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Anna Slovick, Abdel Douiri, Rachel Muir, Andrea Guerra, Konstantinos Tsioulos, Evie Hay, Emily P S Lam, Joanna Kelly, Janet L Peacock, Sun Ying, Mohamed H Shamji, David J Cousins, Stephen R Durham, Stephen J Till
BACKGROUND: Repeated low dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late phase responses, comparable with conventional subcutaneous and sublingual immunotherapy. OBJECTIVE: To evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis. METHODS: We randomly assigned 93 adults with grass pollen allergic rhinitis to receive 7 pre-seasonal intradermal allergen injections (containing 7 nanograms of Phl p 5 major allergen) or histamine control...
October 20, 2016: Journal of Allergy and Clinical Immunology
A Heratizadeh, T Werfel
The pathogenesis of atopic dermatitis (AD) is multi-factorial and complex. Consequently, clinical signs and symptoms vary strongly depending on individually relevant trigger factors and the stage of the disease. So far, treatment of AD was commonly limited to topical treatment or, in more severe cases, to systemic drugs mostly approved for other indications than AD. However, emerging data on new anti-inflammatory agents have been published in the recent years. As these new substances specifically focus on immune responses in AD, these are partially considered as possible "break-through" in the treatment of AD...
October 13, 2016: Allergy
Tao Huang, Meredith Hazen, Yonglei Shang, Meijuan Zhou, Xiumin Wu, Donghong Yan, Zhonghua Lin, Margaret Solon, Elizabeth Luis, Hai Ngu, Yongchang Shi, Arna Katewa, David F Choy, Nandhini Ramamoorthi, Erick R Castellanos, Mercedesz Balazs, Min Xu, Wyne P Lee, Marissa L Matsumoto, Jian Payandeh, Joseph R Arron, Jo-Anne Hongo, Jianyong Wang, Isidro Hötzel, Cary D Austin, Karin Reif
Eosinophilic inflammation and Th2 cytokine production are central to the pathogenesis of asthma. Agents that target either eosinophils or single Th2 cytokines have shown benefits in subsets of biomarker-positive patients. More broadly effective treatment or disease-modifying effects may be achieved by eliminating more than one inflammatory stimulator. Here we present a strategy to concomitantly deplete Th2 T cells, eosinophils, basophils, and type-2 innate lymphoid cells (ILC2s) by generating monoclonal antibodies with enhanced effector function (19A2) that target CRTh2 present on all 4 cell types...
May 19, 2016: JCI Insight
Piotr Kuna, Leif Bjermer, Göran Tornling
BACKGROUND: Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma. OBJECTIVES: The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control. PATIENTS AND METHODS: Adults aged 18-60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510])...
2016: Drug Design, Development and Therapy
Zhihong Chen, Jue Pan, Yi Jia, Dandan Li, Zhihui Min, Xiaoqiong Su, Honglei Yuan, Geng Shen, Shengxuan Cao, Lei Zhu, Xiangdong Wang
BACKGROUND: Recent data have demonstrated that long-lived memory T cells are present in the human lung and can play significant roles in the pathogenesis of specific allergic and autoimmune diseases. However, most evidence has been obtained from mouse studies, and the potential roles of memory T cells in human allergic diseases, such as asthma, remain largely unknown. METHODS: Thirty-three asthmatics, 26 chronic obstructive pulmonary disease (COPD) patients, and 22 healthy volunteers were enrolled in this study...
August 31, 2016: Cell Biology and Toxicology
Ken Grime, Rikard Pehrson, Pär Nordell, Michael Gillen, Wolfgang Kühn, Timothy Mant, Marie Brännström, Petter Svanberg, Barry Jones, Clive Brealey
AIM: AZD1981 is an orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist progressed to phase II trials for the treatment of allergic asthma. Previously performed in vitro human hepatocyte incubations identified N-deacetylated AZD1981 as a primary metabolite. We report on metabolite exposure from a clinical excretion balance, on in vitro studies performed to determine the likelihood of a metabolite-dependent drug-drug interaction (DDI) and on a clinical warfarin DDI study...
August 24, 2016: British Journal of Clinical Pharmacology
Fa-Qing Tian, Juan Li, Ju-Heng Li, Mei-Qin Tang, Xiao-Hui Cheng, Ying-Cai Huang, Hui-Qing Li
Objective:To investigate the promotive effect of dendritic cells(DCs) on proliferation of CRTH2 (CD4(+)CD294(+)Th2) cells and the influence of CRTH2 cells on secretion of immunoglobulin from B cells so as to provide a new approach for amplification and sorting of Th2 cells. Methods:DCs were induced from peripheral blood mononuclear cells, then the loaded-BCGV-Ag-DCs were cocultured with T cells, and the mixed lymphocyte reaction(MLR) was performed by CCK8 method. The phenotypes of DCs and CRTH2 cells were detected by flow cytometry...
August 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Lawrence F Eichenfield, Sheila F Friedlander, Eric L Simpson, Alan D Irvine
The newer and emerging treatments for atopic dermatitis (AD) focus on blockade of inflammatory cytokines, especially those that derive from T helper cell type 2 (TH2) and are associated with a pathway of immunoglobulin E (IgE) sensitization. Among the proinflammatory cytokines that have been identified as promising therapeutic targets are chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2), IgE, thymic stromal lymphopoietin (TSLP), and several monoclonal antibodies that block key cytokine pathways in the innate immune response...
June 2016: Seminars in Cutaneous Medicine and Surgery
Takahisa Murata, Toko Maehara
Nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin are one of the most frequently used classes of drug worldwide and inhibit prostaglandin (PG) production by inhibiting cyclooxygenase activity. Although NSAIDs are broadly used against inflammatory diseases, they have side effects including alimentary canal disorders, kidney damage, infection and cardiovascular disorders. Thus, it is necessary to elucidate the pathophysiological role of each PG in various diseases to develop better therapies with fewer and milder side effects...
August 5, 2016: Journal of Veterinary Medical Science
Ibrahim Sulaiman, Jonathan Chee Woei Lim, Hon Liong Soo, Johnson Stanslas
Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs...
October 2016: Pulmonary Pharmacology & Therapeutics
Pierachille Santus, Dejan Radovanovic
INTRODUCTION: Asthma is a chronic inflammatory disease characterized by bronchial hyper-reactivity. Although many currently available treatment regimens are effective, poor symptom control and refractory severe disease still represent major unmet needs. In the last years, numerous molecular therapeutic targets that interfere with the innate inflammatory response in asthma have been identified. Promising preliminary results concern the signaling cascade promoted by prostaglandin D2 (PGD2) and its receptor antagonists...
September 2016: Expert Opinion on Investigational Drugs
Veit J Erpenbeck, Todor A Popov, David Miller, Steven F Weinstein, Sheldon Spector, Baldur Magnusson, Wande Osuntokun, Paul Goldsmith, Markus Weiss, Jutta Beier
BACKGROUND: There is an unmet medical need for allergic asthma patients who are uncontrolled on conventional therapies. The aim of this study was to collect efficacy and safety data for QAW039, an oral chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist, for the treatment of asthma. METHODS: This was an exploratory phase II, double-blind, randomized, placebo-controlled multi-center study. Patients with mild-to-moderate uncontrolled allergic asthma (N = 170) were either without or weaned off inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) and randomized (1:1) to QAW039 (500 mg once daily) or to placebo for 28 days...
August 2016: Pulmonary Pharmacology & Therapeutics
Marta Calbet, Miriam Andrés, Clara Armengol, Mónica Bravo, Peter Eichhorn, Rosa López, Vicente García-González, Richard Roberts, Montserrat Miralpeix
The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTh2) is a G protein-coupled receptor expressed on the leukocytes most closely associated with asthma and allergy like eosinophils, mast cells, Th2-lymphocytes and basophils. At present it is clear that CRTh2 mediates most prostaglandin D2 (PGD2) pro-inflammatory effects and as a result antagonists for this receptor have reached asthma clinical studies showing a trend of lung function improvement. The challenge remains to identify compounds with improved clinical efficacy when administered once a day...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Yi Jia, Xu Fang, Xuehua Zhu, Chunxue Bai, Lei Zhu, Meiling Jin, Xiangdong Wang, Min Hu, Renhong Tang, Zhihong Chen
RATIONALE: Type 2 innate lymphoid cells (ILC2s) have been shown to produce large amounts of type 2 cytokines in a non-antigen specific manner. These cytokines act upstream and downstream of ILC2 and are increasingly popular in asthma drug development, thus warranting a closer investigation of the mechanism-related clinical manifestations of ILC2 from asthma patient selection perspective. OBJECTIVES: We hypothesized that IL-13+ ILC2s in the circulation might correlate with asthma control status as a result of persistent Th2 inflammation in the lung...
June 17, 2016: American Journal of Respiratory Cell and Molecular Biology
Veit J Erpenbeck, Eva Vets, Lien Gheyle, Wande Osuntokun, Michael Larbig, Srikanth Neelakantham, David Sandham, Gerald Dubois, Walid Elbast, Paul Goldsmith, Markus Weiss
We evaluated the pharmacokinetics (PK), safety, and tolerability of a novel oral CRTh2 antagonist, fevipiprant (QAW039), in healthy subjects. Peak concentrations of fevipiprant in plasma were observed 1-3 hours postdosing. Concentrations declined in a multiexponential manner, followed by an apparent terminal phase (t1/2 , ∼20 hours). Steady state was achieved in 4 days with <2-fold accumulation. Elimination was partly by renal excretion (≤30% of the dose) and glucuronidation. Food had minimal impact on the PK of fevipiprant, and it was well tolerated at single and multiple oral doses up to 500 mg/day...
July 2016: Clinical Pharmacology in Drug Development
Jian Li, Andria L Doty, Atif Iqbal, Sarah C Glover
Deregulation of various components of the immune system has been reported in the inflamed gut of Crohn's disease (CD) patients. Innate lymphoid cells (ILCs) are novel innate effector lymphocytes which can rapidly respond to danger signals, from invading pathogens or tissue damage, to maintain homeostasis, especially along the mucosal surfaces. The purpose of this study is to compare composition of the intestinal ILCs subsets of CD patients with differential inflammatory conditions of the terminal ileum, which are marked by distinct histological appearances and mucosal profiles of cytokines...
June 2016: Cellular Immunology
Sathya Babu, Mottadi Rupa, Santhosh Kumar Nagarajan, Honglae Sohn, Thirumurthy Madhavan
In the present work, molecular modeling studies have been reported on a series of diazine indole acetic acid derivatives to analyze the structure-activity relationship studies of CRTH2 using fragment (Topomer CoMFA and HQSAR) and field (CoMFA and CoMSIA) based QSAR methods. Twenty-six compounds were used as a training set to establish the model, and six compounds were used as a test set to validate the model. The generated models exhibited good statistical results such as correlation coefficient (r2) and the cross-validated correlation coefficient (q2)...
2016: Combinatorial Chemistry & High Throughput Screening
Kathila S Rajapaksa, Tao Huang, Neeraj Sharma, Shannon Liu, Margaret Solon, Arthur Reyes, Sarah Paul, Angie Yee, Janet Tao, Sreedevi Chalasani, Nga Bien-Ly, Kai Barck, Richard A D Carano, Jianyong Wang, Linda Rangell, Meire Bremer, Dimitry M Danilenko, Paula Katavolos, Isidro Hotzel, Karin Reif, Cary D Austin
CRTh2 is expressed on immune cells that drive asthma pathophysiology. Current treatment options for severe asthma are inadequate and therapeutic antibody-mediated depletion of CRTh2-expressing cells represents a promising new therapeutic strategy. Here we report for the first time that CRTh2 is not only expressed on immune cells, but also on microvasculature in the central nervous system (CNS) and gastric mucosa in humans. Microvascular expression of CRTh2 raises a safety concern because a therapeutic antiCRTh2 antibody with enhanced depletion capacity could lead to vascular damage...
July 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Kengo Kanai, Mitsuhiro Okano, Tazuko Fujiwara, Shin Kariya, Takenori Haruna, Ryotaro Omichi, Sei-Ichiro Makihara, Yuji Hirata, Kazunori Nishizaki
BACKGROUND: Vascular endothelial growth factor (VEGF) is known to be associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). VEGF is produced by a variety of cells including fibroblasts. It was recently reported that prostaglandin (PG) E2 induces VEGF release by nasal polyp fibroblasts. However, little is known regarding possible regulation of VEGF by other PGs. We have reported that molecules that regulate PGD2 metabolism play roles in the pathogenesis of CRS including in local eosinophilia and type 2 cytokine production...
April 15, 2016: Allergology International: Official Journal of the Japanese Society of Allergology
N S Palikhe, C Laratta, D Nahirney, D Vethanayagam, M Bhutani, H Vliagoftis, L Cameron
BACKGROUND: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a receptor for PGD2 and expressed by T cells, eosinophils, basophils, and ILC2 cells. CRTh2 expression by CD4(+) T cells identifies the Th2 subset, and these cells have been characterized as allergen-specific central memory Th2 cells. Recently, activation of the PGD2 -CRTh2 pathway in the lungs was associated with severe asthma. OBJECTIVE: To assess circulating levels of Th2 cells and related mediators in severe asthma and those who experience asthma exacerbations...
June 2016: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
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