting that these receptors were internalized following encounter with ligand in the airway. Our data therefore suggests a role for CCR6 and CXCR3, in conjunction with other chemoattractant receptors, in the recruitment of inflammatory T cells into the BAL during the allergic asthmatic response.

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Section: Discussionmentioning

confidence: 80%

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

Thomas

Banerji

Medoff

et al. 2007

The Journal of Immunology

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“…The pathogenesis of asthma involves cytokines produced by the T-helper-2 (TH-2) cells that express interleukin (IL)-4, IL-5 and IL-13 [3,4]. IL-13 receptors are expressed on a multitude of cell types, and the action of IL-13 on these cells is to promote the acute inflammatory process, AHR and underlying structural changes to the airways [5].…”

Section: Introductionmentioning

confidence: 99%

An open‐label, single‐dose bioavailability study of the pharmacokinetics of CAT‐354 after subcutaneous and intravenous administration in healthy males

Oh¹,

Faggioni²,

Jin³

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The safety profile and effective dose of CAT-354 have been determined with intravenous (i.v.) administration, but no information is available on subcutaneous (s.c.) administration. WHAT THIS STUDY ADDS• This study characterized the pharmacokinetics of CAT-354 following s.c. administration of 150 mg and 300 mg doses, and indicated a bioavailability of approximately 60%. AIMTo assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration. METHODSThis was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20-54 years were randomly assigned to one of three dose groups (n = 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed. RESULTSCAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3-9 (median 5) days, with a mean elimination half-life of 19.2 Ϯ 3.1 days (150 mg) and 19.4 Ϯ 3.59 days (300 mg) after s.c. and 21.4 Ϯ 2.46 days after i.v. administration. Volume of distribution at steady state (Vss) was 4960 Ϯ 1440 ml kg -1 after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 Ϯ 82.3 and 307 Ϯ 109 ml day -1 after 150 and 300 mg s.c., respectively; systemic CL of 188 Ϯ 84.0 ml day -1 after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception. CONCLUSIONSCAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.

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“…Increased airway levels of ROS (3,4), coupled with decreased levels of antioxidants such as glutathione (5), may lead to an oxidant͞ antioxidant imbalance in the lungs of patients with asthma and activation of redox-sensitive transcription factors activator protein-1 (AP-1) and nuclear factor B (NF-B). These transcription factors, in collaboration with Th2-specific transcription factors (i.e., c-maf, GATA-3, Stat6), control expression of Th2 cytokines (e.g., IL-4, IL-5, IL-13), the molecular hallmarks of asthma (6). Corticosteroids, which inhibit both NF-B and AP-1 transcription, are the most effective treatment for asthma but have severe adverse effects when administered systemically (7).…”

mentioning

confidence: 99%

Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma

Nguyen

Teo

Matsuda

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Asthma is characterized by an oxidant͞antioxidant imbalance in the lungs leading to activation of redox-sensitive transcription factors, nuclear factor B (NF-B), and activator protein-1 (AP-1). To develop therapeutic strategies for asthma, we used a chemogenomics approach to screen for small molecule inhibitor(s) of AP-1 transcription. We developed a ␤-strand mimetic template that acts as a reversible inhibitor (pseudosubstrate) of redox proteins. This template incorporates an enedione moiety to trap reactive cysteine nucleophiles in the active sites of redox proteins. Specificity for individual redox factors was achieved through variations in X and Y functionality by using a combinatorial library approach. A limited array (2 ؋ 6) was constructed where X was either NHCH 3

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TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis

Cited by 205 publications

References 26 publications

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

An open‐label, single‐dose bioavailability study of the pharmacokinetics of CAT‐354 after subcutaneous and intravenous administration in healthy males

Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma

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