PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-6 (6)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Research needs in allergy: an EAACI position paper, in collaboration with EFA 
Papadopoulos, Nikolaos G | Agache, Ioana | Bavbek, Sevim | Bilo, Beatrice M | Braido, Fulvio | Cardona, Victoria | Custovic, Adnan | deMonchy, Jan | Demoly, Pascal | Eigenmann, Philippe | Gayraud, Jacques | Grattan, Clive | Heffler, Enrico | Hellings, Peter W | Jutel, Marek | Knol, Edward | Lötvall, Jan | Muraro, Antonella | Poulsen, Lars K | Roberts, Graham | Schmid-Grendelmeier, Peter | Skevaki, Chrysanthi | Triggiani, Massimo | vanRee, Ronald | Werfel, Thomas | Flood, Breda | Palkonen, Susanna | Savli, Roberta | Allegri, Pia | Annesi-Maesano, Isabella | Annunziato, Francesco | Antolin-Amerigo, Dario | Apfelbacher, Christian | Blanca, Miguel | Bogacka, Ewa | Bonadonna, Patrizia | Bonini, Matteo | Boyman, Onur | Brockow, Knut | Burney, Peter | Buters, Jeroen | Butiene, Indre | Calderon, Moises | Cardell, Lars Olaf | Caubet, Jean-Christoph | Celenk, Sevcan | Cichocka-Jarosz, Ewa | Cingi, Cemal | Couto, Mariana | deJong, Nicolette | Del Giacco, Stefano | Douladiris, Nikolaos | Fassio, Filippo | Fauquert, Jean-Luc | Fernandez, Javier | Rivas, Montserrat Fernandez | Ferrer, Marta | Flohr, Carsten | Gardner, James | Genuneit, Jon | Gevaert, Philippe | Groblewska, Anna | Hamelmann, Eckard | Hoffmann, Hans Jürgen | Hoffmann-Sommergruber, Karin | Hovhannisyan, Lilit | Hox, Valérie | Jahnsen, Frode L | Kalayci, Ömer | Kalpaklioglu, Ayse Füsun | Kleine-Tebbe, Jörg | Konstantinou, George | Kurowski, Marcin | Lau, Susanne | Lauener, Roger | Lauerma, Antti | Logan, Kirsty | Magnan, Antoine | Makowska, Joanna | Makrinioti, Heidi | Mangina, Paraskevi | Manole, Felicia | Mari, Adriano | Mazon, Angel | Mills, Clare | Mingomataj, ErvinÇ | Niggemann, Bodo | Nilsson, Gunnar | Ollert, Markus | O'Mahony, Liam | O'Neil, Serena | Pala, Gianni | Papi, Alberto | Passalacqua, Gianni | Perkin, Michael | Pfaar, Oliver | Pitsios, Constantinos | Quirce, Santiago | Raap, Ulrike | Raulf-Heimsoth, Monika | Rhyner, Claudio | Robson-Ansley, Paula | Alves, Rodrigo Rodrigues | Roje, Zeljka | Rondon, Carmen | Rudzeviciene, Odilija | Ruëff, Franziska | Rukhadze, Maia | Rumi, Gabriele | Sackesen, Cansin | Santos, Alexandra F | Santucci, Annalisa | Scharf, Christian | Schmidt-Weber, Carsten | Schnyder, Benno | Schwarze, Jürgen | Senna, Gianenrico | Sergejeva, Svetlana | Seys, Sven | Siracusa, Andrea | Skypala, Isabel | Sokolowska, Milena | Spertini, Francois | Spiewak, Radoslaw | Sprikkelman, Aline | Sturm, Gunter | Swoboda, Ines | Terreehorst, Ingrid | Toskala, Elina | Traidl-Hoffmann, Claudia | Venter, Carina | Vlieg-Boerstra, Berber | Whitacker, Paul | Worm, Margitta | Xepapadaki, Paraskevi | Akdis, Cezmi A
In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.
The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients’ organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.
Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.
doi:10.1186/2045-7022-2-21
PMCID: PMC3539924  PMID: 23121771
Allergy; Allergic diseases; Policy; Research needs; Research funding; Europe
3.  In Vitro Evolution of Allergy Vaccine Candidates, with Maintained Structure, but Reduced B Cell and T Cell Activation Capacity 
PLoS ONE  2011;6(9):e24558.
Allergy and asthma to cat (Felis domesticus) affects about 10% of the population in affluent countries. Immediate allergic symptoms are primarily mediated via IgE antibodies binding to B cell epitopes, whereas late phase inflammatory reactions are mediated via activated T cell recognition of allergen-specific T cell epitopes. Allergen-specific immunotherapy relieves symptoms and is the only treatment inducing a long-lasting protection by induction of protective immune responses. The aim of this study was to produce an allergy vaccine designed with the combined features of attenuated T cell activation, reduced anaphylactic properties, retained molecular integrity and induction of efficient IgE blocking IgG antibodies for safer and efficacious treatment of patients with allergy and asthma to cat. The template gene coding for rFel d 1 was used to introduce random mutations, which was subsequently expressed in large phage libraries. Despite accumulated mutations by up to 7 rounds of iterative error-prone PCR and biopanning, surface topology and structure was essentially maintained using IgE-antibodies from cat allergic patients for phage enrichment. Four candidates were isolated, displaying similar or lower IgE binding, reduced anaphylactic activity as measured by their capacity to induce basophil degranulation and, importantly, a significantly lower T cell reactivity in lymphoproliferative assays compared to the original rFel d 1. In addition, all mutants showed ability to induce blocking antibodies in immunized mice.The approach presented here provides a straightforward procedure to generate a novel type of allergy vaccines for safer and efficacious treatment of allergic patients.
doi:10.1371/journal.pone.0024558
PMCID: PMC3172221  PMID: 21931754
4.  Targeting the Extracellular Membrane-Proximal Domain of Membrane-Bound IgE by Passive Immunization Blocks IgE Synthesis In Vivo1 
The classical allergic reaction starts seconds or minutes after Ag contact and is committed by Abs produced by a special subset of B lymphocytes. These Abs belong to the IgE subclass and are responsible for Type I hyperreactivity reactions. Treatment of allergic diseases with humanized anti-IgE Abs leads primarily to a decrease of serum IgE levels. As a consequence, the number of high-affinity IgE receptors on mast cells and basophils decreases, leading to a lower excitability of the effector cells. The biological mechanism behind anti-IgE therapy remains partly speculative; however, it is likely that these Abs also interact with membrane IgE (mIgE) on B cells and possibly interfere with IgE production. In the present work, we raised a mouse mAb directed exclusively against the extracellular membrane-proximal domain of mIgE. The interaction between the monoclonal anti-mIgE Ab and mIgE induces receptor-mediated apoptosis in vitro. Passive immunization experiments lead to a block of newly synthesized specific IgEs during a parallel application of recombinant Bet v1a, the major birch pollen allergen. The decrease of allergen-specific serum IgE might be related to tolerance-inducing mechanisms stopping mIgE-displaying B cells in their proliferation and differentiation.
PMCID: PMC2959155  PMID: 18390733
5.  Display of E. coli Alkaline Phosphatase pIII or pVIII Fusions on Phagemid Surfaces Reveals Monovalent Decoration with Active Molecules 
Active alkaline phosphatase of Escherichia coli (PhoA, EC 3.1.3.1) was displayed via the leucine zipper element of the Jun-Fos heterodimer on the surface of filamentous phage and the kinetic parameters Km and kcat were determined. The phoA gene was cloned downstream of fos while jun was inserted upstream of pIII or pVIII, alternatively, in the pJuFo phagemid vector. Both fusion genes are regulated by independent lacZ promoters. PhoA displayed on the phagemid pIII surface exhibited a Km of 11.2 µM with 4-nitrophenyl phosphate as substrate, which is consistent with data published for soluble PhoA. Based on these data we calculated the decoration of pJuFo phagemid with PhoA using the minor and major coat proteins pIII and pVIII as fusion partners under variable inducing conditions. We found that, even if the promoters are fully induced at a concentration of 1000 µM IPTG, the phagemids display maximally one copy of PhoA-Fos-Jun-coat protein fusion, irrespective of whether the protein is presented via pIII or pVIII. However, since PhoA is displayed in a native-like fashion, as deduced from the kinetic parameters of the enzymatic reaction, the pJuFo technology provides a versatile tool for the functional screening of complex cDNA libraries displayed on the phagemids' surface.
doi:10.2174/1874091X00802010038
PMCID: PMC2570559  PMID: 18949073
6.  GATA3-Driven Th2 Responses Inhibit TGF-β1–Induced FOXP3 Expression and the Formation of Regulatory T Cells 
PLoS Biology  2007;5(12):e329.
Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-β–mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy.
Author Summary
Specific immune responses against foreign or autologous antigens are driven by specialized epitope-specific T cells, whose numbers expand upon recognition of antigen found on professional antigen-presenting cells. The subsequent maturation process involves the differentiation of certain T cell phenotypes such as pro-inflammatory cells (Th1, Th2, Th17) or regulatory T (Treg) cells, which serve to keep the immune response in check. The current study focuses on the role of two key transcription factors—FOXP3 and GATA3—in controlling the commitment of these cells. We demonstrate that the Th2 cytokine IL-4 inhibits the induction of FOXP3 and thus inhibits the generation of inducible Treg cells. We show that IL-4–induced GATA3 mediates FOXP3 inhibition by directly binding to a GATA element in the FOXP3 promoter. We hypothesize that therapeutic agents aimed at neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and thus promotion of tolerance in allergies and other Th2-dominated diseases.
It is shown that Th2 responses prevent the generation of inducible Tregs. This is mediated by IL-4 induction of GATA3, which binds directly to and represses the FOXP3 promoter. This mechanism is likely to be relevant in the induction of immunotolerance, particularly in allergic diseases.
doi:10.1371/journal.pbio.0050329
PMCID: PMC2222968  PMID: 18162042

Results 1-6 (6)