Non-eosinophilic Airway Hyper-reactivity in Mice, Induced by IFN-γProducing CD4+and CD8+Lung T cells, is Responsive to Steroid Treatment

Non-eosinophilic asthma is characterized by infiltration of neutrophils into the lung and variable responsiveness to glucocorticoids. The pathophysiological mechanisms have not been characterized in detail. Here, we present an experimental asthma model in mice associated with non-eosinophilic airway inflammation and airway hyper-responsiveness (AHR). For this, BALB/c mice were sensitized by biolistic DNA immunization with a plasmid encoding the model antigen β-galactosidase (pFascin-βGal mice). For comparison, eosinophilic airway inflammation was induced by subcutaneous injection of βGal protein (βGal mice). Intranasal challenge of mice in both groups induced AHR to a comparable extent as w…

Free Serum IgE In Patients With Severe Allergic Asthma Treated With Omalizumab

Viral Components Enhance Antigen Presentation And Induce Sensitization Towards Harmless Inhaled Antigens

THE INHIBITORY EFFECT OF THE PLANT KALANCHOE PINNATA AND ITS FLAVONOID QUERCETIN ON AIRWAY HYPERRESPOSIVENESS

Monitoring free serum IgE in severe asthma patients treated with omalizumab

SummaryBackgroundBenefit of treatment with the monoclonal anti-IgE-antibody omalizumab in severe IgE-dependent asthma requires a significant reduction of serum free IgE concentrations. It is unclear if monitoring free serum IgE is clinically meaningful once omalizumab treatment is initiated.MethodsFree IgE and omalizumab serum concentrations were quantified in 22 patients with severe asthma (68% female, 47 ± 11 yrs, mean (±SD) pre-bronchodilator FEV1 62 ± 13%, baseline mean (±SEM) free serum IgE 652 ± 136 ng/ml) treated with omalizumab for 4 months using a Recovery-ELISA.ResultsOmalizumab treatment reduced free serum IgE prior to the second omalizumab injection by 73%, after 16 weeks by 81%…

Lithium Chloride Affects The Development Of Allergic Airway Disease

Disease-Modifikation und Dauer einer Omalizumab-Therapie bei Patienten mit schwerem allergischen Asthma

Hintergrund und Methodik: Omalizumab ist ein monoklonaler Anti-IgE-Antikorper zur Behandlung des schweren allergischen Asthma bronchiale. Ziel dieser Arbeit war die Bewertung der vorhandenen Evidenz durch ein Expertengremium und die Formulierung daraus resultierender Empfehlungen zu moglichen krankheitsmodifizierenden Effekten und der Dauer der Behandlung mit Omalizumab. Ergebnisse: Eine direkte oder indirekte Interaktion zwischen Omalizumab und der IgE-Produktion ist wahrscheinlich. Die aufgrund eines pharmakokinetisch-pharmakodynamischen Modells erwarteten IgE-modulierenden Eigenschaften von Omalizumab werden derzeit in der klinischen Anwendung uberpruft. Therapieentscheidungen auf Grundl…

Cytokine Production Profile Of T-lymphocytes In Patients With Allergic Asthma Receiving Anti-IgE Therapy

Prospective evaluation of current asthma control using ACQ and ACT compared with GINA criteria

Background The goal of asthma treatment is to achieve and maintain current best control and reduce future risk of exacerbations and long-term morbidity. Objective To prospectively compare current asthma control as defined by ACQ (asthma control questionnaire) and ACT (asthma control test) criteria with the GINA (Global Initiative for Asthma) classification in treated patients in a real-life setting. Methods In 150 adult patients (48% male, age 46.3 ± 14.4 years., forced expiratory volume in 1 second [FEV 1 ], 2.3 ± 0.9 L or 78.5 ± 21.8% pred.), asthma control was evaluated using the GINA classification as the "true" and ACQ-7, ACQ-5, and ACT as "predictor" criteria. The relationship between…

Th1-induced Allergic Airway Disease Is More Susceptible To NTreg-mediated Suppression In Contrast ToTh2 Responses

TH17 cells mediate pulmonary collateral priming

Background Our laboratory has shown that inhalational sensitization to new antigens is facilitated through an ongoing T H 2-polarized inflammation of the lung, a phenomenon we call "collateral priming." Objective We were interested to analyze whether a T H 1-polarized pulmonary inflammation also facilitates priming toward new antigens and which cytokine or cytokines are involved. Methods T H 1-polarized T cells were generated in vitro and transferred into congenic mice. Mice were challenged initially with cognate antigen and an unrelated antigen; consecutively, they received cognate antigen or the secondary antigen. Airway inflammation, antigen-specific IgG2a levels, and airway hyperrespons…

Regulatory T Cells More Effectively Suppress Th1-Induced Airway Inflammation Compared with Th2

Abstract Asthma is a syndrome with different inflammatory phenotypes. Animal models have shown that, after sensitization and allergen challenge, Th2 and Th1 cells contribute to the development of allergic airway disease. We have previously demonstrated that naturally occurring regulatory T cells (nTregs) can only marginally suppress Th2-induced airway inflammation and airway hyperresponsiveness. In this study, we investigated nTreg-mediated suppression of Th2-induced and Th1-induced acute allergic airway disease. We demonstrate in vivo that nTregs exert their suppressive potency via cAMP transfer on Th2- and Th1-induced airway disease. A comparison of both phenotypes revealed that, despite …

Enhanced production of CCL18 by tolerogenic dendritic cells is associated with inhibition of allergic airway reactivity

Background IL-10–treated dendritic cells (DCs) have been shown to inhibit T-cell responses through induction of anergy and regulatory T cells in various model systems, including allergic inflammation, but the factors being involved in this inhibition are still unclear. Objective This study set out to analyze such factors produced or induced by IL-10–treated DCs by using gene expression profiling and to explore their function. Methods CD4 + T cells from allergic donors were stimulated with autologous monocyte-derived allergen-pulsed mature DCs or IL-10–treated DCs. After 24 hours, the transcriptional profile was analyzed by using Affymetrix technology. Results were validated by using quantit…

GARP inhibits allergic airway inflammation in a humanized mouse model

Background Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model. Methods To analyze the therapeutic effects of sGARP, adult NOD/Scidγc−/− (NSG) mice received peripheral blood mononuclear cells (PBMC) …

PAR-2 depletion protects against the development of pulmonary hypertension

Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells.

AbstractNaturally occurring CD4+CD25+ regulatory T cells (Tregs) represent a unique T-cell lineage that is endowed with the ability to actively suppress immune responses. Therefore, approaches to modulate Treg function in vivo could provide ways to enhance or reduce immune responses and lead to novel therapies. Here we show that the CD4 binding human immunodeficiency virus-1 envelope glycoprotein gp120 is a useful and potent tool for functional activation of human Tregs in vitro and in vivo. Gp120 activates human Tregs by binding and signaling through CD4. Upon stimulation with gp120, human Tregs accumulate cyclic adenosine monophosphate (cAMP) in their cytosol. Inhibition of endogeneous cA…

Effectiveness of omalizumab in patients 50 years and older with severe persistent allergic asthma.

Omalizumab is approved for the treatment of severe allergic asthma.To compare the efficacy of omalizumab therapy in patients 50 years or older with patients younger than 50 years.Between November 2005 and November 2007 a total of 174 asthma patients 50 years or older (40.7% male, 51.1% taking oral corticosteroids, and mean [SD] serum IgE level of 315 [353] U/L) and 297 asthma patients younger than 50 years (40.0% male, 50.5% taking oral corticosteroids, and mean [SD] serum IgE level of 363 [431] U/L) who met the European Union criteria for add-on therapy with anti-IgE were treated prospectively with omalizumab for 4 months as part of 2 postmarketing surveillance trials.Compared with the pre…

Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells

Despite a broad cell-type tropism, cytomegalovirus (CMV) is an evidentially pulmonary pathogen. Predilection for the lungs is of medical relevance in immunocompromised recipients of hematopoietic cell transplantation, in whom interstitial CMV pneumonia is a frequent and, if left untreated, fatal clinical manifestation of human CMV infection. A conceivable contribution of CMV to airway diseases of other etiology is an issue that so far attracted little medical attention. As the route of primary CMV infection upon host-to-host transmission in early childhood involves airway mucosa, coincidence of CMV airway infection and exposure to airborne environmental antigens is almost unavoidable. For i…

Reduction Of Pulmonary Inflammation Through HIV-1 Envelope Protein GP120 In A Humanized Mouse Model Of Allergic Asthma Depends On Regulatory T Cells

Mast Cells Induce Migration of Dendritic Cells in a Murine Model of Acute Allergic Airway Disease

<i>Background: </i>The migration of dendritic cells (DCs) from the lungs to the regional lymph nodes is necessary for the development of allergic airway disease. Following activation, mast cells release a variety of stored or de novo-produced inflammatory mediators, several of them being capable of activating DCs. In this study, the role of mast cells on DC migration from the lungs to the thoracic lymph nodes was investigated in sensitized mice. <i>Methods:</i> Mast cell-deficient mice (Kit<sup>W-sh/W-sh</sup>) and their wild-type counterparts were sensitized intraperitoneally with ovalbumine (OVA) in saline and challenged by a single intranasal administr…

Cylindromatosis (Cyld) gene mutation in T cells promotes the development of an IL-9-dependent allergic phenotype in experimental asthma

Cylindromatosis (CYLD) is a ubiquitously expressed deubiquitinating enzyme which removes activating ubiquitin residues from important signaling molecules of the NF-κB pathway. In CYLDex7/8 transgenic mice, a naturally occurring short isoform (sCYLD) is overexpressed in the absence of full length CYLD, leading to excessive NF-κB activity. Herein, we investigated the impact of the CYLDex7/8 mutation selectively in T cells on the development of experimental allergic airway disease induced by sensitization and challenge with ovalbumin. Compared with their wildtype littermates, mice bearing the T cell-specific mutation (CD4+CYLDex7/8) display stronger eosinophilia and mucus production in the lun…

Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance

Infection with the gastric bacterial pathogen Helicobacter pylori is typically contracted in early childhood and often persists for decades. The immunomodulatory properties of H. pylori that allow it to colonize humans persistently are believed to also account for H. pylori ’s protective effects against allergic and chronic inflammatory diseases. H. pylori infection efficiently reprograms dendritic cells (DCs) toward a tolerogenic phenotype and induces regulatory T cells (Tregs) with highly suppressive activity in models of allergen-induced asthma. We show here that two H. pylori virulence determinants, the γ-glutamyl transpeptidase GGT and the vacuolating cytotoxin VacA, contribute critic…

The Tick Salivary Protein Sialostatin L Inhibits the Th9-Derived Production of the Asthma-Promoting Cytokine IL-9 and Is Effective in the Prevention of Experimental Asthma

Abstract Ticks developed a multitude of different immune evasion strategies to obtain a blood meal. Sialostatin L is an immunosuppressive cysteine protease inhibitor present in the saliva of the hard tick Ixodes scapularis. In this study, we demonstrate that sialostatin L strongly inhibits the production of IL-9 by Th9 cells. Because we could show recently that Th9-derived IL-9 is essentially involved in the induction of asthma symptoms, sialostatin L was used for the treatment of experimental asthma. Application of sialostatin L in a model of experimental asthma almost completely abrogated airway hyperresponsiveness and eosinophilia. Our data suggest that sialostatin L can prevent experime…

The prognostic impact of blood group-related antigen Lewis Y and the ABH blood groups in resected non-small cell lung cancer.

The blood group antigen Lewis Y is expressed on epithelial tumors of the respiratory, digestive and reproductive system. Despite being regarded as an attractive target for immunotherapy, its function is still not well defined and its prognostic value remains a subject of discussion. Eighty-three paraffin-embedded tissue sections of non-small cell lung cancer (NSCLC) patients in stage I-IIIa, who underwent surgical resection of the primary tumor (73% male; 43% adenocarcinoma), were stained with a new, highly specific monoclonal antibody against Lewis Y (clone A70-C/C8). A positive Lewis Y expression was observed in 51% of patients; adenocarcinomas were favorably stained (67%). Multivariate a…

Die Th2 Zytokine IL5 und IL13 wirken synergistisch auf die Aktivierung und Transmigration von Eosinophilen

Bcl-2, Bcl-xl, and pp32/PHAPI in resected non-small-cell lung cancer patients

Einleitung: Fur viele Tumorarten ist der Einfluss des Apoptosesignalweges auf die Prognose der Tumorerkrankung beschrieben worden. So konnte fur die antiapoptotischen Proteine wie Bcl-2 und Bcl-xL gezeigt werden, dass sie den mitochondrialen Selbstzerstorungsmechanismus der Zellen herunterregulieren konnen. Fur nicht-kleinzellige Lungenkarzinomen (NSCLC) hingegen existieren widerspruchliche Angaben in der wissenschaftlichen Literatur in Bezug auf die prognostische Wertigkeit apoptotischer und insbesondere antiapoptotischer Faktoren. Ein weiterer wichtiger Faktor im genannten Mechanismus, welches NSCLC fur apoptotische Stimuli sensibilisieren soll, ist das Protein pp32/PHAPI. Fur bereits che…

S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma

ZusammenfassungDie vorliegende Leitlinie ist eine Neufassung und Aktualisierung der Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma, welche die bisher für den deutschen Sprachraum gültige Version aus dem Jahr 2006 ablöst. Die Fülle an neuen Erkenntnissen zur Pathophysiologie und zu den Phänotypen von Asthma und das erweiterte Spektrum an diagnostischen und therapeutischen Möglichkeiten bei dieser Erkrankung machte eine Neufassung und Aktualisierung notwendig. Es werden sowohl für Kinder und Jugendliche als auch für Erwachsene mit Asthma die aktuellen, Evidenz-basierten diagnostischen und therapeutischen Empfehlungen dargelegt.

Dual role of interleukin-1alpha in delayed-type hypersensitivity and airway hyperresponsiveness.

<i>Background:</i> Using a T helper (Th)1/Th2 disease model, we previously showed that genetically determined Th development depends on dendritic cell-derived interleukin (IL)-1α. In <i>Leishmania major</i> infections, Th1 immunity develops if IL-1α is present during T cell priming, whereas at later time points, IL-1α worsens disease outcome. In the present study, we determined the role of IL-1α in other Th2-mediated diseases. <i>Methods:</i> BALB/c mice were subjected to delayed-type hypersensitivity (DTH) or ovalbumin (OVA)/alum-induced allergic asthma in the presence or absence of IL-1α. <i>Results:</i> In DTH, mice treated with IL-1α durin…

Mast cells are crucial for early inflammation, migration of Langerhans cells, and CTL responses following topical application of TLR7 ligand in mice.

Abstract Until recently, IgE-activated mast cells have been regarded merely as effector cells of adaptive immune responses, involved in allergic reactions and mucosal immunity to parasites. Herein, we report that murine dermal mast cells, activated by local administration of a cream containing the synthetic TLR7 ligand imiquimod, are essential to initiate an early inflammatory reaction. The mast-cell–derived cytokines TNF-α and IL-1β play an important role in this process. Furthermore, TLR7-activated mast cells are also able to promote the emigration of Langerhans cells, which partly depends on the expression of mast-cell–derived IL-1β. We have previously shown that TLR7 ligation enhances t…

Allergen-Immuntherapie in der aktuellen COVID-19-Pandemie – ein Positionspapier von ARIA, EAACI, AeDA, GPA und DGAKI (Kurzversion) – Positionspapier der deutschen ARIA-GruppeA in Kooperation mit der österreichischen ARIA-GruppeB, der schweizerischen ARIA-GruppeC, dem Ärzteverband Deutscher Allergologen (AeDA)D, der Deutschen Gesellschaft für Allergologie und Klinische Immunologie (DGAKI)E und der Gesellschaft für Pädiatrische Allergologie (GPA)F in Kooperation mit der AG Klinische Immunologie, Allergologie und Umweltmedizin der DGHNO-KHCG und der Europäischen Akademie für Allergologie und Klinische Immunologie (EAACI)H

Impaired Mast Cell-Driven Immune Responses in Mice Lacking the Transcription Factor NFATc2

Abstract The three calcium-dependent factors NFATc1, c2, and c3 are expressed in cells of the immune system and play pivotal roles in modulating cellular activation. With regard to NFATc2, it was reported that NFATc2-deficient mice display increased immune responses in several models for infection and allergy in vivo. This led to the assumption that NFATc2 is involved in the maintenance of immune homeostasis. Using the synthetic TLR7 agonist imiquimod as an adjuvant in epicutaneous peptide immunization, we observed that both the inflammatory reaction and the peptide-specific CTL response are severely impaired in NFATc2-deficient mice. Detailed analyses revealed that early production of proi…

The canonical but not the noncanonical wnt pathway inhibits the development of allergic airway disease

Abstract Asthma is a syndrome with multifactorial causes, resulting in a variety of different phenotypes. Current treatment options are not curative and are sometimes ineffective in certain disease phenotypes. Therefore, novel therapeutic approaches are required. Recent findings have shown that activation of the canonical Wnt signaling pathway suppresses the development of allergic airway disease. In contrast, the effect of the noncanonical Wnt signaling pathway activation on allergic airway disease is not well described. The aim of this study was to validate the therapeutic effectiveness of Wnt-1–driven canonical Wnt signaling compared with Wnt-5a–driven noncanonical signaling in murine mo…

Mast cell-derived tumour necrosis factor is essential for allergic airway disease

Mast cells are thought to contribute to allergic airway disease. However, the role of mast cell-produced mediators, such as tumour necrosis factor (TNF), for the development of allergic airway disease is unclear. In order to define the role of mast cells in acute allergic airway disease two strains of mast cell-deficient mice (Kit W/Wv and Kit W-sh/W-sh ) were studied. Compared with their wild-type littermates, Kit W/Wv and Kit W-sh/W-sh mice developed significantly lower airway responsiveness to methacholine and less airway inflammation and goblet cell metaplasia, following sensitisation in the absence of adjuvant and airway challenge. Transfer of bone marrow-derived mast cells (BMMCs) fro…

A Non-Interventional Study of Tiotropium/Olodaterol versus Any Triple Combination Therapy for Chronic Obstructive Pulmonary Disease: The EVELUT® Study Protocol

Roland Buhl,1 Michael Dreher,2 Stephanie Korn,1 Christian Taube,3 Christian Stock,4 Christoph M Zehendner,5 Anke Kondla,5 Claus F Vogelmeier6 1Pulmonary Department, Johannes Gutenberg University Mainz, Mainz, Germany; 2Clinic of Cardiology, Pneumology, Angiology and Internal Medicine Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; 3Clinic for Pneumonology, University Medicine Essen – Ruhrlandklinik, Essen, Germany; 4Biostatistics + Data Sciences Corp, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 5HP Country Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 6Department of Pneumology,…

Use of a portable device to record maximum inspiratory flow in relation to dyspnoea in patients with COPD

SummaryForced inspiratory measures have been described to reflect the reduction in dyspnoea upon bronchodilation in severe COPD. Based on this we evaluated the applicability and usefulness of a portable device for the assessment of forced inspiration. In 37 patients with COPD (GOLD II/II/IV n = 16/15/6, mean ± SD FEV1 46.2 ± 15.4%pred) lung function was recorded prior to inhalation of 24 μg formoterol and 30 min later. Assessments comprised spirometry including forced inspiration, body plethysmography, maximum inspiratory flow (InCheck, Clement Clarke), and changes in dyspnoea via visual analogue scale (VAS). The sequence was repeated on a second day to assess reproducibility. Bronchodilati…

Effects of inhaled corticosteroids in stable chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) has been described as a heterogeneous multifactorial disorder associated with an abnormal inflammatory response of the peripheral airways and with variable morphologic, physiologic and clinical phenotypes. This notion of the disease is actually poorly supported by data, and there are substantial discrepancies and a weak correlation between inflammation, structural damage, functional impairment and degree of clinical symptoms. This problem is compounded by a poor understanding of the complexity and intricacies on the inflammatory pathways in COPD. Despite the evidence for efficacy of inhaled corticosteroids (ICS) on selected clinical endpoints in …

Quantification Of Total Serum IgE In Patients With Asthma Using 3 Different Methods

Similar Camp Transfer Of Naturally Occurring Regulatory T Cells More Effectively Suppresses Effector Functions Of Th1 Compared To Th2 Cells

S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma – Addendum 2020

ZusammenfassungDas vorliegende Addendum zur Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma (2017) ergänzt wichtige neue Erkenntnisse zur Diagnostik und Therapie von Asthma sowie zu neu für die Therapie des Asthmas zugelassenen Medikamenten. Es werden sowohl für Kinder und Jugendliche als auch für Erwachsene mit Asthma die aktuellen, Evidenz-basierten diagnostischen und therapeutischen Empfehlungen dargelegt.

TA-MUC1 epitope in non-small cell lung cancer

MUC1 (CD227), an established tumor marker, is expressed on glandular epithelia and on epithelial tumors. Tumor MUC1 differs from normal MUC1 by modified glycan side chains. Recently, a novel carbohydrate-induced conformational tumor-associated MUC1 epitope (TA-MUC1) was described, whose clinical relevance in lung cancer is not known. Eighty-five paraffin embedded tissue sections of non-small cell lung cancer (NSCLC) patients (73% male; mean age 64+/-9 years) were stained with the monoclonal antibody PankoMab (against TA-MUC1) and compared with the established antibodies E29 and 214D4 regarding prognostic relevance. TA-MUC1 is virtually absent in bronchial epithelium. As shown by multivariat…

Specific and Redundant Roles for NFAT Transcription Factors in the Expression of Mast Cell-Derived Cytokines

Abstract By virtue of their ability to express a plethora of biologically highly active mediators, mast cells (MC) are involved in both adaptive and innate immune responses. MC-derived Th2-type cytokines are thought to act as local amplifiers of Th2 reactions, including chronic inflammatory disorders such as allergic asthma, whereas MC-derived TNF-α is a critical initiator of antimicrobial defense. In this study, we demonstrate that the transcription factors NFATc1 and NFATc2 are part of a MC-specific signaling network that regulates the expression of TNF-α and IL-13, whereas NFATc3 is dispensable. Primary murine bone marrow-derived MC from NFATc2−/− mice, activated by either ionomycin or I…

Mast cell-derived mediators promote murine neutrophil effector functions

Mast cells are able to trigger life-saving immune responses in murine models for acute inflammation. In such settings, several lines of evidence indicate that the rapid and protective recruitment of neutrophils initiated by the release of mast cell-derived pro-inflammatory mediators is a key element of innate immunity. Herein, we investigate the impact of mast cells on critical parameters of neutrophil effector function. In the presence of activated murine bone marrow-derived mast cells, neutrophils freshly isolated from bone marrow rapidly lose expression of CD62L and up-regulate CD11b, the latter being partly driven by mast cell-derived TNF and GM-CSF. Mast cells also strongly enhance neu…

IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease

Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22-deficiency led to increased eosinophil infiltration lymphocyte invasion and production…

The Wnt/beta-Catenin Pathway Attenuates Experimental Allergic Airway Disease

Abstract Signaling via the Wnt/β-catenin pathway plays crucial roles in embryogenesis and homeostasis of adult tissues. In the lung, the canonical Wnt/β-catenin pathway has been implicated in remodeling processes, development of emphysema, and fibrosis. However, its relevance for the modulation of allergic responses in the lung remains unclear. Using genetically modified mice with lung-specific inducible (doxycycline) Wnt-1 expression (CCSP-rtTA × tetO-Wnt1), the impact of Wnt on the development of allergic airway disease was analyzed. Overexpression of Wnt during the allergen challenge phase attenuated the development of airway inflammation in an acute model, as well as in a more therapeut…

The Immunomodulatory Capacity of Wnt on Human Dendritic Cells – Wnt/β-Catenin Signalling as a Potential Target for Bronchial Asthma

Regulation of IgE production and airway reactivity by CD4(-)CD8(-) regulatory T cells

The mechanisms of tolerance induction occurring in the course of allergen-specific immunotherapy have not been elucidated in full detail. Our study aimed to characterize high zone tolerance in mouse models of type I allergy and of allergic airway inflammation induced by subcutaneous sensitization of mice with high doses of the model allergen ovalbumin (OVA) without the use of adjuvant. Mice were immunized by subcutaneous injection of high doses (HD) of OVA or, for comparison, low doses (LD) of OVA in saline. HD-mice showed lower specific IgE, but augmented IgG in sera than LD-mice. Pre-treatment of mice with HD-OVA antigen-specifically inhibited IgE production subsequently induced by LD-OVA…

Asthma bronchiale: neue Erkenntnisse und Entwicklungen

In mild asthma low-dose steroid inhalation treatment reduces severe exacerbations and exacerbation associated loss of lung function. In patients with mild asthma, symptom-driven use of a combination of inhaled steroid and short-acting beta-2-sympathomimetics in a single inhaler is feasible. In moderate and severe asthma the fixed combination of formoterol and budesonide can be used a maintenance therapy but also as treatment of acute symptoms. Monotherapy with long-acting beta 2-sympathomimetics should be completely avoided. Long-acting anticholinergic drugs are equally efficacious as long-acting beta-2-sympathomimetics, but have not yet been approved for use in patients with asthma. The co…

Eosinophilic and Noneosinophilic Asthma

Background Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. Research Question What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? Study Design and Methods This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a pre…

Rolle der Mastzelle bei allergischem Asthma bronchiale

Mastzellen sind seit Jahrzehnten als „Allergieeffektorzellen“ im Rahmen akuter allergischer Reaktionen beschrieben. Neuere Daten belegen nun, dass Mastzellen nicht nur an der Auslosung anaphylaktischer Reaktionen beteiligt sind, sondern auch masgeblich fur die Entstehung und Unterhaltung allergischer Entzundungsreaktionen sind. Insbesondere Untersuchungen an Modellen des allergischen Asthmas belegen eine zentrale Rolle von Mastzellen bei der initialen Entwicklung einer Atemwegsentzundung und bronchialen Uberempfindlichkeit. Dies scheint durch Mastzellmediatoren, wie Histamin und Tumor-Nekrose-Faktor, vermittelt zu werden.

Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial

Background: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (…

Inhibition of cAMP Degradation Improves Regulatory T Cell-Mediated Suppression

Abstract Naturally occurring regulatory T cells (nTreg cells) are crucial for the maintenance of peripheral tolerance. We have previously shown that a key mechanism of their suppressive action is based on a contact-dependent transfer of cAMP from nTreg cells to responder T cells. Herein, we further elucidate the important role of cAMP for the suppressive properties of nTreg cells. Prevention of cAMP degradation by application of the phosphodiesterase 4 inhibitor rolipram led to strongly increased suppressive potency of nTreg cells for Th2 cells in vitro and in vivo. Detailed analyses revealed that rolipram caused, in the presence of nTreg cells, a synergistic increase of cAMP in responder T…

Mast cells in allergic asthma and beyond.

Mast cells have been regarded for a long time as effector cells in IgE mediated type I reactions and in host defence against parasites. However, they are resident in all environmental exposed tissues and express a wide variety of receptors, suggesting that these cells can also function as sentinels in innate immune responses. Indeed, studies have demonstrated an important role of mast cells during the induction of life-saving antibacterial responses. Furthermore, recent findings have shown that mast cells promote and modulate the development of adaptive immune responses, making them an important hinge of innate and acquired immunity. In addition, mast cells and several mast cell-produced me…

Short-Term Reproducibility Of Non-Invasive Clinical And Inflammatory Parameters In Asthma

Genetic Variation Determines Mast Cell Functions in Experimental Asthma

Abstract Mast cell-deficient mice are a key for investigating the function of mast cells in health and disease. Allergic airway disease induced as a Th2-type immune response in mice is employed as a model to unravel the mechanisms underlying inception and progression of human allergic asthma. Previous work done in mast cell-deficient mouse strains that otherwise typically mount Th1-dominated immune responses revealed contradictory results as to whether mast cells contribute to the development of airway hyperresponsiveness and airway inflammation. However, a major contribution of mast cells was shown using adjuvant-free protocols to achieve sensitization. The identification of a traceable ge…

Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10

The prevalence of allergic asthma and other atopic diseases has reached epidemic proportions in large parts of the developed world. The gradual loss of the human indigenous microbiota has been held responsible for this trend. The bacterial pathogen Helicobacter pylori is a constituent of the normal gastric microbiota whose presence has been inversely linked to allergy and asthma in humans and experimental models. Here we show that oral or i.p. tolerization with H. pylori extract prevents the airway hyperresponsiveness, bronchoalveolar eosinophilia, pulmonary inflammation, and Th2 cytokine production that are hallmarks of allergen-induced asthma in mice. Asthma protection is not conferred by…

Experimentelle Allergologie/Immunologie

CD4-mediated regulatory T-cell activation inhibits the development of disease in a humanized mouse model of allergic airway disease

Background Based on their potency to control allergic diseases, regulatory T (Treg) cells represent a promising target for novel strategies to interfere with allergic airway inflammation. We have previously demonstrated that stimulation of the CD4 molecule on human Treg cells activates their suppressive activity in vitro and in vivo . Objective We sought to determine the effect of CD4-mediated Treg-cell activation on pulmonary inflammation in a humanized mouse model of allergic airway inflammation. Methods PBMCs obtained from donors allergic to birch pollen or from healthy donors were injected into NOD-severe combined immunodeficiency γc −/− mice, followed by allergen airway challenges and …

Single and Synergistic Effects of Type 2 Cytokines on Eosinophils and Asthma Hallmarks

Abstract The type 2 cytokines IL-5, IL-13, and IL-4 play an important role in the induction and progression of asthma. According to the Global Initiative for Asthma guidelines, blood eosinophil numbers are one marker that helps to guide treatment decisions in patients suffering from severe forms of asthma. Effects of type 2 cytokines were analyzed, alone or in combination, on eosinophils in blood and other compartments and on the development of asthma symptoms. C57BL/6 mice received a single intranasal application of equimolar amounts of IL-5, IL-13, and IL-4, alone or in combination. Numbers, activation state, and migratory behavior of eosinophils in bone marrow (BM), blood, lung, and bron…

Interruption of CD28-mediated costimulation during allergen challenge protects mice from allergic airway disease

Background Allergic asthma is a T H 2-promoted hyperreactivity with an immediate, IgE, and mast cell–dependent response followed by eosinophil-dominated inflammation and airway obstruction. Objective Because costimulation by CD28 is essential for T H 2 but not T H 1 responses, we investigated the effect of selective interference with this pathway in mice using the models of ovalbumin and house dust mite–induced airway inflammation. Methods To study the role of CD28 in the effector phase of allergic airway inflammation, we developed an inducibly CD28-deleting mouse strain or alternatively used a CD28 ligand-binding site–specific mouse anti-mouse mAb blocking CD28 engagement. Results We show …

Advances in the understanding of mast cell function

Mast cells were formerly thought to contribute mainly to, sometimes even, fatal allergic reactions through the release of biologically highly active cytokines, chemokines, lipid mediators, proteases and biogenic amines. This potential harmful response is triggered by crosslinking of cell-bound IgE by the respective allergen. This review updates our current understanding of the emerging roles of mast cells with an emphasis on their relevance in protective host immunity. The activation of mast cells independently of Immunoglobulin E can lead to the initiation of fast inflammatory reactions, which were shown to be life-saving in murine models of bacterial infections. Besides their critical fun…

Murine genetic deficiency of neuronal nitric oxide synthase (nNOS-/-) and interstitial cells of Cajal (W/Wv): Implications for achalasia?

Background and aim Nitric oxide (NO) is an important inhibitory mediator of esophageal function, and its lack leads to typical features of achalasia. In contrast, the role of intramuscular interstitial cells of Cajal (ICC-IM) and vasoactive intestinal peptide (VIP) in lower esophageal sphincter (LES) function is still controversial. Therefore, we examined the function and morphology of the LES in vivo in NO-deficient (nNOS(-/-) ), ICC-IM-deficient (W/W(v) )-, and wild-type (WT) mice. Methods Esophageal manometry was performed with a micro-sized transducer catheter to quantify LES pressure, swallow evoked LES relaxation, and esophageal body motility. The LES morphology was examined by semiqu…

Exposure to Toll like Receptor 7 (TLR7)-Ligand Supports Sensitization to an Inhaled Allergen.

Kalanchoe pinnata inhibits mast cell activation and prevents allergic airway disease

Aqueous extract of Kalanchoe pinnata (Kp) have been found effective in models to reduce acute anaphylactic reactions. In the present study, we investigate the effect of Kp and the flavonoid quercetin (QE) and quercitrin (QI) on mast cell activation in vitro and in a model of allergic airway disease in vivo. Treatment with Kp and QE in vitro inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/FcɛRI crosslinking, whereas treatment with QI had no effect. Similarly, in vivo treatment with Kp and QE decreased development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and production of IL-5, IL-13 and TNF. In contrast, treatm…

Analysis Of Pulmonary Inflammation Using Humanized Mouse Models

Comparison of Exhaled Nitric Oxide (eNO) Measurements with 5 Different Analyzers.

Mast cells and the development of allergic airway disease

Murine models have highlighted the importance of T-cells and TH2 cytokines in development of allergen-induced airway disease. In contrast, the role of mast cells for the development of allergic airway disease has been controversial. Recent studies in murine models demonstrate a significant contribution of mast cells during the development of airway hyperresponsiveness and airway inflammation. Furthermore these models have allowed identifying certain mast cell-produced mediators (e.g. histamine and leukotriene B4) to be involved in the recruitment of effector T-cells into the lung. Additionally, mast cell-produced TNF can directly activate TH2 cells and contribute to the development of aller…

Inhibition of cAMP Degradation Improves Regulatory T Cell-Mediated Suppression of Allergic Airway Disease.

Omalizumab in patients with severe persistent allergic asthma in a real-life setting in Germany

Omalizumab is a humanized monoclonal anti-immunoglobulin E (IgE) antibody indicated in Europe for the treatment of uncontrolled severe persistent allergic (IgE-mediated) asthma despite optimal therapy with inhaled corticosteroids and long-acting beta(2) agonists. Between 2005 and 2007 280 patients (58% female, mean age 44+/-16 yrs., 46% on oral corticosteroids, median serum IgE level 235IU/ml) who met the EU criteria for add-on therapy with anti-IgE were treated prospectively with omalizumab by 134 physicians as part of a post-marketing surveillance trial and were followed-up for 6 months. The median follow-up time was 195 days, the patients were treated with a median dose of 450mg omalizum…

Divergent effects of biolistic gene transfer in a mouse model of allergic airway inflammation.

Particle-mediated epidermal delivery (PMED) of allergen genes efficiently prevents systemic sensitization and suppresses specific immunoglobulin E synthesis. We investigated in a mouse model of allergic airway disease the effect of PMED on the elicitation of local inflammatory reactions in the lung. BALB/c mice were biolistically transfected with plasmids encoding beta-galactosidase (betaGal) as model allergen under control of the DC-targeting fascin promoter and the ubiquitously active cytomegalovirus promoter, respectively. Mice were challenged intranasally with betaGal-protein with or without intermediate sensitization with betaGal adsorbed to aluminiumhydroxide. Subsequently, local cyto…

EXPRESSION OF T-CELL TRANSCRIPTION FACTOR T-BET IS INCREASED IN COPD

Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma.

The role of IgE in patients with severe asthma is not fully understood.We sought to investigate whether IgE to Staphylococcus aureus enterotoxins might be relevant to disease severity in adult asthmatic patients.Specific IgE antibody concentrations in serum against enterotoxins, grass pollen (GP), and house dust mite allergens and total IgE levels were measured in adult cohorts of 69 control subjects, 152 patients with nonsevere asthma, and 166 patients with severe asthma. Severe asthma was defined as inadequately controlled disease despite high-dose inhaled corticosteroids plus at least 2 other controller therapies, including oral steroids.Enterotoxin IgE positivity was significantly great…

Tc9 cells, a new subset of CD8+T cells, support Th2-mediated airway inflammation

Similar to T-helper (Th) cells, CD8(+) T cells also differentiate into distinct subpopulations. However, the existence of IL-9-producing CD8(+) T (Tc9) cells has not been elucidated so far. We show that murine CD8(+) T cells activated in the presence of IL-4 plus TGF-β develop into transient IL-9 producers characterized by specific IFN-γ and IL-10 expression patterns as well as by low cytotoxic function along with diminished expression of the CTL-associated transcription factors T-bet and Eomesodermin. Similarly to the CD4(+) counterpart, Tc9 cells required for their differentiation STAT6 and IRF4. Tc9 cells deficient for these master regulators displayed increased levels of Foxp3 that in t…

<p>Switch from IL-5 to IL-5-Receptor α Antibody Treatment in Severe Eosinophilic Asthma</p>

Background Anti-IL-5 antibodies represent an established therapy for severe eosinophilic asthma (SEA), but some patients show inadequate response. The objective of this study was to assess the effects of a switch to anti-IL-5Rα therapy in patients with inadequate response to anti-IL-5 therapy. Methods In this retrospective multi-centre, real-life study, we analysed all SEA patients switched from anti-IL-5 to anti-IL-5Rα therapy due to inadequate response or intolerability. Pulmonary function tests, blood gas analyses, asthma control tests (ACT) and oral corticosteroid (OCS) usage were analysed and compared at three timepoints: baseline (BL, before anti-IL-5 therapy), timepoint 1 (T1, under …

Tick Salivary Sialostatin L Represses the Initiation of Immune Responses by Targeting IRF4-Dependent Transcription in Murine Mast Cells

Abstract Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R–deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cel…

Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells.

Summary Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4 + T cell subset designated Th9. IRF4-deficient CD4 + T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4 + T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the ind…