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Anti IL5 treatment

Lara Ravanetti, Annemiek Dijkhuis, Yanaika S Sabogal Pineros, Suzanne M Bal, Barbara S Dierdorp, Tamara Dekker, Adrian Logiantara, Ian M Adcock, Navin L Rao, Louis Boon, Gino Villetti, Peter J Sterk, Fabrizio Facchinetti, René Lutter
BACKGROUND: Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics. AIM: We developed and characterized a robust, consistent and reproducible mouse model of severe exacerbation of chronic allergic asthma. METHODS: Chronic allergic airway inflammation was induced following a house dust mite (HDM)-sensitization protocol...
October 3, 2016: Allergy
Vanessa Popp, Katharina Gerlach, Stefanie Mott, Agnieszka Turowska, Holger Garn, Raja Atreya, Hans-Anton Lehr, I-Cheng Ho, Harald Renz, Benno Weigmann, Markus F Neurath
BACKGROUND & AIMS: GATA3 is a transcription factor that regulates T-cell production of cytokines. We investigated the role of GATA3 in development of colitis in mice. METHODS: We performed quantitative PCR and immunofluorescence analyses of colon tissues from patients with Crohn's disease (n= 61) or ulcerative colitis (UC, n= 74), or patients without inflammatory bowel diseases (n= 22), to measure levels of GATA3. Colitis was induced by administration of oxazolone or 2,4,6-Trinitrobenzenesulfonic acid (TNBS) to control mice, mice with T-cell specific deletion of GATA3, and mice with deletion of tumor necrosis factor receptor-1 (TNFR1) and TNFR2 (TNFR double knockouts); some mice were given a GATA3-specific DNAzyme (hgd40) or a control DNAzyme via intrarectal administration, or systemic injections of an antibody to TNF prior or during sensitization and challenge phase of colitis induction...
September 14, 2016: Gastroenterology
Ramakrishna Edukulla, Kira Lee Rehn, Bo Liu, Jaclyn W McAlees, Gurjit K Hershey, Yui Hsi Wang, Ian Lewkowich, Andrew W Lindsley
INTRODUCTION: Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis. METHODS: Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo...
September 2016: Immunity, Inflammation and Disease
Gretchen M Oakley, Richard J Harvey
Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory condition with heterogeneous pathophysiology. A cornerstone of the management of this condition is the use of anti-inflammatory agents. Corticosteroids are very effective and the most commonly used, but other drugs with immunodulatory activity such as anti-IL5, doxycycline (Th2), and macrolides (anti-neutrophilic/IL8) have been shown to have efficacy. Although systemic corticosteroids have shown benefit in managing this condition, the frequency of use often required in this condition is associated with significant adverse effects...
2016: Advances in Oto-rhino-laryngology
Naohiro Tsukamoto, Naoki Takahashi, Hiroshi Itoh, Isabelle Pouliquen
Interleukin 5 (IL-5) and eosinophils are thought to play an important role in the pathology of asthma. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of mepolizumab, a humanized anti-IL5 IgG1 monoclonal antibody, in development for the treatment of severe eosinophilic asthma. This single-blind study randomized 35 healthy Japanese male subjects (3:1) to receive either a single mepolizumab intravenous dose (10, 75, 250, or 750 mg) or placebo. Subjects were observed for up to 151 days postdose, depending on the dose administered...
March 2016: Clinical Pharmacology in Drug Development
Bram D van Rhijn, Joanne Verheij, Marius A van den Bergh Weerman, Caroline Verseijden, René M J G J van den Wijngaard, Wouter J de Jonge, Andreas J P M Smout, Albert J Bredenoord
OBJECTIVES: The esophageal mucosal integrity is impaired in patients with eosinophilic esophagitis (EoE). We aimed to evaluate the effect of fluticasone propionate on inflammation and functional and structural markers of esophageal mucosal barrier integrity in adult patients with EoE. METHODS: In this prospective study, we included 15 EoE patients (median age (IQR), 43 (30-45) years). Patients underwent upper endoscopy before and after an 8-week course of swallowed fluticasone propionate 500 μg BID...
September 2015: American Journal of Gastroenterology
Qi Yang, Moyar Q Ge, Blerina Kokalari, Imre G Redai, Xinxin Wang, David M Kemeny, Avinash Bhandoola, Angela Haczku
BACKGROUND: Asthmatic patients are highly susceptible to air pollution and in particular to the effects of ozone (O3) inhalation, but the underlying mechanisms remain unclear. OBJECTIVE: Using mouse models of O3-induced airway inflammation and airway hyperresponsiveness (AHR), we sought to investigate the role of the recently discovered group 2 innate lymphoid cells (ILC2s). METHODS: C57BL/6 and BALB/c mice were exposed to Aspergillus fumigatus, O3, or both (3 ppm for 2 hours)...
February 2016: Journal of Allergy and Clinical Immunology
J Lemale, L Dainese, P Tounian
Eosinophilic gastrointestinal disorders are a heterogeneous group of disorders characterized by no specific digestive symptoms associated with dense eosinophilic inflammation of the gastrointestinal tract in the absence of known causes for such tissue eosinophilia. Among these diseases, eosinophilic gastroenteritis (EGE) and colitis (EC) are less common than esophagitis, but their incidence and prevalence have been increasing over the past decade due in part to increased disease recognition. The exact pathophysiology is not clear: EGE and EC are immune-mediated diseases implicating adaptive T-helper cell type 2 immunity...
July 2015: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
Manali Mukherjee, Roma Sehmi, Parameswaran Nair
Airway inflammation is considered to be the primary component contributing to the heterogeneity and severity of airway disorders. Therapeutic efficacies of diverse novel biologics targeting the inflammatory pathways are under investigation. One such target is IL-5, a type-1 cytokine that is central to the initiation and sustenance of eosinophilic airway inflammation. Over the past decade, anti-IL5 molecules have been documented to have mixed therapeutic benefits in asthmatics. Post hoc analyses of the trials reiterate the importance of identifying the IL-5-responsive patient endotypes...
2014: World Allergy Organization Journal
B Hilvering, I D Pavord
Asthma is a heterogeneous airway disease characterized by typical symptoms in combination with variable airway obstruction. Most patients with asthma have well controlled symptoms and a low risk of asthma attacks with inhaled corticosteroid (ICS) treatment. However, a clinically important subgroup (~ 10%) remains symptomatic and/or at risk of asthma attacks despite maximum inhaled therapy. Patients with severe asthma are responsible for a significant proportion of healthcare costs attributable to asthma and have a large unmet need for better treatments...
July 2015: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
Teresa Hemmerle, Silvana Zgraggen, Mattia Matasci, Cornelia Halin, Michael Detmar, Dario Neri
BACKGROUND: The antibody-mediated delivery of cytokines ("immunocytokines") to sites of pathological angiogenesis represents an attractive strategy for the development of innovative biopharmaceuticals, capable of modulating the activity of the immune system in cancer and in chronic inflammatory conditions. OBJECTIVE: Recombinant IL4 has previously been shown to be therapeutically active in patients with psoriasis. The antibody-mediated delivery of this cytokine to sites of chronic skin inflammatory conditions should lead to an improved potency and selectivity, compared to non-targeted IL4...
November 2014: Journal of Dermatological Science
Ronen Bar Yoseph, Galit Livnat, Zeev Schnapp, Fahed Hakim, Husein Dabbah, Aviv Goldbart, Lea Bentur
BACKGROUND: Cross-sectional studies have reported an association of vitamin D deficiency with increased asthma prevalence and severity, and with allergies. The effect of vitamin D as sole therapy on airway hyper-reactivity (AHR) and airway inflammation has not been reported. AIM: To evaluate the effect of vitamin D therapy on AHR as assessed by methacholine concentration, causing a 20% reduction in FEV1 (PC20 -FEV1 ) and fractional exhaled nitric oxide (FeNO), systemic markers of allergy and inflammation, and exhaled breath condensate cytokines...
August 2015: Pediatric Pulmonology
C Persson
Primary lysis of eosinophils liberates free eosinophil granules (FEGs) releasing toxic proteins in association with bronchial epithelial injury repair. Eosinophil lysis may be significantly pathogenic. Bronchial mucosal FEGs are associated with uncontrolled asthma, severe asthma, aspirin-sensitive asthma, and lethal asthma. FEGs in the bronchial wall may characterize severe asthma without sputum eosinophilia. Excessive numbers of sputum FEGs occur in severe exacerbations of asthma and are reduced along with clinical improvement...
February 2014: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
Wiparat Manuyakorn, Peter H Howarth, Stephen T Holgate
Asthma is an airway inflammatory disease with functional and structural changes, leading to bronchial hyperresponsiveness (BHR) and airflow obstruction. Airway structural changes or airway remodelling consist of epithelial injury, goblet cell hyperplasia, subepithelial layer thickening, airway smooth muscle hyperplasia and angiogenesis. These changes were previously considered as a consequence of chronic airway inflammation. However, several studies have demonstrated that inflammation and remodelling can occur as separate but parallel aspects of the asthmatic process...
March 2013: Asian Pacific Journal of Allergy and Immunology
Joanne C Masterson, Eóin N McNamee, Lindsay Hosford, Kelley E Capocelli, Joseph Ruybal, Sophie A Fillon, Alfred D Doyle, Holger K Eltzschig, Anil K Rustgi, Cheryl A Protheroe, Nancy A Lee, James J Lee, Glenn T Furuta
OBJECTIVE: Eosinophilic oesophagitis (EoE) is a chronic inflammatory condition of the oesophagus with limited treatment options. No previous transgenic model has specifically targeted the oesophageal mucosa to induce oesophageal eosinophilia. DESIGN: We developed a mouse model that closely resembles EoE by utilising oxazolone haptenation in mice with transgenic overexpression of an eosinophil poietic and survival factor (interleukin (IL)-5) in resident squamous oesophageal epithelia...
January 2014: Gut
Jonathan Corren
Elevated numbers of blood and tissue eosinophils are present in allergic diseases and experimental evidence suggests that eosinophils play an important pathogenic role in these conditions. Regulation of eosinophil maturation, recruitment, and survival is under the control of a small group of factors, including interleukin-5 (IL-5). Given the probable importance of eosinophils to allergy and other associated disorders, IL-5 has been proposed as a potential molecular target in the treatment of these diseases...
April 2012: Discovery Medicine
A H Poon, D H Eidelman, J G Martin, C Laprise, Q Hamid
Patients with severe asthma have asthma symptoms which are difficult to control, require high dosages of medication, and continue to experience persistent symptoms, asthma exacerbations or airflow obstruction. Epidemiological and clinical evidences point to the fact that severe asthma is not a single phenotype. Cluster analyses have identified subclasses of severe asthma using parameters such as patient characteristics, and cytokine profiles have also been useful in classifying moderate and severe asthma. The IL-4/IL-13 signalling pathway accounts for the symptoms experienced by a subset of severe asthmatics with allergen-associated symptoms and high serum immunoglobulin E (IgE) levels, and these patients are generally responsive to anti-IgE treatment...
May 2012: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
Alfredo J Lucendo, Angel Arias, Livia C De Rezende, Jose Luis Yagüe-Compadre, Teresa Mota-Huertas, Sonia González-Castillo, Rubén A Cuesta, José M Tenias, Teresa Bellón
BACKGROUND: Recent research shows that both pediatric and adult patients with eosinophilic esophagitis (EoE) experience esophageal remodeling marked by increased collagen deposition in which TGF-β plays an important role. However, limited data are available on the intensity and reversibility of fibrous remodeling in adults with EoE. OBJECTIVE: We sought to analyze differences in collagen deposition in the lamina propria (LP) and profibrogenic cytokine gene expression along with other changes induced by prolonged treatment with fluticasone propionate in adults with EoE...
November 2011: Journal of Allergy and Clinical Immunology
Zobair M Younossi, Dolores Limongi, Maria Stepanova, Mariaelena Pierobon, Arian Afendy, Rohini Mehta, Ancha Baranova, Lance Liotta, Emanuel Petricoin
Only half of chronic hepatitis C (CH-C) patients treated with pegylated interferon and ribavirin (PEG-IFN+RBV) achieve sustained virologic response) SVR. In addition to known factors, we postulated that activation of key protein signaling networks in the peripheral blood mononuclear cells (PBMCs) may contribute to SVR due to inherent patient-specific basal immune cell signaling architecture. In this study, we included 92 patients with CH-C. PBMCs were collected while patients were not receiving treatment and used for phosphoprotein-based network profiling...
February 4, 2011: Journal of Proteome Research
C E Brightling
Eosinophilic airway inflammation is commonly observed in chronic cough in patients with asthma and non-asthmatic eosinophilic bronchitis. Indeed asthma and non-asthmatic eosinophilic bronchitis are amongst the commonest causes of chronic cough accounting for about 25 and 10% of cases respectively. In most cases the trigger that causes the cough is uncertain; however removal of potential triggers is important to consider in particular with respect to occupational exposure to known sensitizers. In both conditions the cough improves subjectively and objectively following treatment with corticosteroids...
June 2011: Pulmonary Pharmacology & Therapeutics
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