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1.  Asthma and allergy: The emerging epithelium 
Nature medicine  2010;16(3):273-274.
Thinking about how asthma and allergic diseases arise is undergoing several shifts. In ‘Bedside to Bench’, Clare M. Lloyd and Sejal Saglani examine how recent human studies are putting the focus on the epithelium as a major contributor to asthma. The findings shift the emphasis away from the T helper type 2 immune response, and call into question the utility of current animal models of the disease. Although asthma and other allergic disorders are known to have origins in infancy, some researchers are looking even earlier, to effects in utero and before conception. In ‘Bench to Bedside’, Catherine Hawrylowicz and Kimuli Ryanna highlight animal studies that outline some of the effects of the maternal environment, and they examine the potential implications for prevention of disease.
doi:10.1038/nm0310-273
PMCID: PMC3380503  PMID: 20208514
2.  Chair’s Summary: Innate and Adaptive Immune Responses in Airway Disease 
Annals of the American Thoracic Society  2014;11(Suppl 5):S234-S235.
doi:10.1513/AnnalsATS.201405-210AW
PMCID: PMC4298975  PMID: 25525725
3.  Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life 
Thorax  2015;70(6):528-536.
Background
Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model.
Methods
Pregnant mice were administered paracetamol or saline by oral gavage from the day of mating throughout pregnancy and/or lactation. Subsequently, their pups were exposed to intranasal HDM or saline from day 3 of life for up to 6 weeks. Assessments of airway hyper-responsiveness, inflammation and remodelling were made at weaning (3 weeks) and 6 weeks of age.
Results
Maternal paracetamol exposure either during pregnancy and/or lactation did not affect development of AAD in offspring at weaning or at 6 weeks. There were no effects of maternal paracetamol at any time point on airway remodelling or IgE levels.
Conclusions
Maternal paracetamol did not enhance HDM induced AAD in offspring. Our mechanistic data do not support the hypothesis that prenatal paracetamol exposure increases the risk of childhood asthma.
doi:10.1136/thoraxjnl-2014-205280
PMCID: PMC4453715  PMID: 25841236
Asthma; Allergic lung disease; Paediatric asthma
4.  Interleukin-33 promotes airway remodelling in paediatric severe steroid resistant asthma 
Background
Th2 cytokines are not responsible for the on-going symptoms and pathology in children with severe therapy resistant asthma (STRA). Interleukin (IL)-33 induces airway hyperresponsiveness (AHR), but its role in airway remodelling and steroid resistance is unknown.
Objective
To investigate the relationship between IL-33 and airway remodelling in paediatric STRA.
Methods
IL-33 was quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodelling and IL-33 was assessed. HDM induced allergic airways disease (AAD) in neonatal ST2−/− mice lacking the IL-33 receptor was assessed, together with collagen production following IL-33 administration. Impact of steroid therapy on IL-33 levels in neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsies from children with STRA and related to remodelling, and collagen production by paediatric airway fibroblasts stimulated with IL-33 and budesonide quantified.
Results
Blocking IL-13 after AAD was established in neonatal mice did not reduce remodelling or IL-33 levels; AHR was only partially reduced. IL-33 promoted collagen synthesis both from paediatric asthmatic fibroblasts, and following intra-nasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in endobronchial biopsies from children with STRA, whilst remodelling was absent in HDM exposed ST2−/− mice. IL-33 was maintained whilst IL-13 was abrogated by steroid treatment in neonatal HDM exposed mice, and in endobronchial biopsies from children with STRA.
Conclusion
IL-33 is a relatively steroid resistant mediator that promotes airway remodelling in STRA, and is an important therapeutic target.
doi:10.1016/j.jaci.2013.04.012
PMCID: PMC4218948  PMID: 23759184
Asthma; paediatric; airway remodelling; steroid resistance; IL-33; therapy
5.  Alternaria-derived serine protease activity drives IL-33–mediated asthma exacerbations 
Background
The fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear.
Objective
We sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation.
Methods
IL-33 levels were quantified in wild-type and ST2−/− mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria, and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later.
Results
Alternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease–IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model.
Conclusion
Alternaria-specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust TH2 inflammation and exacerbation of allergic airway disease.
doi:10.1016/j.jaci.2014.02.002
PMCID: PMC4152000  PMID: 24636086
Alternaria alternata; allergic airway disease; asthma exacerbation; protease; IL-33; AEBSF, 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride; ALT, Alternaria; BALF, BAL fluid; CAT, Cat dander; HDM, House dust mite; MCPT-1, Mast cell protease-1; MMP-9, Matrix metalloproteinase-9; PAP, Papain; PAR-2, Protease activated receptor 2; RAG, Ragweed; TRYP, Trypsin
6.  CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling 
Background
CD4+CD25+ regulatory T cells can inhibit excessive T-cell responses in vivo. We have previously demonstrated that prophylactic administration of CD4+CD25+ regulatory T cells suppresses the development of acute allergen-induced airway inflammation in vivo.
Objective
We sought to determine the effect of therapeutic transfer of CD4+CD25+ regulatory T cells on established pulmonary inflammation and the subsequent development of airway remodeling.
Methods
CD4+CD25+ cells were transferred after the onset of allergic inflammation, and airway challenges were continued to induce chronic inflammation and airway remodeling.
Results
Administration of CD4+CD25+ regulatory T cells reduced established lung eosinophilia, TH2 infiltration, and expression of IL-5, IL-13, and TGF-β. Moreover, subsequent mucus hypersecretion and peribronchial collagen deposition were reduced after prolonged challenge. In contrast, transfer of CD4+CD25+ regulatory T cells had no effect on established airway hyperreactivity either 7 days or 4 weeks after transfer.
Conclusions
In this study we demonstrate for the first time that therapeutic transfer of CD4+CD25+ regulatory T cells can resolve features of chronic allergen-induced inflammation and prevent development of airway remodeling.
doi:10.1016/j.jaci.2008.05.048
PMCID: PMC3389733  PMID: 18672278
Regulatory T cells; TH2 cells; eosinophils; TGF-β; airway remodeling; allergic inflammation
7.  CXCR2 Mediates the Recruitment of Endothelial Progenitor Cells During Allergic Airways Remodeling 
Stem cells (Dayton, Ohio)  2009;27(12):3074-3081.
Airway remodeling is a central feature of asthma and includes the formation of new peribronchial blood vessels, which is termed angiogenesis. In a number of disease models, bone marrow-derived endothelial progenitor cells (EPCs) have been shown to contribute to the angiogenic response. In this study we set out to determine whether EPCs were recruited into the lungs in a model of allergic airways disease and to identify the factors regulating EPC trafficking in this model. We observed a significant increase in the number of peribronchial blood vessels at day 24, during the acute inflammatory phase of the model. This angiogenic response was associated with an increase in the quantity of EPCs recoverable from the lung. These EPCs formed colonies after 21 days in culture and were shown to express CD31, von Willebrand factor, and vascular endothelial growth factor (VEGF) receptor 2, but were negative for CD45 and CD14. The influx in EPCs was associated with a significant increase in the proangiogenic factors VEGF-A and the CXCR2 ligands, CXCL1 and CXCL2. However, we show directly that, while the CXCL1 and CXCL2 chemokines can recruit EPCs into the lungs of allergen-sensitized mice, VEGF-A was ineffective in this respect. Further, the blockade of CXCR2 significantly reduced EPC numbers in the lungs after allergen exposure and led to a decrease in the numbers of peribronchial blood vessels after allergen challenge with no effect on inflammation. The data presented here provide in vivo evidence that CXCR2 is critical for both EPC recruitment and the angiogenic response in this model of allergic inflammation of the airways.
doi:10.1002/stem.222
PMCID: PMC3385349  PMID: 19785013
CXC chemokines; Progenitor cell; Asthma; Angiogenesis
8.  Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology 
Background
IL-9-secreting (TH9) T cells are thought to represent a distinct T-cell subset. However, evidence for their functionality in disease is uncertain.
Objective
To define a functional phenotype for TH9-driven pathology in vivo.
Methods
We used fluorescence-activated cell sorting to identify circulating TH9 cells in atopic and nonatopic subjects. In mice we utilized a model of allergic airways disease induced by house dust mite to determine TH9 cell function in vivo and the role of activin A in TH9 generation.
Results
Allergic patients have elevated TH9 cell numbers in comparison to nonatopic donors, which correlates with elevated IgE levels. In a murine model, allergen challenge with house dust mite leads to rapid TH9 differentiation and proliferation, with much faster kinetics than for TH2 cell differentiation, resulting in the specific recruitment and activation of mast cells. The TGF-β superfamily member activin A replicates the function of TGF-β1 in driving the in vitro generation of TH9 cells. Importantly, the in vivo inhibition of TH9 differentiation induced by allergen was achieved only when activin A and TGF-β were blocked in conjunction but not alone, resulting in reduced airway hyperreactivity and collagen deposition. Conversely, adoptive transfer of TH9 cells results in enhanced pathology.
Conclusion
Our data identify a distinct functional role for TH9 cells and outline a novel pathway for their generation in vitro and in vivo. Functionally, TH9 cells promote allergic responses resulting in enhanced pathology mediated by the specific recruitment and activation of mast cells in the lungs.
doi:10.1016/j.jaci.2011.12.965
PMCID: PMC3385370  PMID: 22277204
Activin A; TH9 cells; IL-9; asthma; allergy; mast cells; house dust mite; TGF-β
9.  Building Better Mouse Models of Asthma 
Allergic asthma is a complex disease that has been modeled extensively in small rodents. Airway eosinophilia and changes in lung function have been documented using a variety of protocols. However, recent efforts have improved these models by trying to replicate the structural remodeling that occurs in the lung as a consequence of chronic allergen-driven inflammation. This review documents the recent developments in protocols and systems designed to examine pathways leading to allergen-induced airway remodeling.
PMCID: PMC3384569  PMID: 17448336
10.  Pathophysiological Features of Asthma Develop in Parallel in House Dust Mite–Exposed Neonatal Mice 
Asthma frequently commences in early life during airway and immune development and exposure to new environmental challenges. Endobronchial biopsies from children with asthma are abnormal, and lung function is maximally reduced by 6 years of age. As longitudinal biopsy studies are unethical in children, the relationship between development of pathology and reduced lung function is unknown. We aimed to establish a novel neonatal mouse model of allergic airways disease to investigate the developmental sequence of the pathophysiologic features of asthma. Neonatal Balb/c mice were challenged three times weekly from Day 3 of life using intranasal house dust mite (HDM) or saline for up to 12 weeks. Weekly assessments of airway inflammation and remodeling were made. Airway hyperresponsiveness (AHR) to methacholine was assessed from Week 2 onward. Total and eosinophilic inflammation was significantly increased in the lungs of HDM-exposed neonates from Week 2 onwards, and a peak was seen at 3 weeks. Goblet cells and peribronchiolar reticulin deposition were significantly increased in HDM-exposed neonates from Week 3, and peribronchiolar collagen was significantly greater from Week 4. HDM-exposed neonates had increased AHR from Week 2 onward. Although inflammation and AHR had subsided after 4 weeks without allergen challenge, the increased reticulin and collagen deposition persisted in HDM-exposed mice. Neonatal mice exposed to intranasal HDM developed eosinophilic inflammation, airway remodeling, and AHR as reported in pediatric asthma. Importantly, all abnormalities developed in parallel, not sequentially, between 2 and 3 weeks of age.
doi:10.1165/rcmb.2008-0396OC
PMCID: PMC3380517  PMID: 19151316
pediatric; remodeling; asthma pathophysiology; mouse model; allergic airways disease
11.  IL-33 family members and asthma – bridging innate and adaptive immune responses 
Current opinion in immunology  2010;22(6):800-806.
The discovery of IL-33 as the ligand for the orphan Th2 associated receptor ST2 has uncovered a whole range of different avenues for this pathway. Although the extracellular functions of ST2 as a marker for Th2 cell and mast cell activity were well defined, the complexities of IL-33 regulation, nuclear function and secretion are only just being realised. The well documented expression pattern of ST2 has identified a role for the IL-33/ST2 axis in the classical Th2 cell and mast cell driven pathogenesis of asthma and anaphylaxis. However, the induction of IL-33 expression by environmental or endogenous triggers now suggests a wider role for the pathway during infection, inflammation and tissue damage.
doi:10.1016/j.coi.2010.10.006
PMCID: PMC3380518  PMID: 21071194
12.  Pulmonary Epithelial Cell-Derived Cytokine TGF-β1 Is a Critical Cofactor for Enhanced Innate Lymphoid Cell Function 
Immunity  2015;43(5):945-958.
Summary
Epithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions.
Graphical Abstract
Highlights
•Epithelial-derived TGF-β drives pulmonary response to allergen•Epithelial TGF-β promotes GATA3-driven cytokine production by suppression of Sox4•TGF-β is chemoactive for innate lymphoid cells that express TGF-βRII•The local pulmonary environmental niche defines the nature of immune reactions
The role of epithelial-derived TGF-β in the pathogenesis of asthma is unknown. Lloyd and colleagues demonstrate that epithelial TGF-β is essential for the generation of the pulmonary allergic response to allergen by acting as a chemoactive factor for innate lymphoid type 2 cells and promoting GATA3-induced cytokine expression.
doi:10.1016/j.immuni.2015.10.012
PMCID: PMC4658339  PMID: 26588780
13.  Special delivery: How macrophages get the message across 
doi:10.1084/jem.2125insight1
PMCID: PMC4419351  PMID: 25941317
14.  Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection 
Nature Communications  2015;6:8423.
Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline–glycine–proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.
Proteases degrade extracellular matrix during inflammation, releasing peptides that can recruit neutrophils. Here the authors show that degradation of such bioactive peptide by the enzyme leukotriene A4 hydrolase is critical to limit pulmonary inflammation during bacterial infection in mice.
doi:10.1038/ncomms9423
PMCID: PMC4595997  PMID: 26400771
15.  Activin and TGF-β signalling pathways are activated after allergen challenge in mild asthma 
Background
Both transforming growth factor (TGF)-β1 and activin-A have been implicated in airway remodelling in asthma but the modulation of their specific signalling pathways after disease activation remains undefined.
Objective
To define the expression kinetics of TGF-β1, activin-A ligands and follistatin (a natural activin inhibitor), their Type I and Type II receptors (ALK-1, ALK-5 and ALK-4 and TβRII and ActRIIA/RIIB) and activation of signalling (via pSmad2), in the asthmatic airway following allergen challenge.
Methods
Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic asthmatics (median age 25 years, median FEV1% predicted 97%) at baseline and 24 hours after allergen inhalation. Functional effects of activin-A were evaluated using cultured normal human bronchial epithelial (NHBE) cells.
Results
pSmad2+ epithelial cells increased at 24 hours (p=0.03) and pSmad2 was detected in submucosal cells. No modulation of activin-A, follistatin or TGF-β1 expression was demonstrated. Activin receptor+ cells increased after allergen challenge.: ALK-4 in epithelium (p=0.04) and submucosa (p=0.04), and ActRIIA in epithelium (p=0.01). The TGF-β receptor ALK-5 expression was minimal in the submucosa at baseline and after challenge and was down-regulated in the epithelium after challenge (p=0.02), whereas ALK-1 and TβRII expression in the submucosa increased after allergen challenge (p=0.03 and p=0.004 respectively). ALK-1 and ALK-4 expression by T cells was increased after allergen challenge. Activin-A induced NHBE cell proliferation, was produced by NHBE cells in response to TNF-α, and down-regulated TNF-α and IL-13-induced chemokine production by NHBE cells.
Conclusion
Both TGF-β and activin signalling pathways are activated upon allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.
doi:10.1016/j.jaci.2009.06.022
PMCID: PMC4579560  PMID: 19733294
Asthma; activin-A; TGF-β1
16.  Overexpression of Smad2 Drives House Dust Mite–mediated Airway Remodeling and Airway Hyperresponsiveness via Activin and IL-25 
Rationale: Airway hyperreactivity and remodeling are characteristic features of asthma. Interactions between the airway epithelium and environmental allergens are believed to be important in driving development of pathology, particularly because altered epithelial gene expression is common in individuals with asthma.
Objectives: To investigate the interactions between a modified airway epithelium and a common aeroallergen in vivo.
Methods: We used an adenoviral vector to generate mice overexpressing the transforming growth factor-β signaling molecule, Smad2, in the airway epithelium and exposed them to house dust mite (HDM) extract intranasally.
Measurements and Main Results: Smad2 overexpression resulted in enhanced airway hyperreactivity after allergen challenge concomitant with changes in airway remodeling. Subepithelial collagen deposition was increased and smooth muscle hyperplasia was evident resulting in thickening of the airway smooth muscle layer. However, there was no increase in airway inflammation in mice given the Smad2 vector compared with the control vector. Enhanced airway hyperreactivity and remodeling did not correlate with elevated levels of Th2 cytokines, such as IL-13 or IL-4. However, mice overexpressing Smad2 in the airway epithelium showed significantly enhanced levels of IL-25 and activin A after HDM exposure. Blocking activin A with a neutralizing antibody prevented the increase in lung IL-25 and inhibited subsequent collagen deposition and also the enhanced airway hyperreactivity observed in the Smad2 overexpressing HDM-exposed mice.
Conclusions: Epithelial overexpression of Smad2 can specifically alter airway hyperreactivity and remodeling in response to an aeroallergen. Moreover, we have identified novel roles for IL-25 and activin A in driving airway hyperreactivity and remodeling.
doi:10.1164/rccm.200905-0725OC
PMCID: PMC2913231  PMID: 20339149
asthma; lung; epithelium; smooth muscle; collagen
17.  A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice 
Thorax  2014;69(6):565-573.
Background
CpG-containing oligodeoxynucleotides (CpG-ODN) are potent inhibitors of Th2-mediated allergic airway disease in sensitized mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease.
Objective
To optimize the treatment regimen and determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment.
Methods
A limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were given to ragweed allergen-sensitized mice chronically exposed to allergen during and after the 1018 ISS treatment regimen. Treatment effects were evaluated by measuring effect on lung Th2 cytokines and eosinophilia as well as lung dendritic cell function and T cell responses.
Results
Twelve intranasal 1018 ISS treatments induced significant suppression of BAL eosinophilia and IL-4, IL-5, and IL-13 levels and suppression was maintained through 13 weekly ragweed exposures administered after treatment cessation. At least 5 treatments were required for lasting Th2 suppression. CpG-ODN induced moderate Th1 responses but Th2 suppression did not require IFN-γ. Th2 suppression was associated with induction of a regulatory T cell response.
Conclusion
A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen.
doi:10.1136/thoraxjnl-2013-204605
PMCID: PMC4558941  PMID: 24464743
Allergic airway inflammation; asthma; CpG-containing oligodeoxynucleotides; dendritic cells; disease-modification; mouse; ragweed; therapy; T cells
18.  Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression 
The Journal of Experimental Medicine  2009;206(7):1535-1547.
Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10+ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.
doi:10.1084/jem.20082901
PMCID: PMC2715096  PMID: 19528258
19.  Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33 
Background
The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored.
Objective
We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33.
Methods
Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model.
Results
Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13+ innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2−/− mice lacking a functional receptor for IL-33.
Conclusion
Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33–mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS.
doi:10.1016/j.jaci.2015.01.016
PMCID: PMC4534777  PMID: 25746970
Severe asthma; fungal sensitization; pediatric; IL-33; innate immunity; steroid resistance; ABPA, Allergic bronchopulmonary aspergillosis; AHR, Airway hyperresponsiveness; BAL, Bronchoalveolar lavage; HDM, House dust mite; ICOS, Inducible costimulator; ILC, Innate lymphoid cell; MMP-9, Matrix metalloproteinase 9; SAFS, Severe asthma with fungal sensitization; sIgE, Specific IgE; SPT, Skin prick test; STRA, Severe therapy-resistant asthma
20.  Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti–Tim-3 antibody in vivo 
The Journal of Experimental Medicine  2007;204(6):1289-1294.
T cell immunoglobulin and mucin domain–containing molecule-3 (Tim-3) is a surface molecule that is preferentially expressed on activated Th1 cells in comparison to Th2 cells. Blockade of Tim-3 has been shown to enhance Th1-driven pathology in vivo, suggesting that blockade of Tim-3 may improve the development of Th2-associated responses such as allergy. To examine the effects of Tim-3 blockade on the Th2 response in vivo, we administered anti–Tim-3 antibody during pulmonary inflammation induced by transfer of ovalbumin (OVA)-reactive Th2 cells, and subsequent aerosol challenge with OVA. In this model, anti–Tim-3 antibody treatment before each airway challenge significantly reduced airway hyperreactivity, with a concomitant decrease in eosinophils and Th2 cells in the lung. We examined Th1 and Th2 cytokine levels in the lung after allergen challenge and found that pulmonary expression of the Th2 cytokine IL-5 was significantly reduced, whereas IFN-γ levels were significantly increased by anti–Tim-3 antibody treatment. Thus, blocking Tim-3 function has a beneficial effect during pulmonary inflammation by skewing the Th2 response toward that of a Th1 type, suggesting an important role for Tim-3 in the regulation of allergic disease.
doi:10.1084/jem.20062093
PMCID: PMC2118608  PMID: 17517968
21.  Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent 
The Journal of Experimental Medicine  2005;202(11):1539-1547.
Deficient suppression of T cell responses to allergen by CD4+CD25+ regulatory T cells has been observed in patients with allergic disease. Our current experiments used a mouse model of airway inflammation to examine the suppressive activity of allergen-specific CD4+CD25+ T cells in vivo. Transfer of ovalbumin (OVA) peptide–specific CD4+CD25+ T cells to OVA-sensitized mice reduced airway hyperreactivity (AHR), recruitment of eosinophils, and T helper type 2 (Th2) cytokine expression in the lung after allergen challenge. This suppression was dependent on interleukin (IL) 10 because increased lung expression of IL-10 was detected after transfer of CD4+CD25+ T cells, and regulation was reversed by anti–IL-10R antibody. However, suppression of AHR, airway inflammation, and increased expression of IL-10 were still observed when CD4+CD25+ T cells from IL-10 gene–deficient mice were transferred. Intracellular cytokine staining confirmed that transfer of CD4+CD25+ T cells induced IL-10 expression in recipient CD4+ T cells, but no increase in IL-10 expression was detected in airway macrophages, dendritic cells, or B cells. These data suggest that CD4+CD25+ T cells can suppress the Th2 cell–driven response to allergen in vivo by an IL-10–dependent mechanism but that IL-10 production by the regulatory T cells themselves is not required for such suppression.
doi:10.1084/jem.20051166
PMCID: PMC1350743  PMID: 16314435
22.  Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent 
The Journal of experimental medicine  2005;202(11):1539-1547.
Deficient suppression of T cell responses to allergen by CD4+CD25+ regulatory T cells has been observed in patients with allergic disease. Our current experiments used a mouse model of airway inflammation to examine the suppressive activity of allergen-specific CD4+CD25+ T cells in vivo. Transfer of ovalbumin (OVA) peptide-specific CD4+CD25+ T cells to OVA-sensitized mice reduced airway hyperreactivity (AHR), recruitment of eosinophils, and T helper type 2 (Th2) cytokine expression in the lung after allergen challenge. This suppression was dependent on interleukin (IL) 10 because increased lung expression of IL-10 was detected after transfer of CD4+CD25+ T cells, and regulation was reversed by anti-IL-10R antibody. However, suppression of AHR, airway inflammation, and increased expression of IL-10 were still observed when CD4+CD25+ T cells from IL-10 gene-deficient mice were transferred. Intracellular cytokine staining confirmed that transfer of CD4+CD25+ T cells induced IL-10 expression in recipient CD4+ T cells, but no increase in IL-10 expression was detected in airway macrophages, dendritic cells, or B cells. These data suggest that CD4+CD25+ T cells can suppress the Th2 cell-driven response to allergen in vivo by an IL-10-dependent mechanism but that IL-10 production by the regulatory T cells themselves is not required for such suppression.
doi:10.1084/jem.20051166
PMCID: PMC1350743  PMID: 16314435
23.  The Absence of Interleukin 9 Does Not Affect the Development of Allergen-induced Pulmonary Inflammation nor Airway Hyperreactivity 
Interleukin (IL)-9 is a pleiotropic cytokine secreted by T helper (Th)2 cells and has been proposed as a candidate gene for asthma and allergy. We have used mice genetically deficient in IL-9 to determine the role of this cytokine in the pathophysiologic features of the allergic pulmonary response–airway hyperreactivity (AHR) and eosinophilia. We have demonstrated that IL-9 is not required for the development of a robust Th2 response to allergen in sensitized mice. IL-9 knockout mice developed a similar degree of eosinophilic inflammation and AHR to their wild-type littermates. Goblet cell hyperplasia and immunoglobulin (Ig) E production were also unaffected by the lack of IL-9. Moreover, levels of bronchoalveolar lavage (BAL) IL-4, IL-5, and IL-13 were comparable between wild-type and knockout mice. These findings indicate that IL-9 is not obligatory for the development of eosinophilia and AHR, and imply that other Th2 cytokines can act in a compensatory fashion.
doi:10.1084/jem.20011732
PMCID: PMC2196020  PMID: 11781365
Th2 cytokines; asthma; airway hyperreactivity; eosinophilia; mucus
24.  Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma 
Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRβ, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRβ inhibitor (CP-673451) to investigate the role of PDGFRβ signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRβ signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRβ signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma.
doi:10.1152/ajplung.00286.2014
PMCID: PMC4385988  PMID: 25637607
asthma; house dust mite; airway hyperresponsiveness; pericyte; remodeling
25.  Th17 Responses in Chronic Allergic Airway Inflammation Abrogate Regulatory T cell-mediated Tolerance and Contribute to Airway Remodeling 
Mucosal immunology  2012;6(2):335-346.
The role of Th17 responses in airway remodeling in asthma is currently unknown. We demonstrate that both parenteral and mucosal allergen sensitization followed by allergen inhalation leads to Th17-biased lung immune responses. Unlike Th17 cells generated in vitro, lung Th17 cells did not produce TNF-α or IL-22. Eosinophilia predominated in acute inflammation while neutrophilia and IL-17 increased in chronic disease. Allergen-induced tolerance involved Foxp3, Helios and GARP expressing regulatory T cells (Treg) and IL-10/IFN-γ priming. This Treg phenotype was altered in inflamed lungs and abrogated by inhalation of IL-17. Using Th17-deficient mice with genetic disruption of gp130 in T cells, we showed that Th17 cells induce airway remodeling independent of the Th2 response. All-trans retinoic acid administration ameliorated Th17-mediated disease and increased Treg activity, while dexamethasone inhibited eosinophilia but not neutrophilia and enhanced Th17 development in vitro. Targeting the Th17/Treg axis might therefore be therapeutic in neutrophilic and glucocorticoid-refractory asthma.
doi:10.1038/mi.2012.76
PMCID: PMC4233308  PMID: 22892938
Th17; asthma; regulatory T cell; airway remodeling; neutrophilia

Results 1-25 (51)