ABSTRACT
We report here the first successful synthesis of planar triphenylborane 1 with the phenyl groups bridged by oxygen and nitrogen atoms via double nucleophilic aromatic substitution reaction. The hetero atom-bridged 1 has excellent planarity. Its structural and photophysical properties are tunable by altering the bridging atoms.
ABSTRACT
BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.
Subject(s)
ADAM Proteins , Asthma/blood , Asthma/genetics , Interleukin-4 Receptor alpha Subunit , ADAM Proteins/blood , ADAM Proteins/genetics , Adult , Aged , Asthma/drug therapy , Follow-Up Studies , Genetic Markers , Humans , Interleukin-4 Receptor alpha Subunit/blood , Interleukin-4 Receptor alpha Subunit/genetics , Middle Aged , Risk FactorsABSTRACT
BACKGROUND: Interleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation. OBJECTIVE: The goal of this project was to investigate the role of cellular oxidative stress in controlling IL-33 release in airway epithelium. METHODS: Complementary approaches were used that included human bronchial epithelial cells and mouse models of airway type-2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me) was used to evaluate the role of Nrf2-induced antioxidant molecules. RESULTS: Human bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N-acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL-33 release. Administration of CDDO-Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO-Me treatment reduced allergen-induced ATP secretion and IL-33 release by airway epithelial cells in vitro and protected mice from IL-33 release and asthma-like pathological changes in the lungs. CONCLUSIONS: The balance between oxidative stress and antioxidant responses plays a key role in controlling IL-33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.
Subject(s)
Interleukin-33/metabolism , Oxidative Stress , Adenosine Triphosphate/metabolism , Allergens/immunology , Animals , Antioxidants/metabolism , Calcium/metabolism , Epithelial Cells/metabolism , Female , Humans , Lung/drug effects , Lung/immunology , Lung/metabolism , Mice , Mice, Knockout , NF-E2-Related Factor 2/metabolism , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/pharmacology , Reactive Oxygen Species/metabolism , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolismABSTRACT
Asthma is independently associated with HLA-DR3 and increased risks of pneumococcal diseases. We aimed to determine whether HLA-DR polymorphism (HLA-DRB1*03), sensitization to house dust mite (HDM), or their interaction affects humoral immune responses to pneumococcal polysaccharide and protein antigens of intact pneumococci. Induction of serum titers of anti-pneumococcal polysaccharide and anti-surface protein IgM and IgG in response to immunization with intact pneumococci (Pn) serotype 14 was determined using humanized HLA-DR3 and DR2 transgenic mice. Transgenic mice were sensitized by injecting HDM and challenged with intranasal HDM. Mice were subsequently immunized with heat-killed Pn14 at day 24. Serum titers of anti-phosphorylcholine (PC) IgM and IgG, anti-pneumococcal polysaccharide, capsular type 14 (PPS14) IgM and IgG, and anti-pneumococcal surface protein A (PspA) IgG were measured. We included a total of 44 mice (22 DR3 and 22 DR2 mice) and half of mice in each group were sensitized with HDM (i.e. 22 HDM-sensitized and 22 control mice). HDM-sensitized mice, irrespective of HLA-DR polymorphism, had significantly lower humoral immune responses. HLA-DR3 mice, irrespective of HDM sensitization, elicited a significantly lower anti-PC IgG response. In contrast, the anti-PspA IgG response was higher in DR3 relative to DR2 mice. The effect of HDM sensitization on lowering humoral immune responses to Pn14 was observed in DR3 mice regardless of the nature of the antigen, whereas such decreases were observed only for the anti-PPS14 IgG and anti-PC IgM responses in DR2 mice. HDM sensitization lowered humoral immune responses to intact pneumococcus and this effect was significantly modified by the HLA-DR polymorphism.
Subject(s)
Antibodies, Bacterial/biosynthesis , HLA-DR2 Antigen/immunology , HLA-DR3 Antigen/immunology , Immunity, Humoral/drug effects , Immunization , Polymorphism, Genetic , Streptococcus pneumoniae/immunology , Animals , Bacterial Proteins/administration & dosage , Bacterial Proteins/immunology , HLA-DR2 Antigen/genetics , HLA-DR3 Antigen/genetics , HLA-DRB1 Chains/genetics , HLA-DRB1 Chains/immunology , Hot Temperature , Humans , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Mice , Mice, Transgenic , Polysaccharides, Bacterial/administration & dosage , Polysaccharides, Bacterial/immunology , Pyroglyphidae/immunology , Streptococcus pneumoniae/chemistryABSTRACT
BACKGROUND: Exposure to aeroallergens induces eosinophilic airway inflammation in patients with asthma and allergic airway diseases. The circulating number of eosinophils in peripheral blood is relatively small, leading us to hypothesize that bone marrow needs to be engaged quickly to meet the demands of the tissues. METHODS: To investigate the communication between the lungs and bone marrow, we used acute allergen exposure and airway inflammation models in mice. Gene-deficient mice and cytokine reporter mice as well as in vitro cell culture models were used to dissect the mechanisms. RESULTS: Naïve BALB/c mice produced increased numbers of eosinophil precursors and mature eosinophils in the bone marrow when their airways were exposed to a common fungal allergen, Alternaria alternata. Expression of IL-5 and IL-33 increased rapidly in the lungs, but not in the bone marrow. Sera from allergen-exposed mice promoted eosinophilopoiesis in bone marrow cells from naïve mice, which was blocked by anti-IL-5 antibody. Mice deficient in the IL-33 receptor ST2 (i.e., Il1rl1(-/-) mice) were unable to increase their serum levels of IL-5 and allergen-induced eosinophilopoiesis in the bone marrow after allergen exposure. Finally, group 2 innate lymphoid cells (ILC2s) in the lungs showed robust expression of IL-5 after Alternaria exposure. CONCLUSIONS: These finding suggests that lung IL-33, through innate activation of ILC2s and their production of IL-5, plays a key role in promoting acute reactive eosinophilopoiesis in the bone marrow when naïve animals are exposed to airborne allergens. Therefore, bone marrow eosinophilopoiesis may be affected by atmospheric environmental conditions.
Subject(s)
Allergens/immunology , Environmental Exposure/adverse effects , Eosinophilia/blood , Eosinophilia/immunology , Eosinophils/immunology , Eosinophils/metabolism , Interleukin-33/metabolism , Myelopoiesis , Animals , Bone Marrow/immunology , Bone Marrow/metabolism , Bone Marrow/pathology , Eosinophilia/genetics , Female , Interleukin-5/blood , Interleukin-5/metabolism , Leukocyte Count , Lung/immunology , Lung/metabolism , MiceABSTRACT
BACKGROUND: The mechanisms and immune pathways associated with chronic rhinosinusitis (CRS) are not fully understood. Immunological changes during acute exacerbation of CRS may provide valuable clues to the pathogenesis and perpetuation of the disease. OBJECTIVE: To characterize local and systemic immune responses associated with acute worsening of sinonasal symptoms during exacerbation in CRS with nasal polyps (CRSwNP) compared to controls. METHODS: This was a non-interventional prospective study of individuals with CRSwNP and normal controls. Subjects underwent a baseline visit with collection of nasal secretions, nasal washes, and serum specimens. Within 3 days of acute worsening of sinonasal symptoms, subjects underwent a study visit, followed by a post-visit 2 weeks later. The sinonasal outcome test-22 (SNOT-22) scores and immunological parameters in the specimens were analysed using a novel, unsupervised learning method and by conventional univariate analysis. RESULTS: Both CRSwNP patients and control subjects showed a significant increase in SNOT-22 scores during acute exacerbation. Increased nasal levels of IL-6, IL-5, and eosinophil major basic protein were observed in CRSwNP patients. A network analysis of serum specimens revealed changes in a set of immunological parameters, which are distinctly associated with CRSwNP but not with controls. In particular, systemic increases in VEGF and GM-CSF levels were notable and were validated by a conventional analysis. CONCLUSIONS: CRSwNP patients demonstrate distinct immunological changes locally and systemically during acute exacerbation. Growth factors VEGF and GM-CSF may be involved in the immunopathogenesis of subjects with CRS and nasal polyps experiencing exacerbation.
Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/blood , Nasal Polyps/complications , Rhinitis/blood , Rhinitis/complications , Sinusitis/blood , Sinusitis/complications , Vascular Endothelial Growth Factor A/blood , Adult , Biomarkers/blood , Case-Control Studies , Chronic Disease , Cluster Analysis , Cytokines/blood , Disease Progression , Female , Humans , Inflammation Mediators/blood , Male , Middle Aged , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Prospective Studies , Protein Interaction Mapping , Protein Interaction Maps , Rhinitis/diagnosis , Rhinitis/immunology , Sinusitis/diagnosis , Sinusitis/immunology , Young AdultABSTRACT
BACKGROUND: Innate lymphoid cells (ILCs) play important roles in innate immunity and tissue remodeling via production of various cytokines and growth factors. Group 2 ILCs (ILC2s) were recently shown to mediate the immune pathology of asthma even without adaptive immunity. However, little is known about possible interactions between ILC2s and other immune cells. We sought to investigate the capacity of ILC2s to regulate effector functions of T cells. METHODS: We isolated ILC2s from the lungs of naïve mice. We cultured CD4(+) T cells with ILC2s in vitro and examined the functions of these cell types. The mechanisms were investigated using blocking antibodies and cells isolated from cytokine-deficient mice. For the in vivo study, we adoptively transferred ILC2s and CD4(+) T cells into Il7ra(-/-) mice and subsequently exposed the mice to ovalbumin and a cysteine protease. RESULTS: Lung ILC2s enhanced CD4(+) T-cell proliferation and promoted production of type 2 cytokines in vitro. The interaction between ILC2s and CD4(+) T cells involved costimulatory molecule OX40L and cytokine IL-4, which was mainly derived from ILC2s. Adoptive transfer of both ILC2 and CD4(+) T-cell populations, but not each population alone, into Il7ra(-/-) mice resulted in induction of a robust antigen-specific type 2 cytokine response and airway inflammation. CONCLUSION: Lung ILC2s function to promote adaptive immunity in addition to their established roles in innate immunity. This novel function of ILC2s needs to be taken into account when considering the pathophysiology of asthma and other allergic airway diseases.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Immunity, Innate/immunology , Lymphocytes/immunology , Adoptive Transfer , Animals , Asthma/immunology , Coculture Techniques , Cytokines/biosynthesis , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Lung/cytology , Lung/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Real-Time Polymerase Chain ReactionABSTRACT
BACKGROUND: The mechanisms for producing weals in chronic spontaneous (idiopathic) urticaria (CSU) are incompletely understood. Leucocyte infiltration with vascular leakage and expression of the potent vasoactive agents' calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) are features of late-phase allergic skin reactions, previously proposed as a model of CSU. OBJECTIVE: To measure CGRP and VEGF expression in lesional and non-lesional skin from CSU patients and to compare results with a control group. METHODS: Eight paired biopsies (one from 4-8 h spontaneous weals and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects and studied by immunohistochemistry and confocal microscopy. RESULTS: Lesional skin in CSU contained significantly more CGRP+ and VEGF+ cells than non-lesional skin. No significant differences were observed in CGRP and VEGF expression between non-lesional skin and controls. In lesional skin, VEGF and CGRP co-localised to UEA-1+ blood vessels. CGRP was also expressed by neutrophils and eosinophils and to a lesser extent by CD90(+) fibroblasts, mast cells, CD3(+) and CD68(+) cells. CGRP and VEGF expression was not related to the duration of disease. CONCLUSION AND CLINICAL RELEVANCE: Increased expression of CGRP and VEGF in lesional, but not uninvolved, skin indicates that these potent vasoactive agents may play a role in wealing and tissue oedema in CSU so representing novel targets in therapy.
Subject(s)
Calcitonin Gene-Related Peptide/metabolism , Urticaria/immunology , Urticaria/metabolism , Vascular Endothelial Growth Factor A/metabolism , Adult , Aged , Antigens, Surface/metabolism , Biopsy , Calcitonin Gene-Related Peptide/genetics , Chronic Disease , Female , Gene Expression , Humans , Immunohistochemistry , Male , Middle Aged , Urticaria/genetics , Urticaria/pathology , Vascular Endothelial Growth Factor A/geneticsABSTRACT
BACKGROUND: In chronic spontaneous urticaria (CSU) mast cell activation together with inflammatory changes in the skin are well documented and may play an important role in mechanisms of tissue oedema. OBJECTIVES: To confirm and extend these observations by measuring microvascular markers, leucocytes and mast cell numbers in lesional and uninvolved skin and to compare findings with a control group. METHODS: Paired biopsies (one from 4-8-h spontaneous weals and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects and studied using immunohistochemistry and confocal microscopy using the lectin Ulex europaeus agglutinin 1 (UEA-1). RESULTS: Lesional skin in CSU contained significantly more CD31+ endothelial cells; CD31+ blood vessels, neutrophils, eosinophils, basophils and macrophages; and CD3+ T cells than nonlesional skin. Increased vascularity was confirmed by confocal imaging using the lectin UEA-1. Uninvolved skin from CSU contained significantly more CD31+ endothelial cells, CD31+ blood vessels and eosinophils compared with the control subjects. There was a threefold increase in mast cell numbers when CSU was compared with controls but no difference was observed between lesional and uninvolved skin. CONCLUSIONS: Increased vascular markers together with eosinophil and neutrophil infiltration are features of lesional skin in CSU and might contribute to tissue oedema. Eosinophils and microvascular changes persist in uninvolved skin, which, together with increased mast cells, suggests that nonlesional skin is primed for further wealing.
Subject(s)
Leukocytosis/pathology , Mast Cells/pathology , Urticaria/metabolism , Adult , Aged , Biomarkers/metabolism , Blood Vessels/pathology , Case-Control Studies , Chronic Disease , Female , Humans , Leukocytes/pathology , Male , Middle Aged , Skin/blood supply , Urticaria/pathologyABSTRACT
BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.
Subject(s)
Asthma/genetics , Asthma/physiopathology , Genetic Variation , Receptors, Glucocorticoid/genetics , Administration, Inhalation , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/therapeutic use , Aged , Asthma/drug therapy , Asthma/immunology , Cell Adhesion Molecules/blood , Eosinophils/immunology , Female , Forced Expiratory Volume , Genetic Association Studies , Heat-Shock Proteins/genetics , Humans , Leukocyte Count , Male , Middle Aged , Polymorphism, Single Nucleotide , Respiratory Function Tests , Risk FactorsABSTRACT
Exposure and sensitivity to ubiquitous airborne fungi such as Alternaria alternata have long been implicated in the development, onset, and exacerbation of chronic allergic airway disorders. This present study is the first to investigate global changes in host gene expression during the interaction of cultured human bronchial epithelial cells and live Alternaria spores. In in vitro experiments human bronchial epithelial cells (BEAS-2B) were exposed to spores or media alone for 24 h. RNA was collected from three biological replicates per treatment and was used to assess changes in gene expression patterns using Affymetrix Human Genome U133 Plus 2.0 Arrays. In cells treated with Alternaria spores compared to controls, 613 probe sets representing 460 individual genes were found differentially expressed (p ≤ 0.05). In this set of 460 statistically significant, differentially expressed genes, 397 genes were found to be up-regulated and 63 were down-regulated. Of these 397 up-regulated genes, 156 genes were found to be up-regulated ≥2 fold. Interestingly, none of the 63 down-regulated genes were found differentially expressed at ≤-2 fold. Differentially expressed genes were identified following statistical analysis and subsequently used for pathway and network evaluation. Interestingly, many cytokine and chemokine immune response genes were up-regulated with a particular emphasis on interferon-inducible genes. Genes involved in cell death, retinoic acid signaling, and TLR3 response pathways were also significantly up-regulated. Many of the differentially up-regulated genes have been shown in other systems to be associated with innate immunity, inflammation and/or allergic airway diseases. This study now provides substantial information for further investigating specific genes and innate immune system pathways activated by Alternaria in the context of allergic airway diseases.
ABSTRACT
PURPOSE: We previously reported that asthmatics had lower anti-serotype-specific pneumococcal polysaccharide antibody levels than non-asthmatics, and the T-helper 2 (Th2) immune profile was associated with suboptimal pneumococcal polysaccharide antibody. Our objective was to determine the influence of asthma status on anti-pneumococcal protein antigen antibody levels. METHODS: We conducted a cross-sectional study, which enrolled 16 children and adults with asthma and 14 subjects without asthma. Asthma was ascertained by predetermined criteria. Serum IgG antibody levels to pneumococcal surface protein A (PspA), pneumococcal surface protein C (PspC), pneumococcal choline-binding protein A (PcpA), and pneumolysin (PLY) were measured by enzyme-linked immunosorbent assays (ELISA). These antibody levels were compared between asthmatics and non-asthmatics. The Th2 immune profile was determined by IL-5 secretion from PBMCs cultured with house dust mite (HDM) and staphylococcal enterotoxin B (SEB) at day 7. The correlation between the anti-pneumococcal antibody levels and the Th2-HDM and SEB-responsive immune profile was assessed. RESULTS: Of the 30 subjects, 16 (53%) were male and the median age was 26 years. There were no significant differences in anti-PspA, anti-PspC, anti-PcpA, and anti-PLY antibody levels between asthmatics and non-asthmatics. The Th2 immune profile was inversely correlated with the anti-PspC antibody levels (r = -0.53, p = 0.003). This correlation was significantly modified by asthma status (r = -0.74, p = 0.001 for asthmatics vs. r = -0.06, p = 0.83 for non-asthmatics). Other pneumococcal protein antibodies were not correlated with the Th2 immune profile. CONCLUSION: No significant differences in the anti-pneumococcal protein antigen antibody levels between asthmatics and non-asthmatics were found. Asthma status is an important effect modifier determining the negative influence of the Th2 immune profile on anti-PspC antibody levels.
Subject(s)
Antibodies, Bacterial/blood , Antigens, Bacterial/immunology , Asthma/immunology , Bacterial Proteins/immunology , Streptococcus pneumoniae/immunology , Adult , Asthma/microbiology , Case-Control Studies , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Interleukin-5/blood , Leukocytes, Mononuclear , Male , Streptolysins/immunology , Th2 Cells/immunologyABSTRACT
The globus pallidus consists of the external (GPe) and the internal (GPi) segments. The GPe and GPi have different functional roles. The GPe is located centrally within multiple basal ganglia feedforward and feedback connections. The GPi is an output nucleus of the basal ganglia. A complex interplay between intrinsic pacemaking conductances and the balance of glutamatergic and GABAergic input largely determines the rate and pattern of firing of pallidal neurons. The initial part of this article introduces recent findings made in vivo that are related to the roles of glutamatergic and GABAergic inputs in the control of pallidal activity. The latter part describes the roles of intrinsic mechanisms of GPe neurons in the integration of the synaptic inputs. The presence of dendritic voltage-gated sodium channels may allow the initiation of dendritic spikes, giving distal inputs on the long and thin GPe dendrites an opportunity to strongly shape spiking activity. Basal ganglia disorders including Parkinson's disease, hemiballismus, and dystonias are accompanied by increased irregularity and synchronized bursts of pallidal activity. These changes may be in part due to changes in the GABA release in the GPe and GPi, but also involve intrinsic cellular changes in pallidal neurons.
Subject(s)
Globus Pallidus/cytology , Nerve Net/physiology , Neurons/physiology , Action Potentials/physiology , Animals , Globus Pallidus/physiology , Nerve Net/cytology , Neural Pathways/physiology , Neurons/cytology , Neurotransmitter Agents/metabolism , Synapses/physiologyABSTRACT
We and others have reported that HLA-DRB1*03 is associated with childhood asthma. To extend this observation and to prove this association, we sensitized and challenged either HLA-DR2 (HLA-DRB1*1502) or HLA-DR3 (HLA-DRB1*0301) transgenic mice with house-dust mite extract. Inflammatory cell counts and cytokine levels in the bronchoalveolar lavage (BAL) fluid between HLA-DR3 and DR2 mice were compared. HLA-DR3 transgenic mice had significantly elevated eosinophil counts, Interleukin-4 and Interleukin-13 levels in the BAL fluid but not interferron gamma-γ. Thus, our study suggests that HLA-DRB1*0301 plays an important role in mounting a Th2-predominant immune response to house dust mite and Th2-type inflammation in the lung.
Subject(s)
HLA-DR Antigens/genetics , HLA-DR2 Antigen/genetics , HLA-DR3 Antigen/genetics , Polymorphism, Genetic , Pyroglyphidae/genetics , Animals , Bronchoalveolar Lavage Fluid , HLA-DRB1 Chains , Humans , Immune System , Inflammation , Interferon-gamma/metabolism , Interleukin-13/metabolism , Interleukin-4/metabolism , Mice , Mice, Transgenic , Th2 CellsABSTRACT
Endoscopic submucosal dissection (ESD) is a promising procedure that enables en bloc resection of large superficial tumors in the upper gastrointestinal tract. On the other hand, ESD in the colon and rectum is technically difficult to perform because of its anatomical features. At our institution, 137 consecutive superficial colorectal tumors larger than 20 mm in diameter in 137 patients were treated by ESD between April 2007 and October 2010, and 132 lesions were successfully resected. The average procedure time was 79.2 minutes, and the rate of en bloc resection was 89.1% (122/137). The rate of complete resection, defined as en bloc resection with tumor-free lateral and vertical margins, was 85.4% (117/137). The rate of perforation was 3.6% (5/137). Colorectal ESD achieved a high rate of en bloc resection and complete resection and is applicable in the colorectum.
Subject(s)
Gastroscopes , Gastroscopy/methods , Lymphoma, Mantle-Cell/diagnosis , Stomach Neoplasms/diagnosis , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy , Cyclophosphamide/therapeutic use , Doxorubicin/analogs & derivatives , Doxorubicin/therapeutic use , Female , Humans , Image Enhancement/methods , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/pathology , Neoplasm Staging , Prednisone/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Vincristine/therapeutic useABSTRACT
OBJECTIVE: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated. METHODS: Eleven adults with active EoO (>20 peak eosinophil number/high power field (hpf) and dysphagia) were randomised to 750 mg of mepolizumab (n = 5) or placebo (n = 6) and received two intravenous infusions, 1 week apart. Those not in complete remission (<5 peak eosinophil number/hpf) after 8 weeks received two further doses 4 weeks apart, 1500 mg of mepolizumab or placebo. The effect of mepolizumab was assessed clinically, endoscopically, histologically, and via blood and tissue biomarkers. RESULTS: As assessed by immunofluorescence, a marked reduction of mean oesophageal eosinophilia (p = 0.03) was seen in the mepolizumab group (-54%) compared with the placebo group (-5%) 4 weeks after initiation of treatment. No further reduction of eosinophil numbers was observed in response to the two additional infusions in either group. Mepolizumab reduced tenascin C (p = 0.033) and transforming growth factor beta1 (p = 0.05) expression in the oesophageal epithelial layer 13 weeks after initiation of treatment. Clinically, limited improvement of symptoms was seen, although a trend was seen between 4 and 13 weeks after initiation of mepolizumab treatment. Mepolizumab was well tolerated. CONCLUSIONS: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesophageal remodelling were reversed. Minimal clinical improvement was achieved in a subgroup of patients with EoO. Mepolizumab had an acceptable safety profile, even at the high 1500 mg dose level. TRIAL REGISTRATION NUMBER: NCT00274703.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Eosinophilia/drug therapy , Esophagitis/drug therapy , Interleukin-5/immunology , Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Deglutition Disorders/drug therapy , Deglutition Disorders/etiology , Double-Blind Method , Drug Administration Schedule , Eosinophil-Derived Neurotoxin/metabolism , Eosinophilia/blood , Eosinophilia/complications , Eosinophilia/immunology , Eosinophils/pathology , Esophagitis/blood , Esophagitis/complications , Esophagitis/immunology , Esophagoscopy , Female , Humans , Inflammation Mediators/metabolism , Leukocyte Count , Male , Treatment OutcomeABSTRACT
Thrombocytopenic patients with chronic hepatitis C virus (HCV) infection are poor candidates for antiviral treatment with interferon (IFN), but no standard treatment for thrombocytopenia has yet been established. We evaluated the safety of splenectomy and its efficacy for the initiation and continuation of antiviral therapy. From March 2003 to April 2006, 10 patients (mean age 62.5 years) with HCV-related cirrhosis, low platelet count (<==106 000/mm(3)) and splenomegaly (spleen size >==10 cm) underwent splenectomy. Platelet counts significantly increased at 4-8 weeks after splenectomy [pre: 64 200 +/- 6900/mm(3)vs post 209 000 +/- 40 600/mm(3) (P = 0.004)]. No severe operative complications were observed. All patients subsequently received antiviral therapy. Of the eight patients who were infected with HCV genotype 1 and had a high viral load (>==100 KIU/mL), four received combination therapy with pegylated IFNalpha-2b plus ribavirin, and the other four received standard IFNalpha-2b plus ribavirin. One patient infected with HCV genotype 2 and another with HCV genotype 1 and a low viral load (<100 KIU/mL) were treated with pegylated IFNalpha-2a. Six patients achieved sustained virologic response (SVR). Among four patients who failed to achieve SVR, one was given retreatment with pegylated IFN plus ribavirin, and the other three received low-dose long-term IFN therapy. Although this study was small, the treatment results were similar to those for patients without thrombocytopenia and suggested that splenectomy would not reduce the antiviral efficacy of IFNalpha-based treatment.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Splenectomy , Splenomegaly/surgery , Thrombocytopenia/therapy , Aged , Female , Humans , Interferon alpha-2 , Interferon-alpha/therapeutic use , Male , Middle Aged , Polyethylene Glycols/therapeutic use , Recombinant Proteins , Ribavirin/therapeutic use , Treatment Outcome , Viral LoadABSTRACT
The relationship between allergic airway inflammation and pneumococcal pneumonia is not well understood. We assessed susceptibility to experimental pneumococcal pneumonia in mice with and without allergic airway inflammation. Susceptibility to pneumococcal pneumonia was evaluated by challenging mice with a bioluminescent Streptococcus pneumoniae strain after sensitization with ovalbumin (OVA), with subsequent monitoring of pneumococcal infection using real-time photonic imaging. Of 46 OVA-sensitized mice challenged with pneumococci, 13 (28%) developed imaging findings consistent with pneumococcal pneumonia. In comparison, 28 (57%) of 49 non-sensitized control mice developed pneumococcal pneumonia (P = 0.005). While none of the control group developed meningitis (0%, none of 28), two mice in the OVA-sensitized group developed meningitis (15.4%, two of 13) (P = 0.09). The mean bacterial count in the lung was significantly lower in the OVA-sensitized than the non-sensitized group (8.26 +/- 0.69 versus 9.21 +/- 0.67 log(10) colony-forming units (CFU)/g, P = 0.002). There was a trend towards the mean bacterial count in the spleen being higher in the OVA-sensitized versus the non-sensitized group (8.14 +/- 0.89 versus 7.45 +/- 1.07 log(10) CFU/g, P = 0.071). A high level of interleukin (IL)-4 in lung homogenates was associated with risk of pneumococcal infection independent of sensitization with OVA (odds ratio: 49.7, 95% confidence interval 2.92-846.5, per increment of 1.0 pg/ml). In the murine model studied, acute allergic airway inflammation reduced susceptibility to pneumococcal pneumonia. IL-4 may increase the risk of pneumococcal pneumonia independently of allergic airway inflammation.