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https://www.readbyqxmd.com/read/28442583/seletalisib-characterization-of-a-novel-potent-and-selective-inhibitor-of-pi3k%C3%AE
#1
Rodger A Allen, Daniel C Brookings, Mark J Powell, Jean Delgado, Lindsay K Shuttleworth, Mark Merriman, Ian J Fahy, Roohi Tewari, John P Silva, Louise J Healy, Gareth C G Davie, Breda Twomey, Rona M Cutler, Apoorva Kotian, Andrea Crosby, Gillian McCluskey, Gillian Watt, Andrew Payne
PI3Ks are key signaling enzymes regulating cellular survival, development and function. Expression of the PI3Kδ isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a novel small molecule inhibitor of PI3Kδ that was evaluated in biochemical assays, cellular assays of adaptive and innate immunity, and an in vivo rat model of inflammation. Our findings show that seletalisib is a potent, ATP-competitive and highly selective PI3Kδ inhibitor able to block AKT phosphorylation following activation of the BCR in a B-cell line...
April 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28441991/in-vitro-impact-of-anti-immunoglobulin-e-monoclonal-antibodies-including-omalizumab-on-whole-blood-basophil-histamine-release-assessment-of-direct-induction-of-basophil-histamine-release-and-evaluation-of-modulation-of-allergen-induced-basophil-histamine-release
#2
Krzysztof Kowal, Pawel Bielecki, Ilona V DuBuske, Lawrence M DuBuske
AIM: The aim of this study was to evaluate the potential of anti-immunoglobulin E (IgE) and/or anti-IgE-IgE immune complexes to release histamine from peripheral blood basophils. In addition, a potential modulating effect of anti-IgE-IgE complexes on allergen-induced peripheral blood basophil histamine release was evaluated. METHODS: Whole blood basophil histamine release (WBB-HR) tests done by using glass-fiber-based microtiter plates were performed in 62 patients with allergic rhinitis and/or asthma sensitized to perennial allergens...
May 1, 2017: Allergy and Asthma Proceedings:
https://www.readbyqxmd.com/read/28439933/effect-of-anti-ige-in-occupational-asthma-caused-by-exposure-to-low-molecular-weight-agents
#3
M Ollé-Monge, M J Cruz, S Gomez-Ollés, I Ojanguren, J Vanoirbeek, X Muñoz
BACKGROUND: The role of immunoglobulin (Ig)-E in occupational asthma (OA) due to low molecular weight (LMW) agents is not well established compared to classical atopic asthma. In the present study we evaluate whether anti-IgE monoclonal antibody (mAb) has an effect in a mouse model of OA, using persulfate salts. METHODS: On days 1 and 8, BALB/C mice were dermally sensitized with 5% ammonium persulfate (AP) or dimethyl sulfoxide (DMSO). On days 15, 18 and 21 animals were injected intraperitoneally with anti-IgE mAb or PBS 6 hours before challenge with AP or saline...
April 25, 2017: Allergy
https://www.readbyqxmd.com/read/28438838/allosteric-mechanism-of-action-of-the-therapeutic-anti-ige-antibody-omalizumab
#4
Anna M Davies, Elizabeth G Allan, Anthony H Keeble, Jean Delgado, Benjamin P Cossins, Alkistis N Mitropoulou, Marie O Y Pang, Tom Ceska, Andrew J Beavil, Graham Craggs, Marta Westwood, Alistair J Henry, James M McDonnell, Brian J Sutton
Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically-approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI...
April 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28435464/clinical-efficacy-of-omalizumab-in-chronic-spontaneous-urticaria-is-associated-with-a-reduction-of-fc%C3%AE%C2%B5ri-positive-cells-in-the-skin
#5
Martin Metz, Petra Staubach, Andrea Bauer, Randolf Brehler, Janine Gericke, Michael Kangas, Joanna Ashton-Chess, Philip Jarvis, Panayiotis Georgiou, Janice Canvin, Rainer Hillenbrand, Veit J Erpenbeck, Marcus Maurer
Background. Treatment with omalizumab, a humanized recombinant monoclonal anti-IgE antibody, results in clinical efficacy in patients with Chronic Spontaneous Urticaria (CSU). The mechanism of action of omalizumab in CSU has not been elucidated in detail. Objectives. To determine the effects of omalizumab on levels of high affinity IgE receptor-positive (FcεRI(+)) and IgE-positive (IgE(+)) dermal cells and blood basophils. Treatment efficacy and safety were also assessed. Study design. In a double-blind study, CSU patients aged 18‑75 years were randomized to receive 300 mg omalizumab (n=20) or placebo (n=10) subcutaneously every 4 weeks for 12 weeks...
2017: Theranostics
https://www.readbyqxmd.com/read/28429307/emerging-approaches-to-food-desensitization-in-children
#6
REVIEW
Ahmad Hamad, Wesley A Burks
PURPOSE OF REVIEW: The purpose of this review is to highlight the recent advances in food desensitization in children with food allergy. RECENT FINDINGS: Recent advancements in epicutaneous, sublingual, and oral immunotherapy for food allergy in the future may offer children with food allergy and their families a viable option to reduce risk or severity of anaphylaxis with phase III trials ongoing for two of these treatment modalities. Food allergy prevalence in children is estimated to be up to 8%...
May 2017: Current Allergy and Asthma Reports
https://www.readbyqxmd.com/read/28427296/predictors-of-response-to-therapy-with-omalizumab-in-patients-with-severe-allergic-asthma-a-real-life-study
#7
Maria Kallieri, Andriana I Papaioannou, Evgenia Papathanasiou, Polyxeni Ntontsi, Spyridon Papiris, Stelios Loukides
INTRODUCTION: Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody, used for the treatment of severe refractory allergic asthma. However, not all patients with IgE levels within the limits of administration, respond to treatment. The aim of the present study, was to determine clinical and inflammatory characteristics that could predict response to omalizumab. METHODS: We studied retrospectively patients treated with omalizumab as per GINA guidelines in one asthma tertiary referral center...
April 21, 2017: Postgraduate Medicine
https://www.readbyqxmd.com/read/28401621/mouse-models-of-severe-asthma-understanding-the-mechanisms-of-steroid-resistance-tissue-remodelling-and-disease-exacerbation
#8
REVIEW
Steven Maltby, Hock L Tay, Ming Yang, Paul S Foster
Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for individuals with severe asthma are often ineffective. Mouse models are useful to identify mechanisms underlying disease pathogenesis and for the preclinical assessment of new therapies. In fact, existing mouse models have contributed significantly to our understanding of allergic/eosinophilic phenotypes of asthma and facilitated the development of novel targeted therapies (e...
April 11, 2017: Respirology: Official Journal of the Asian Pacific Society of Respirology
https://www.readbyqxmd.com/read/28396318/blocking-allergic-reaction-through-targeting-surface-bound-ige-with-low-affinity-anti-ige-antibodies
#9
Ke Zhang, Jeffrey Liu, Thao Truong, Elyssa Zukin, Wendy Chen, Andrew Saxon
Allergic disorders have now become a major worldwide public health issue, but the effective treatment options remain limited. We report a novel approach to block allergic reactivity by targeting the surface-bound IgE of the allergic effector cells via low-affinity anti-human IgE Abs with dissociation constants in the 10(-6) to 10(-8) M range. We demonstrated that these low-affinity anti-IgE mAbs bind to the cell surface-bound IgE without triggering anaphylactic degranulation even at high concentration, albeit they would weakly upregulate CD203c expression on basophils...
April 10, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28330497/atopic-dermatitis-anti-ige-paediatric-trial-adapt-the-role-of-anti-ige-in-severe-paediatric-eczema-study-protocol-for-a-randomised-controlled-trial
#10
Susan Chan, Victoria Cornelius, Tao Chen, Suzana Radulovic, Mandy Wan, Rahi Jahan, Gideon Lack
BACKGROUND: The evidence for systemic treatments for severe childhood eczema is limited and largely based on extrapolation of data from adult studies. Current therapies are often immunosuppressant and may be associated with both short- and long-term side effects. There is increasing in vitro and murine-model evidence for the role of IgE in the immunopathogenesis of atopic eczema. The aim of the study is to assess whether anti-IgE treatment (omalizumab) improves eczema, compared to placebo...
March 22, 2017: Trials
https://www.readbyqxmd.com/read/28328081/btk-inhibition-is-a-potent-approach-to-block-ige-mediated-histamine-release-in-human-basophils
#11
D Smiljkovic, K Blatt, G Stefanzl, Y Dorofeeva, C Skrabs, M Focke-Tejkl, W R Sperr, U Jaeger, R Valenta, P Valent
BACKGROUND: Recent data suggest that Bruton's tyrosine kinase (BTK) is an emerging therapeutic target in IgE receptor (IgER)-cross-linked basophils. METHODS: We examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL-292, and CNX-774) on IgE-dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and nonallergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU812 and the human mast cell line HMC-1...
March 22, 2017: Allergy
https://www.readbyqxmd.com/read/28303277/basophil-fc%C3%AE%C2%B5ri-expression-in-chronic-spontaneous-urticaria-a-potential-immunological-predictor-of-response-to-omalizumab-therapy
#12
Gustavo Deza, Marta Bertolín-Colilla, Ramon M Pujol, Laia Curto-Barredo, Dulce Soto, Maribel García, Pilar Hernández, Ramon Gimeno, Ana M Giménez-Arnau
Although the efficacy of omalizumab has been clearly demonstrated in the treatment of chronic spontaneous urticaria (CSU), its mechanism of action, which results in improvement in CSU symptoms, is not entirely understood. This study investigated the effect of omalizumab on expression of the high-affinity IgE receptor (FcεRI) on blood basophils from patients with active CSU, and its association with the clinical response. Patients exhibiting significant clinical improvement showed a sharp reduction in the levels of basophil FcεRI after 4 weeks, which was maintained throughout the total duration of the treatment...
March 17, 2017: Acta Dermato-venereologica
https://www.readbyqxmd.com/read/28294590/successful-omalizumab-treatment-in-hiv-positive-patient-with-chronic-spontaneous-urticaria-a-case-report
#13
E Iemoli, F Niero, L Borgonovo, M V Cossu, S Piconi
We described a case of a 56 year old homosexual HIV positive man who presented a history of CSU since one year (2012). All the allergologic, immunologic and microbiologic tests to evaluate the pathogenesis of wheals resulted negative. Therefore in June 2015 we decided to start therapy with Omalizumab while the patient kept on effective antiretroviral therapy with 310 cells/mm3 TCD4 counts and undetectable HIV viremia. After two monthly subcutaneuous injection of 150 mg of Omalizumab the patient had no more urticarial symptoms...
March 2017: European Annals of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28293414/galectin-3-an-early-predictive-biomarker-of-modulation-of-airway-remodeling-in-patients-with-severe-asthma-treated-with-omalizumab-for-36%C3%A2-months
#14
Anna Maria Riccio, Pierluigi Mauri, Laura De Ferrari, Rossana Rossi, Dario Di Silvestre, Louise Benazzi, Alessandra Chiappori, Roberto Walter Dal Negro, Claudio Micheletto, Giorgio Walter Canonica
BACKGROUND: Bronchial asthma is a heterogeneous disease characterized by three cardinal features: chronic inflammation, variable airflow obstruction, and airway hyperresponsiveness. Asthma has traditionally been defined using nonspecific clinical and physiologic variables that encompass multiple phenotypes and are treated with nonspecific anti-inflammatory therapies. Based on the modulation of airway remodeling after 12 months of anti-immunoglobulin E (IgE) treatment, we identified two phenotypes (omalizumab responder, OR; and non-omalizumab responder, NOR) and performed morphometric analysis of bronchial biopsy specimens...
2017: Clinical and Translational Allergy
https://www.readbyqxmd.com/read/28287273/novel-monoclonal-treatments-in-severe-asthma
#15
Howraman Meteran, Hanieh Meteran, Celeste Porsbjerg, Vibeke Backer
AIM: To provide a general overview of the current biological treatments and discuss their potential anti-asthmatic effects. DATA SOURCES: We reviewed articles in PubMed found using the search words "Asthma/therapy AND antibodies, monoclonal/therapeutic use AND cytokines." STUDY SELECTIONS: Only articles published in English since 2000 were considered. The search identified 29 studies; 8 additional studies were found by hand search, generating 37 studies...
March 13, 2017: Journal of Asthma: Official Journal of the Association for the Care of Asthma
https://www.readbyqxmd.com/read/28283151/immunotherapy-for-food-allergy-are-we-there-yet
#16
Yael Gernez, Anna Nowak-Węgrzyn
Current clinical research focuses on food allergen-specific immunotherapy through oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. Immunotherapy relies on the delivery of gradually increasing doses of specific allergens to induce desensitization (defined as temporary antigen hyporesponsiveness that depends on regular food ingestion) and, ultimately, tolerance (defined as the ability to ingest food without symptoms despite prolonged periods of avoidance or irregular intake). Although the majority of the patients treated with OIT achieve desensitization, only a minority achieves tolerance...
March 2017: Journal of Allergy and Clinical Immunology in Practice
https://www.readbyqxmd.com/read/28281330/basophil-activation-test-implementation-and-standardization-between-systems-and-between-instruments
#17
Anne-Emmanuelle Depince-Berger, Khaled Sidi-Yahya, Mohammed Jeraiby, Claude Lambert
The basophil activation test (BAT) is a good ex vivo alternative for measuring hypersensitivity to an allergen in sensitized patients but still lacks standardization. In this present study, we have implemented one of the systems and proposed inter-systems, inter-instrument standardization. Our method for basophil activation and labeling on whole blood: EDTA in one step using BasoflowEx(®) and FlowCast(®) . Setup on Navios and fluorescence targets converted to set up FACSCanto™ instrument. Our results: 1) A CD203c/CD63 (BasoflowEx) method was adapted for EDTA samples and simplified...
March 2017: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
https://www.readbyqxmd.com/read/28254561/extracorporeal-ige-immunoadsorption-in-allergic-asthma-safety-and-efficacy
#18
RANDOMIZED CONTROLLED TRIAL
Christian Lupinek, Kurt Derfler, Silvia Lee, Thomas Prikoszovich, Oliver Movadat, Eva Wollmann, Carolin Cornelius, Milena Weber, Renate Fröschl, Regina Selb, Katharina Blatt, Dubravka Smiljkovic, Volker Schoder, René Cervenka, Thomas Plaichner, Gottfried Stegfellner, Hans Huber, Rainer Henning, Justyna Kozik-Jaromin, Thomas Perkmann, Verena Niederberger, Ventzislav Petkov, Peter Valent, Adelheid Gauly, Hans Peter Leinenbach, Ingrid Uhlenbusch-Koerwer, Rudolf Valenta
BACKGROUND: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE. OBJECTIVE: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes...
March 2017: EBioMedicine
https://www.readbyqxmd.com/read/28247460/effectiveness-of-omalizumab-in-a-case-of-urticarial-vasculitis
#19
A Fueyo-Casado, L Campos-Muñoz, E González-Guerra, J Pedraz-Muñoz, J A Cortés-Toro, E López-Bran
Urticarial vasculitis (UV) is a mainly leucocytoclastic vasculitis with urticarial plaques. Treating these patients is challenging as the available treatments have poor efficacy. Oral corticosteroids are considered the first-line treatment, but H1 antihistamines, dapsone, colchicine, antimalarials, ciclosporin and antileucotrienes have all been tried also. However, because of their adverse effects and/or lack of efficacy, new agents are still needed. Omalizumab, an anti-IgE antibody, shows efficacy in chronic spontaneous urticaria, and might also be a good treatment for angio-oedema and urticarial vasculitis...
March 1, 2017: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/28236656/recovery-from-desensitization-of-ige-dependent-responses-in-human-lung-mast-cells
#20
A Lewis, D W MacGlashan, S K Suvarna, P T Peachell
BACKGROUND: Clinical desensitization and oral food immunotherapy are therapeutic interventions that allow individuals who react adversely to an allergen (drug or food) to be made tolerant to the allergen. However, tolerance is brief, and allergen hypersensitivity can recur within days following allergen withdrawal. OBJECTIVE: We hypothesize that the reason these treatments are temporary reflects rapid recovery of mast cells from a desensitized state. We sought to test this...
February 25, 2017: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
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