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3. IL‐10‐modulated dendritic cells from birch pollen‐ and hazelnut‐allergic patients facilitate Treg‐mediated allergen‐specific and cross‐reactive tolerance.

Author

Heinl, Patricia Vanessa, Graulich, Edith, Weigmann, Benno, Wangorsch, Andrea, Ose, Robert, Bellinghausen, Iris, Khatri, Rahul, Raker, Verena K., Scheurer, Stephan, Vieths, Stefan, Saloga, Joachim, and Steinbrink, Kerstin

Subjects
REGULATORY T cells, MONONUCLEAR leukocytes, FOOD allergy, TH2 cells, ALLERGIES
Abstract

Background: Approximately 70% of individuals allergic to birch pollen (Bet v 1.01 [Bet]) develop a secondary food allergy (e.g., hazelnut: Cor a 1.04 [Cor]), due to allergen cross‐reactivity. However, standard immunotherapy for type I allergies often does not improve the food allergy sufficiently. We analyzed the allergen‐specific and cross‐reactive suppressive capacity of primary human regulatory T cells (Treg) induced by autologous IL‐10‐modulated dendritic cells (IL‐10 DC) in vitro and in vivo. Methods: CD4+ T cells of patients with birch pollen and associated hazelnut allergies were differentiated into Bet‐specific or non‐specific induced Treg (iTreg). After Bet‐ or Cor‐specific restimulation the phenotype, proliferation, and suppressive capacity of iTreg subsets were analyzed. iTreg function was further investigated in humanized mouse models of airway and intestinal allergy, generated by engraftment of peripheral blood mononuclear cells from allergic donors into immunodeficient animals. Results: After IL‐10 DC priming and allergen‐specific restimulation (Bet or Cor), non‐specific control iTreg remained anergic, whereas Bet‐specific iTreg proliferated extensively and exhibited a regulatory phenotype (enhanced expression of CTLA‐4, PD‐1, TNFR2, IL‐10). Accordingly, activated Bet‐specific iTreg displayed a high capacity to suppress Bet‐ and Cor‐induced responder Th2 cell responses in vitro, indicating induction of both allergen‐specific (birch) and cross‐reactive tolerance (hazelnut). In vivo, the beneficial effect of Bet‐specific iTreg was verified in humanized mouse models of allergic airway and intestinal inflammation, resulting in reduced allergen‐induced clinical symptoms, and immune responses. Conclusion: Human IL‐10 DC‐induced iTreg facilitate allergen‐specific and cross‐reactive tolerance. Therefore, they are potential candidates for regulatory cell therapy in allergic and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility

Author

Flora T. Musuamba, Ine Skottheim Rusten, Raphaëlle Lesage, Giulia Russo, Roberta Bursi, Luca Emili, Gaby Wangorsch, Efthymios Manolis, Kristin E. Karlsson, Alexander Kulesza, Eulalie Courcelles, Jean‐Pierre Boissel, Cécile F. Rousseau, Emmanuelle M. Voisin, Rossana Alessandrello, Nuno Curado, Enrico Dall’ara, Blanca Rodriguez, Francesco Pappalardo, and Liesbet Geris

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Abstract The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk‐informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk‐based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick‐start tool by regulators. Altogether, this white paper provides a practical approach to model evaluation, applicable in both scientific and regulatory evaluation contexts.

Published
2021
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7. Human monocyte-derived type 1 and 2 macrophages recognize Ara h 1, a major peanut allergen, by different mechanisms

Author

Maren Krause, Peter Crauwels, Frank Blanco-Pérez, Martin Globisch, Andrea Wangorsch, Thomas Henle, Jonas Lidholm, Ger van Zandbergen, Stefan Vieths, Stephan Scheurer, and Masako Toda

Subjects
Medicine, Science
Abstract

Abstract Evidence has suggested that major peanut allergen Ara h 1 activates dendritic cells (DCs) via interaction with DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin), a C-type lectin receptor, and contributes to development of peanut allergy. Since macrophages, as well as DCs, play a crucial role in innate immunity, we investigated whether natural Ara h 1 (nAra h 1) activates two different subsets of macrophages, human monocyte derived macrophage type 1 (hMDM1: pro-inflammatory model) and type 2 (hMDM2: anti-inflammatory model). hMDM1 and hMDM2 predominantly produced pro-inflammatory cytokines (IL-6 and TNF-α) and an anti-inflammatory cytokine (IL-10) in response to nAra h 1, respectively. hMDM2 took up nAra h 1 and expressed DC-SIGN at higher levels than hMDM1. However, small interfering RNA knockdown of DC-SIGN did not suppress nAra h 1 uptake and nAra h 1-mediated cytokine production in hMDM2. Inhibitors of scavenger receptor class A type I (SR-AI) suppressed the response of hMDM2, but not of hMDM1, suggesting that SR-AI is a major receptor in hMDM2 for nAra h 1 recognition and internalization. nAra h 1 appears to exert stimulatory capacity on DC and macrophages via different receptors. This study advances our understanding how a major peanut allergen interacts with innate immunity.

Published
2021
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9. Allergenic Properties and Molecular Characteristics of PR-1 Proteins

Author

Andrea Wangorsch, Stephan Scheurer, Miguel Blanca, Natalia Blanca-Lopez, María Luisa Somoza, and Laura Martín-Pedraza

Subjects
pathogenesis-related protein-1, PR-1, allergen, occupational allergy, allergy diagnosis, Immunologic diseases. Allergy, RC581-607
Abstract

Only a small fraction of proteins in plants and animals are classified as allergens. The allergenic properties are frequently attributed to certain functional characteristics of the proteins, such as a role in the plant defense against biotic and abiotic stress, to achieve the systematic acquired resistance. In line with this, eight members out of 17 functional pathogenesis-related (PR) protein families have been characterized as allergens. The present review summarizes the molecular features and allergenic significance of allergens of the PR-1 family. Not many allergens have been identified as belonging to this protein family, with most of them having a pollen origin, like mugwort or Bermuda grass. Molecular and structural features of allergenic PR-1 proteins are discussed and attributed to their IgE-reactive properties, clinical manifestation, and cross-reactivity among different foods and inhalants.

Published
2022
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12. Component-Resolved Diagnosis of American Cockroach (Periplaneta americana) Allergy in Patients From Different Geographical Areas

Author

Andrea Wangorsch, Annette Jamin, Stephanie Eichhorn, Isabel Pablos, Swati Sharma, Bettina Schweidler, Bianca Kastner, Sabrina Wildner, Joachim Saloga, Frank Führer, Reinaldo Rafael Reyna Orozco, Roya Sherkat, Somayeh Sadeghi, Fardis Teifoori, Jung-Won Park, Peter Briza, Stefan Vieths, Fatima Ferreira, Naveen Arora, Jonas Lidholm, Gabriele Gadermaier, and Stephan Scheurer

Subjects
cockroach allergy, American cockroach, Blattella germanica, component-resolved diagnosis, Periplaneta americana (Insecta), Immunologic diseases. Allergy, RC581-607
Abstract

Background: Manifestation of respiratory allergy to American cockroach (Periplaneta americana) is prominent in the subtropical and tropical areas. However, co-existing perennial indoor inhalant allergies frequently compromise clinical diagnosis of cockroach allergy, and the analysis of sensitization pattern is limited by the lack of Periplaneta allergens widely available for component-resolved diagnostics (CRD).Objective: To evaluate a collection of previously described recombinant Periplaneta allergens for CRD in cockroach allergy.Methods: A panel of nine recombinant Periplaneta allergens (Per a 1–5, 7–10) was generated, purified, and subjected to physicochemical characterization by applying circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), amino acid (AA) analysis, and mass spectrometry (MS). Patients (n = 117) from India, Korea, Venezuela, and Iran, reporting perennial respiratory indoor allergies with IgE sensitization to cockroach (P. americana and/or Blattella germanica), were included. The sensitization profile was monitored by the experimental ImmunoCAP testing.Results: ImmunoCAP testing confirmed IgE sensitization to Periplaneta and/or Blattella extract in 98 of 117 patients (r = 0.95). Five out of 117 patients were sensitized to only one of the two cockroach species. Within the whole study group, the prevalence of sensitization to individual allergens varied from 4% (Per a 2) to 50% (Per a 9), with the highest IgE values to Per a 9. Patients from four countries displayed different sensitization profiles at which Per a 3 and Per a 9 were identified as major allergens in India and Korea. Periplaneta-derived lipocalin and myosin light chain were characterized as new minor allergens, designated as Per a 4 and Per a 8. Periplaneta extract showed higher diagnostic sensitivity than all individual components combined, suggesting the existence of allergens yet to be discovered.Conclusion: Utilization of a panel of purified Periplaneta allergens revealed highly heterogeneous sensitization patterns and allowed the classification of lipocalin and myosin light chain from Periplaneta as new minor allergens.

Published
2021
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14. IL-10-modulated dendritic cells from birch pollen- and hazelnut-allergic patients facilitate Treg-mediated allergen-specific and cross-reactive tolerance

Author

Heinl, Patricia Vanessa, primary, Graulich, Edith, additional, Weigmann, Benno, additional, Wangorsch, Andrea, additional, Ose, Robert, additional, Bellinghausen, Iris, additional, Scheurer, Stephan, additional, Vieths, Stefan, additional, Saloga, Joachim, additional, and Steinbrink, Kerstin, additional

Published
2023
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18. The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE2 from Epithelial Cells

Author

Yen-Ju Lin, Adam Flaczyk, Sonja Wolfheimer, Alexandra Goretzki, Annette Jamin, Andrea Wangorsch, Stefan Vieths, Stephan Scheurer, and Stefan Schülke

Subjects
flagellin, Betv1, epithelial cells, vaccine, fusion protein, Cytology, QH573-671
Abstract

Developing new adjuvants/vaccines and better understanding their mode-of-action is an important task. To specifically improve birch pollen allergy treatment, we designed a fusion protein consisting of major birch pollen allergen Betv1 conjugated to the TLR5-ligand flagellin (rFlaA:Betv1). This study investigates the immune-modulatory effects of rFlaA:Betv1 on airway epithelial cells. LA-4 mouse lung epithelial cells were stimulated with rFlaA:Betv1 in the presence/absence of various inhibitors with cytokine- and chemokine secretion quantified by ELISA and activation of intracellular signaling cascades demonstrated by Western blot (WB). Either LA-4 cells or LA-4-derived supernatants were co-cultured with BALB/c bone marrow-derived myeloid dendritic cells (mDCs). Compared to equimolar amounts of flagellin and Betv1 provided as a mixture, rFlaA:Betv1 induced higher secretion of IL-6 and the chemokines CCL2 and CCL20 from LA-4 cells and a pronounced MAPK- and NFκB-activation. Mechanistically, rFlaA:Betv1 was taken up more strongly and the induced cytokine production was inhibited by NFκB-inhibitors, while ERK- and p38-MAPK-inhibitors only suppressed IL-6 and CCL2 secretion. In co-cultures of LA-4 cells with mDCs, rFlaA:Betv1-stimulated LA-4 cells p38-MAPK- and COX2-dependently secreted PGE2, which modulated DC responses by suppressing pro-inflammatory IL-12 and TNF-α secretion. Taken together, these results contribute to our understanding of the mechanisms underlying the strong immune-modulatory effects of flagellin-containing fusion proteins.

Published
2021
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19. Does the Food Ingredient Pectin Provide a Risk for Patients Allergic to Non-Specific Lipid-Transfer Proteins?

Author

Hanna Steigerwald, Frank Blanco-Perez, Melanie Albrecht, Caroline Bender, Andrea Wangorsch, Hans-Ulrich Endreß, Mirko Bunzel, Cristobalina Mayorga, Maria José Torres, Stephan Scheurer, and Stefan Vieths

Subjects
food allergy, pectin, non-specific lipid transfer protein, nsLTP, Pru p 3, Chemical technology, TP1-1185
Abstract

Pectin, a dietary fiber, is a polysaccharide that is widely used in food industry as a gelling agent. In addition, prebiotic and beneficial immunomodulatory effects of pectin have been demonstrated, leading to increased importance as food supplement. However, as cases of anaphylactic reactions after consumption of pectin-supplemented foods have been reported, the present study aims to evaluate the allergy risk of pectin. This is of particular importance since most of the pectin used in the food industry is extracted from citrus or apple pomace. Both contain several allergens such as non-specific lipid transfer proteins (nsLTPs), known to induce severe allergic reactions, which could impair the use of pectins in nsLTP allergic patients. Therefore, the present study for the first time was performed to analyze residual nsLTP content in two commercial pectins using different detection methods. Results showed the analytical sensitivity was diminished by the pectin structure. Finally, spiking of pectin with allergenic peach nsLTP Pru p 3 led to the conclusion that the potential residual allergen content in both pectins is below the threshold to induce anaphylactic reactions in nsLTP-allergic patients. This data suggests that consumption of the investigated commercial pectin products provides no risk for inducing severe reactions in nsLTP-allergic patients.

Published
2021
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20. Stimulation of naïve B cells with a fusion protein consisting of <scp>FlaA</scp> and Bet v 1 induces regulatory B cells ex vivo

Author

Alexandra Goretzki, Yen‐Ju Lin, Clara Meier, Britta Dorn, Sonja Wolfheimer, Annette Jamin, Maike Schott, Andrea Wangorsch, Stefan Vieths, Thilo Jakob, Stephan Scheurer, and Stefan Schülke

Subjects
Immunology, Immunology and Allergy
Abstract

The experimental fusion protein rFlaA:Betv1 was shown to efficiently suppress allergen-specific sensitization in mice. However, the detailed mechanism of rFlaA:Betv1-mediated immune modulation is not fully understood. In this study, we investigated the effect of rFlaA:Betv1 on naïve murine B cells.Immune modulating capacity of rFlaA:Betv1 was screened in IL-10 reporter mice. B cells were isolated from spleens of naïve C57Bl/6, TLR5Upon in vivo application of rFlaA:Betv1 into IL-10-GFP reporter mice, CD19rFlaA:Betv1 can act as a thymus-independent B cell antigen, stimulating the mTOR- and MyD88-dependent differentiation of B cells displaying a regulatory phenotype, IL-10 secretion, antigen-binding antibody production, and a suppressive capacity in vitro.

Published
2022

21. FcγRIIA-specific DARPins as novel tools in blood cell analysis and platelet aggregation

Author

Vanessa Riechert, Sascha Hein, Mayken Visser, Mathias Zimmermann, Jan Wesche, Philipp A. Adams, Samuel A. Theuerkauf, Arezoo Jamali, Andrea Wangorsch, Andreas Reuter, Alexander O. Pasternak, Jessica Hartmann, Andreas Greinacher, Elena Herrera-Carrillo, Ben Berkhout, Klaus Cichutek, Christian J. Buchholz, Experimental Immunology, Medical Microbiology and Infection Prevention, AII - Infectious diseases, and AII - Inflammatory diseases

Subjects
DARPin, binding site, Fc receptors, HIV, Cell Biology, Molecular Biology, Biochemistry, surface plasmon resonance, thrombocytes
Abstract

Fc receptors are involved in a variety of physiologically and disease-relevant responses. Among them, FcγRIIA (CD32a) is known for its activating functions in pathogen recognition and platelet biology, and, as potential marker of T lymphocytes latently infected with HIV-1. The latter has not been without controversy due to technical challenges complicated by T-B cell conjugates and trogocytosis as well as a lack of antibodies distinguishing between the closely related isoforms of FcγRII. To generate high-affinity binders specific for FcγRIIA, libraries of designed ankyrin repeat proteins (DARPins) were screened for binding to its extracellular domains by ribosomal display. Counterselection against FcγRIIB eliminated binders cross-reacting with both isoforms. The identified DARPins bound FcγRIIA with no detectable binding for FcγRIIB. Their affinities for FcγRIIA were in the low nanomolar range and could be enhanced by cleavage of the His-tag and dimerization. Interestingly, complex formation between DARPin and FcγRIIA followed a two-state reaction model, and discrimination from FcγRIIB was based on a single amino acid residue. In flow cytometry, DARPin F11 detected FcγRIIA+ cells even when they made up less than 1% of the cell population. Image stream analysis of primary human blood cells confirmed that F11 caused dim but reliable cell surface staining of a small subpopulation of T lymphocytes. When incubated with platelets, F11 inhibited their aggregation equally efficient as antibodies unable to discriminate between both FcγRII isoforms. The selected DARPins are unique novel tools for platelet aggregation studies as well as the role of FcγRIIA for the latent HIV-1 reservoir.

Published
2023

22. Abstracts from the Food Allergy and Anaphylaxis Meeting 2016

Author

Guillaume Pouessel, Claire Claverie, Julien Labreuche, Jean-Marie Renaudin, Aimée Dorkenoo, Mireille Eb, Anne Moneret-Vautrin, Antoine Deschildre, Stephane Leteurtre, Linus Grabenhenrich, Margitta Worm, Sabine Dölle, Kathrin Scherer, Isidor Hutteger, Morten Christensen, Carsten Bindslev-Jensen, Charlotte Mortz, Esben Eller, Henrik Fomsgaard Kjaer, Leonor Carneiro-Leão, Jenny Badas, Alice Coimbra, Dikla Pivko Levy, Moshe Ben-Shoshan, Ayelet Rimon, Shira Benor, Nicolette J. T. Arends, Nikki Edelbroek, Hans de Groot, Joyce A. M. Emons, H. Kim A. Brand, Dirk Verhoeven, Leonieke N. van Veen, Nicolette W. de Jong, Geunwoong Noh, Eun Ha Jang, Mariona Pascal, Olga Dominguez, Mònica Piquer, Montserrat Alvaro, Rosa Jimenez-Feijoo, Jaime Lozano, Adriana Machinena, Maria del Mar Folqué, Maria Teresa Giner, Ana María Plaza, Paul Turner, Nandinee Patel, Marta Vazquez-Ortiz, Sarah Lindsley, Lucy Walker, Simon Rosenberg, Adriano Mari, Claudia Alessandri, Ivana Giangrieco, Lisa Tuppo, Chiara Rafaiani, Georg Mitterer, Michela Ciancamerla, Rosetta Ferrara, Maria Livia Bernardi, Danila Zennaro, Maurizio Tamburrini, Maria Antonetta Ciardiello, Christian Harwanegg, Antonio Fernandez, Regina Selb, Philippe Egenmann, Michelle Epstein, Karin Hoffmann-Sommergruber, Frits Koning, Martinus Lovik, E. N. Clare Mills, Javier Moreno, Henk van Loveren, Jean-Michel Wal, Susanne Diesner, Cornelia Bergmayr, Barbara Pfitzner, Vera Elisabeth Assmann, Philipp Starkl, David Endesfelder, Thomas Eiwegger, Zsolt Szepfalusi, Heinz Fehrenbach, Erika Jensen-Jarolim, Anton Hartmann, Isabella Pali-Schöll, Eva Untersmayr, Soren Wille, Peter Meyer, Caroline Klingebiel, Jonas Lidholm, Angelica Ehrenberg, Jonas Östling, Isabelle Cleach, Jean-Louis Mège, Joana Vitte, Roberta Aina, Pawel Dubiela, Sabine Pfeifer, Merima Bublin, Christian Radauer, Piotr Humeniuk, Stefan Kabasser, Riccardo Asero, Gador Bogas, Francisca Gomez, Paloma Campo, Maria Salas, Inmaculada Doña, Esther Barrionuevo, Maria Auxiliadora Guerrero, Cristobalina Mayorga, Ana Prieto, Domingo Barber, Maria Jose Torres, Annette Jamin, Andrea Wangorsch, Barbara Ballmer, Stefan Vieths, Stephan Scheurer, Danijela Apostolovic, Jelena Mihailovic, Maja Krstic, Maria Starkhammar, Tanja Cirkovic Velickovic, Carl Hamsten, Marianne van Hage, Francine C. van Erp, Edward F. Knol, Hannah M. Kansen, Bo Pontoppidan, Yolanda Meijer, Cornelis K. van der Ent, André C. Knulst, Rebekah Sayers, Helen Brown, Adnan Custovic, Angela Simpson, Claire Mills, Juliane Schulz, Network for Online Registration of Anaphylaxis (NORA), Jaap Akkerdaas, Muriel Totis, Annabelle Capt, Corinne Herouet-Guicheney, Ronald van Ree, Tushar Banerjee, Antima Banerjee, Mathilde Claude, Grégory Bouchaud, Roberta Lupi, Laure Castan, Olivier Tranquet, Sandra Denery-Papini, Marie Bodinier, Chantal Brossard, Rosella De Poi, Elisa Gritti, Emiliano De Dominicis, Bert Popping, Patrizia Polverino de Laureto, Kati Palosuo, Anna Kaarina Kukkonen, Anna Pelkonen, Mika Mäkelä, Nanju Alice Lee, Johanna Rost, Sridevi Muralidharan, Dianne Campbell, Sam Mehr, Catherine Nock, Joseph Baumert, Steve Taylor, Carla Mastrorilli, Salvatore Tripodi, Carlo Caffarelli, Serena Perna, Andrea Di Rienzo Businco, Ifigenia Sfika, Arianna Dondi, Annamaria Bianchi, Carlotta Povesi Dascola, Giampaolo Ricci, Francesca Cipriani, Nunzia Maiello, Michele Miraglia del Giudice, Tullio Frediani, Simone Frediani, Francesco Macrì, Chiara Pistoletti, Iride Dello Iacono, Maria Francesca Patria, Elena Varin, Diego Peroni, Pasquale Comberiati, Loredana Chini, Viviana Moschese, Sandra Lucarelli, Roberto Bernardini, Giuseppe Pingitore, Umberto Pelosi, Roberta Olcese, Matteo Moretti, Anastasia Cirisano, Diego Faggian, Alessandro Travaglini, Mario Plebani, Maria Carmen Verga, Mauro Calvani, Paolo Giordani, Paolo Maria Matricardi, Noe Ontiveros, Francisco Cabrera-Chavez, Julie Galand, Etienne Beaudouin, The Anaphylaxis Working Group of the French Allergology SocietyThe Anaphylaxis Working Group of the French Allergology Society, Florence Pineau, Shinobu Sakai, Kayoko Matsunaga, Reiko Teshima, Colette Larré, Sandra Denery, Sebastian Tschirner, Valérie Trendelenburg, Gabriele Schulz, Bodo Niggemann, Kirsten Beyer, Youcef Bouferkas, Younes Belabbas, Djamel Saidi, Omar Kheroua, Kamel Eddine El Mecherfi, Malika Guendouz, Abir Haddi, Hanane Kaddouri, Luis Amaral, Ana Pereira, Susana Rodrigues, Mareen Datema, Laurian Jongejan, Michael Clausen, Andre Knulst, Nikolaos Papadopoulos, Marek Kowalski, Frédéric de Blay, Aeilko Zwinderman, Karin Hoffman-Sommergruber, Barbara Ballmer-Weber, Montserrat Fernandez-Rivas, Shan Deng, Jia Yin, Charlotte Eisenmann, Maria Nassiri, Rabea Reinert, Johanna P. M. van der Valk, Roy Gerth van Wijk, Yvonne Vergouwe, Ewout W. Steyerberg, Marit Reitsma, Harry J. Wichers, Huub F. J. Savelkoul, Berber Vlieg-Boerstra, Anthony E. J. Dubois, Fabrícia Carolino, Ana Rodolfo, Josefina Cernadas, Dasha Roa-Medellín, Ana Rodriguez-Fernandez, Joaquín Navarro, Vicente Albendiz, María Luisa Baeza, Sonsoles Intente-Herrero, Andrea Mikkelsen, Kirsten Mehlig, Lauren Lissner, Linda Verrill, Stefano Luccioli, Jolanda van Bilsen, Frieke Kuper, André Wolterbeek, Tanja Rouhani Rankouhi, Lars Verschuren, Hilde Cnossen, Prescilla Jeurink, Johan Garssen, Léon Knippels, Jossie Garthoff, Geert Houben, Winfried Leeman, M. Eleonore Pettersson, Afke M. M. Schins, Gerard H. Koppelman, Boudewjin J. Kollen, Svitlana Zubchenko, Sarah Kuntz, Pablo Mérida, Montserrat Álvaro, Monica Piquer, Carmen Riggioni, Juan Heber Castellanos, Rosa Jimenez, Melanie Cap, Elodie Drumez, Stéphanie Lejeune, Caroline Thumerelle, Clémence Mordacq, Véronique Nève, Sonia Ricò, Margherita Varini, Rita Nocerino, Linda Cosenza, Antonio Amoroso, Margherita Di Costanzo, Carmen Di Scala, Giorgio Bedogni, Roberto Berni Canani, Paul J. Turner, Paloma Poza-Guedes, Ruperto González-Pérez, Inmaculada Sánchez-Machín, Victor Matheu-Delgado, Erik Wambre, Anne-Sofie Ballegaard, Charlotte Madsen, Juliane Gregersen, Katrine Lindholm Bøgh, Philippe Aubert, Michel Neunlist, Antoine Magnan, Daniel Lozano-Ojalvo, Alba Pablos-Tanarro, Leticia Pérez-Rodríguez, Elena Molina, Rosina López-Fandiño, Akila Rekima, Patricia Macchiaverni, Mathilde Turfkruyer, Sebastien Holvoet, Lénaïck Dupuis, Nour Baiz, Isabella Annesi-Maesano, Annick Mercenier, Sophie Nutten, Valérie Verhasselt, Ines Mrakovcic-Sutic, Srdan Banac, Ivana Sutic, Zdenka Baricev-Novakovic, Ingrid Sutic, Valentino Pavisic, Rosa Muñoz-Cano, Teodoríkez Jiménez-Rodríguez, Daniel Corbacho, Jordi Roca-Ferrer, Joan Bartra, Aleksandar Bulog, Vladimir Micovic, Lidia Markiewicz, Agata Szymkiewicz, Anna Szyc, Barbara Wróblewska, Bryan M. Harvey, Lucien F. Harthoorn, A. Wesley Burks, Georgios Rentzos, Anna-Lena Bramstång Björk, Ulf Bengtsson, Colin Barber, Chrystyna Kalicinsky, Christine Breynaert, Lieve Coorevits, Cornelia Jansen, Erna Van Hoeyveld, Kristin Verbeke, Anne-Marie Kochuyt, Rik Schrijvers, Diana Deleanu, Adriana Muntean, Maria Konstantakopoulou, Maria Pasioti, Anastasia Papadopoulou, Anna Iliopoulou, Nikolaos Mikos, Evangelia Kompoti, Eunice Dias de Castro, Borja Bartalomé, Kok Loong Ue, Elizabeth Griffiths, Stephen Till, Kate Grimshaw, Graham Roberts, Anna Selby, Indre Butiene, Jose Ignacio Larco, Ruta Dubakiene, Ana Fiandor, Alessandro Fiocchi, Nikos Papadopoulos, Sigurveig Sigurdardottir, Aline Sprikkelman, Anne-Fleur Schoemaker, Paraskevi Xepapadaki, Thomas Keil, Zizi Cojocariu, Beatriz Secades Barbado, Vasti Iancu, Esozia Arroabarren, Marta Goñi Esarte, Miren Arteaga, Mayra Coutinho Andrade, Denise Borges, Jorge Kalil, Pedro Giavina Bianchi, Rosana Camara Agondi, Rinkesh Kumar Gupta, Akanksha Sharma, Kriti Gupta, Mukul Das, Premendra Dwivedi, Rusudan Karseladze, Liana Jorjoliani, Lali Saginadze, Mariam Tskhakaia, Katia Basello, Gabriele Piuri, Attilio Francesco Speciani, Michela Carola Speciani, Carla Camerotto, Francesco Zinno, Olga Pakholchuk, Svitlana Nedelska, Stefano Pattini, Maria Teresa Costantino, Silvia Peveri, Danilo Villalta, Eleonora Savi, Andrea Costanzi, Vera A. Revyakina, Marina A. Kiseleva, Elena D. Kuvshinova, Inna A. Larkova, Anton A. Shekhetov, Diana Silva, André Moreira, José Plácido, Hanneke van der Kleij, Esther van Twuijver, Robbert Sutorius, Pieter-Jan de Kam, Jenny van Odijk, Helen Lindqvist, Elin Lustig, Amyra Ali Azamar Jácome, Karla Leversia Borjas Aguilar, Miguel García Domínguez, David Alejandro Mendoza Hernández, Cristiano Caruso, Cono Casale, Gian Lodovico Rapaccini, Antonino Romano, Italo De Vitis, Renata R. Cocco, Carolina Aranda, Marcia C. Mallozi, Jackeline F. Motta, Lilian Moraes, Antonio Pastorino, Nelson Rosario, Ekaterini Goudouris, Arnaldo Porto, Neusa F. Wandalsen, Emanuel Sarinho, Flavio Sano, Dirceu Solé, Constantinos Pitsios, Maria Petrodimopoulou, Ekaterini Papadopoulou, Maria Passioti, Meropi Kontogianni, Nino Adamia, Ekaterina Khaleva, Ana Prieto del Prado, George Du Toit, Edyta Krzych, Urszula Samolinska-Zawisza, Konrad Furmanczyk, Aneta Tomaszewska, Filip Raciborski, Agnieszka Lipiec, Piotr Samel-Kowalik, Artur Walkiewicz, Jacek Borowicz, Boleslaw Samolinski, Aimee Lou Nano, Marysia Recto, Maria Luisa Somoza, Natalia Blanca López, Diana Pérez Alzate, Francisco Javier Ruano, Maria Isabel Garcimartín, Elisa Haroun, Maria Vázquez de la Torre, Antonia Rojas, Montserrat López Onieva, Gabriela Canto, Alexandra Rodrigues, Andreia Forno, António Jorge Cabral, Rute Gonçalves, Ilya Vorozhko, Tatyana Sentsova, Olga Chernyak, Svetlana Denisova, Lidia Ilènko, Valery Muhortnich, Caroline Zimmermann, Alexander Rohrbach, Faisal R. Bakhsh, Kollen Boudewijn, Anne-Marie Oomkes-Pilon, Dorien Van Ginkle, Mira Šilar, Anja Jeverica, Tina Vesel, Tadej Avčin, Peter Korošec, Johanna van der Valk, Irene Berends, Nicolette Arends, Maurits van Maaren, Harry Wichers, Joyce Emons, Anthony Dubois, Nicolette de Jong, Oksana Matsyura, Lesya Besh, Chung-Hsiung Huang, Tong-Rong Jan, Gary Stiefel, Jean Tratt, Kerrie Kirk, Fabricia Carolino, Stefania Arasi, Lucia Caminiti, Giuseppe Crisafulli, Chiara Fiamingo, Jlenia Fresta, Giovanni Pajno, Ben Remington, Astrid Kruizinga, W. Marty Blom, Joost Westerhout, Sabina Bijlsma, Joe Baumert, Mark Blankestijn, Henny Otten, Rob Klemans, Anouska D. Michelsen-Huisman, Harmieke van Os-Medendorp, Astrid G. Kruizinga, Astrid Versluis, Gert van Duijn, H. Mary-Lene de Zeeuw-Brouwer, Jacqueline J. M. Castenmiller, Hub P. J. M. Noteborn, Geert F. Houben, Kristian Bravin, David Luyt, Bushra Javed, Phil Couch, Christopher Munro, Phil Padfield, Matt Sperrin, Aideen Byrne, Lizalet Oosthuizen, Carina Kelleher, Fiona Ward, Niamh Brosnan, Graham King, Eva Corbet, Josué Alejandro Huertas Guzmán, Montserrat Bosque García, Oscar Asensio, Laura Valdesoiro Navarrete, Helena Larramona, Xavier Domingo Miró, Katarzyna Pyrz, Moira Austin, Yanne Boloh, Philip Couch, Deirdre Galloway, Pilar Hernandez, Jonathan O’B. Hourihane, Fiona Kenna, Barbara Majkowska-Wojciechowska, Lynne Regent, Marina Themisb, Sabine Schnadt, Aida Semic-Jusufagic, Audrey Dunn Galvin, Tiina Kauppila, Mikael Kuitunen, Nikolaos A. Kitsioulis, Nikolaos Douladiris, Sofia Kostoudi, Ioanna Manolaraki, Dimitris Mitsias, Emmanouil Manousakis, Nikolaos G. Papadopoulos, Rebecca Knibb, Jennifer Hammond, Richard Cooke, Jaakko Yrjänä, Anna-Maija Hanni, Päivi Vähäsarja, Oona Mustonen, Teija Dunder, Petri Kulmala, Eva Lasa, Carmen D’Amelio, Sara Martínez, Alejandro Joral, Gabriel Gastaminza, Maria Jose Goikoetxea, David C. A. Candy, Marleen T. J. Van Ampting, Manon M. Oude Nijhuis, Assad M. Butt, Diego G. Peroni, Adam T. Fox, Jan Knol, Louise J. Michaelis, Ines Padua, Patricia Padrao, Pedro Moreira, Renata Barros, Hanan Sharif, Manzoor Ahmed, Nehad Gomaa, Joris Mens, Koen Smit, Frans Timmermans, Tomaž Poredoš, Anja Koren Jeverica, Marjeta Sedmak, Evgen Benedik, Meta Accetto, Mirjana Zupančič, Glauce Yonamine, Gustavo Soldateli, Bruna Aquilante, Antonio Carlos Pastorino, Cleonir Lui de Moraes Beck, Andrea Keiko Gushken, Mayra de Barros Dorna, Cristiane Nunes dos Santos, Ana Paula Moschione Castro, Abdulhadi Al-Qahtani, Rand Arnaout, Agha Rehan Khaliq, Rashid Amin, Farrukh Sheikh, Jorge Alvarez, Marta Anda, Miriam Palacios, Montserrat De Prada, Carmen Ponce, Bianca Balbino, Riccardo Sibilano, Thomas Marichal, Nicolas Gaudenzio, Hajime Karasuyama, Pierre Bruhns, Mindy Tsai, Laurent L. Reber, Stephen J. Galli, Ana Reis Ferreira, Josefina R. Cernadas, Aida del Campo García, Sara Pereiro Fernández, Nerea Sarmiento Carrera, Fernando Bandrés Sánchez-Cruz, José Ramón Fernández Lorenzo, Stephanie Claus, Claudia Pföhler, Franziska Ruëff, Regina Treudler, Mercedes Escarrer Jaume, Agustin Madroñero, Maria Teresa Guerra Perez, Juan Carlos Julia, Charlotte Hands Plovdiv, Lee Gethings, Jim Langridge, Karine Adel-Patient, Hervé Bernard, Ivona Barcievic-Jones, Raditsa Sokolova, Rumyana Yankova, Mariya Ivanovska, Marianna Murdjeva, Tatyana Popova, Svetlan Dermendzhiev, Martin Karjalainen, Ulrike Lehnigk, Duncan Brown, Julie C. Locklear, Julie Locklear, Ioana Maris, Jonathan Hourihane, Cristina Ornelas, Joana Caiado, Manuel Branco Ferreira, Manuel Pereira-Barbosa, Yolanda Puente, Juan Carlos Daza, Francisco Javier Monteseirin, Natalia Ukleja-Sokolowska, Ewa Gawronska-Ukleja, Magdalena Zbikowska-Gotz, Zbigniew Bartuzi, Lukasz Sokolowski, Aine Adams, Bernard Mahon, Karen English, Nelly Gourdon-Dubois, Laetitia Sellam, Bruno Pereira, Elodie Michaud, Khaled Messaoudi, Bertrand Evrard, Jean-Luc Fauquert, Francisca Palomares, Gador Gomez, Maria Jose Rodriguez, Luisa Galindo, Ana Molina, Lorella Paparo, Maurizio Mennini, Rosita Aitoro, Adam Wawrzeńczyk, Michał Przybyszewski, Anna Wawrzeńczyk, Hulya Ercan Sarıcoban, Meltem Ugras, Zerrin Yalvac, Bertine M. J. Flokstra-de Blok, J. L. van der Velde, Andrea Vereda, Clara Ippolito, Amaranta Traversa, Daniela Adriano, Daniela Manila Bianchi, Silvia Gallina, Lucia Decastelli, Melina Makatsori, Anne Miles, Sonja Posega Devetak, Iztok Devetak, Soraya Ainad Tabet, Jeanette Fisker Trandbohus, Pernille Winther, Hans-Jørgen Malling, Kirsten Skamstrup Hansen, Lene Heise Garvey, Chia-Chi Wang, Yin-Hua Cheng, Chun-Wei Tung, Mariola Dietrich, Ingo Marenholz, Birgit Kalb, Sarah Grosche, Katharina Blümchen, Rupert Schlags, Mareike Price, Sylke Rietz, Jorge Esparza-Gordillo, Susanne Lau, Young-Ae Lee, Ali Almontasheri, Mohammad Al Bahkali, Sahar Elshorbagi, Abdullah Alfhaid, Mashary Altamimi, Eman Madbouly, Hassan Al-Dhekri, Rand K. Arnaout, Maria Basagaña, Sira Miquel, Borja Bartolomé, Bettina Brix, Stefanie Rohwer, Sandra Brandhoff, Alena Berger, Waltraud Suer, Alf Weimann, Cristina Bueno, Laura Martín-Pedraza, Sara Abián, Pablo San Segundo-Acosta, Juan Carlos López-Rodríguez, Rodrigo Barderas, Eva Batanero, Javier Cuesta-Herranz, María Teresa Villalba, Magna Correia, Filipe Benito-Garcia, Cristina Arêde, Susana Piedade, Mário Morais-Almeida, James Hindley, Ross Yarham, Anna Kuklinska-Pijanka, David Gillick, Karine Patient, Martin D. Chapman, Katrine L. Bøgh, Ana Miranda, Eugénia Matos, Anna Sokolova, Huan Rao, Ivona Baricevic-Jones, Frances Smith, Wentong Xue, Helga Magnusdottir, Anna G. Vidarsdottir, Sigrun Lund, Anders Blom Jensen, Bjorn R. Ludviksson, Reyna Simon, Robert Elfont, Sean Bennett, Robert Voyksner, Maria de Lurdes Torre, Songül Yürek, Margaretha A. Faber, Annick Bastiaensen, Evelyne Mangodt, Athina van Gasse, Ine Decuyper, Vito Sabato, Margo M. Hagendorens, Chris H. Bridts, Luc S. De Clerck, Didier Ebo, Susanne Schwarz, Mandy Ziegert, Saskia Albroscheit, Christian Schwager, Skadi Kull, Jochen Behrends, Niels Röckendorf, Frauke Schocker, Andreas Frey, Arne Homann, Wolf-Meinhard Becker, Uta Jappe, Nesrine Zaabat, Sylvia Osscini, Chantal Agabriel, Benoît Sterling, Ania Carsin, Valérie Liabeuf, Monica Maćków, Alina Zbróg, Monica Bronkowska, Justine Courtois, Romy Gadisseur, Catherine Bertholet, Pierre Lukas, Etienne Cavalier, Philippe Delahaut, Birgit Quinting, Margareta Brandt Gertmo, Ewa Ternesten Hasseus, Vladyslava Barzylovych, Júlio Oliveira, Luis F. Ensina, Carolina S. Aranda, Leire Dopazo, Rebeca Lopez, Raquel Perez, Laura Santos-Diez, Agurtzane Bilbao, Juan Miguel Garcia, Ignacio García Núñez, María Ángeles Algaba Mármol, María José Barasona Villarejo, José Antonio Bácter Martos, Marina Suárez Vergara, José María Ignacio García, Agata Michalska, Grzegorz Sergiejko, Robert Zacniewski, Ileana-Maria Ghiordanescu, Cristina Deaconu, Mihaela Popescu, Roxana Silvia Bumbacea, Alkerta Ibranji, Elida Nikolla, Gjustina Loloci, Nanna Juel-Berg, Lau Fabricius Larsen, Lars Kjaergaard Poulsen, João Marcelino, Ricardo Prata, Ana Célia Costa, Fátima Duarte, Marta Neto, Jennifer Santos, Luís Câmara Pestana, Daniel Sampaio, Paola Minale, Paola Dignetti, Donatella Bignardi, Irena Nedelea, Florin-Dan Popescu, Mariana Vieru, Florin-Adrian Secureanu, Carmen Saviana Ganea, Miguel Vieira, José Pedro Moreira Silva, Timothy Watts, Sophia Watts, Marta Lomikovska, Marina Peredelskaya, Natalia Nenasheva, Ivana Filipovic, Zorica Zivkovic, Djordje Filipovic, Jennette Higgs, Amena Warner, and Carla Jones

Subjects
Immunologic diseases. Allergy, RC581-607
Published
2017
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23. Pru p 10: the polygalacturonase described as a new peach tree pollen allergen

Author

Martín-Pedraza, Laura, primary, Wangorsch, Andrea, additional, Scheurer, Stephan, additional, Rojas, Isabel Torres, additional, Haroun-Diaz, Elisa, additional, Vazquez de La Torre, Maria, additional, Puche, Laura Victorio, additional, Fernandez-Caldas, Enrique, additional, Subiza, Jose Luis, additional, Blanca-Lopez, Natalia, additional, Blanca, Miguel, additional, and Somoza, María Luisa, additional

Published
2023
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25. Immunotherapy with Native Molecule rather than Hypoallergenic Variant of Pru p 3, the Major Peach Allergen, Shows Beneficial Effects in Mice

Author

Maria J. Rodriguez, Andrea Wangorsch, Francisca Gomez, Stefan Schülke, Maria J. Torres, Stefan Vieths, Stephan Scheurer, Masako Toda, and Cristobalina Mayorga

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Background. The use of hypoallergenic derivatives is considered beneficial to promote the safety and efficacy of allergen-specific immunotherapy. We aimed to assess the efficacy of reduced and alkylated (R/A) Pru p 3, a hypoallergenic folding variant of the major peach allergen, in subcutaneous immunotherapy (SCIT) using a murine model of peach allergy. Methods and Results. After sensitization with Pru p 3, BALB/c mice received SCIT with Pru p 3 or R/A Pru p 3 and were challenged with Pru p 3. SCIT with Pru p 3, but not with R/A Pru p 3, suppressed anaphylaxis upon the challenge significantly. SCIT with Pru p 3 did not suppress Pru p 3-specific IgE and IgG1 production, but enhanced IgG2a production. In contrast, SCIT with R/A Pru p 3 suppressed IgE and IgG1 production, but enhanced IgG2a production only moderately. The therapeutic efficacy of SCIT with Pru p 3 was associated with induction of IL-10 and IFN-γ. Conclusion. Hypoallergenic folding variant of Pru p 3 is not likely an efficacious therapeutic component in SCIT of peach allergy. The lower efficacy of R/A Pru p 3 might be attributed to poor antigenicity and/or weak stability due to its unfolded conformation.

Published
2018
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26. Allergenicity and IgE Recognition of New Dau c 1 Allergens from Carrot

Author

Julian M. Hendrich, Andrea Wangorsch, Katharina Rödel, Thessa Jacob, Vera Mahler, and Birgitta M. Wöhrl

Subjects
Food Science, Biotechnology
Abstract

Carrot (Daucus carota) allergy is caused by the major carrot allergen Dau c 1, which is a mixture of several isoallergens and variants with sequence identities of67% or90%, respectively. However, little is known about the qualitative and quantitative composition of natural Dau c 1.Mass spectrometry of isolated natural Dau c 1 reveals the existence of several yet unknown Dau c 1-like proteins. The study expresses four Dau c 1-like proteins in Escherichia coli. Two of the purified proteins, designated Dau c 1.0501 and 1.0601, exhibit sequence identities to Dau c 1.0101 and 1.0401 between 54% and 87%. They possess allergenic potential and are accepted as new isoallergens. One protein, designated as Dau c 1-like is50% identical with the new isoallergens but exhibits no allergenicity. Sequence and structural comparisons of this protein with the known Dau c 1 isoallergens offer relevant clues about putative structural IgE epitopes.Identification of new isoallergens and the identification of IgE epitopes may contribute to a more refined component resolved diagnosis and may lay ground for further epitope mapping and personalized targeted treatment approaches of carrot allergy in preclinical and clinical studies.

Published
2022

27. Stimulation of naïve B cells with a fusion protein consisting of FlaA and Bet v 1 induces regulatory B cells ex vivo

Author

Goretzki, Alexandra, primary, Lin, Yen‐Ju, additional, Meier, Clara, additional, Dorn, Britta, additional, Wolfheimer, Sonja, additional, Jamin, Annette, additional, Schott, Maike, additional, Wangorsch, Andrea, additional, Vieths, Stefan, additional, Jakob, Thilo, additional, Scheurer, Stephan, additional, and Schülke, Stefan, additional

Published
2022
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28. A modular systems biological modelling framework studies cyclic nucleotide signaling in platelets

Author

Breitenbach, Tim, primary, Englert, Nils, additional, Osmanoglu, Özge, additional, Rukoyatkina, Natalia, additional, Wangorsch, Gaby, additional, Heinze, Katrin, additional, Friebe, Andreas, additional, Butt, Elke, additional, Feil, Robert, additional, Dittrich, Marcus, additional, Gambaryan, Stepan, additional, and Dandekar, Thomas, additional

Published
2022
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29. Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility

Author

Cécile F. Rousseau, Kristin E. Karlsson, Raphaëlle Lesage, Eulalie Courcelles, Emmanuelle M. Voisin, Francesco Pappalardo, Nuno Curado, Enrico Dall'Ara, Flora T. Musuamba, Gaby Wangorsch, Blanca Rodriguez, Ine Skottheim Rusten, Rossana Alessandrello, Roberta Bursi, Giulia Russo, Luca Emili, Efthymios Manolis, Jean-Pierre Boissel, Liesbet Geris, and Alexander Kulesza

Subjects
Computer science, In silico, Building model, White Paper, Context (language use), RM1-950, Risk Assessment, 030226 pharmacology & pharmacy, VIVO, Terminology, 03 medical and health sciences, 0302 clinical medicine, White paper, Drug Development, Terminology as Topic, Credibility, Humans, Computer Simulation, Pharmacology (medical), Pharmacology & Pharmacy, IDENTIFIABILITY ANALYSIS, 030304 developmental biology, 0303 health sciences, Science & Technology, Management science, Models, Theoretical, EFFICACY, Drug development, Modeling and Simulation, SIMULATION, Arzneimittelentwicklung, Therapeutics. Pharmacology, Life Sciences & Biomedicine, MULTISCALE MATHEMATICAL-MODEL, Verification and validation
Abstract

The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk-informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk-based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick-start tool by regulators. Altogether, this white paper provides a practical approach to model evaluation, applicable in both scientific and regulatory evaluation contexts. ispartof: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY vol:10 issue:8 pages:804-825 ispartof: location:United States status: published

Published
2021

30. Targeting of Immune Cells by Dual TLR2/7 Ligands Suppresses Features of Allergic Th2 Immune Responses in Mice

Author

Jonathan Laiño, Andrea Wangorsch, Frank Blanco, Sonja Wolfheimer, Maren Krause, Adam Flaczyk, Tobias-Maximilian Möller, Mindy Tsai, Stephen Galli, Stefan Vieths, Masako Toda, Stephan Scheurer, and Stefan Schülke

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Background. TLR ligands can promote Th1-biased immune responses, mimicking potent stimuli of viruses and bacteria. Aim. To investigate the adjuvant properties of dual TLR2/7 ligands compared to those of the mixture of both single ligands. Methods. Dual TLR2/7 ligands: CL401, CL413, and CL531, including CL264 (TLR7-ligand) and Pam2CysK4 (TLR2-ligand), were used. Immune-modulatory capacity of the dual ligands with the individual ligands alone or as a mixture in mouse BMmDCs, BMmDC:TC cocultures, or BMCMCs was compared and assessed in naïve mice and in a mouse model of OVA-induced intestinal allergy. Results. CL413 and CL531 induced BMmDC-derived IL-10 secretion, suppressed rOVA-induced IL-5 secretion from OVA-specific DO11.10 CD4+ TCs, and induced proinflammatory cytokine secretion in vivo. In contrast, CL401 induced considerably less IL-10 secretion and led to IL-17A production in BMmDC:TC cocultures, but not BMCMC IL-6 secretion, or IL-6 or TNF-α production in vivo. No immune-modulating effects were observed with single ligands. All dual TLR2/7 ligands suppressed DNP-induced IgE-and-Ag-specific mast cell degranulation. Compared to vaccination with OVA, vaccination with the mixture CL531 and OVA, significantly suppressed OVA-specific IgE production in the intestinal allergy model. Conclusions. Based on beneficial immune-modulating properties, CL413 and CL531 may have utility as potential adjuvants for allergy treatment.

Published
2017
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31. Identification of a defensin as novel allergen in celery root: Api g 7 as a missing link in the diagnosis of celery allergy?

Author

Wangorsch, Andrea; https://orcid.org/0000-0002-5184-5455, Lidholm, Jonas; https://orcid.org/0000-0002-7779-3411, Mattsson, Lars A, Larsson, Håkan, Reuter, Andreas, Gubesch, Michaela, Gadermaier, Gabriele; https://orcid.org/0000-0002-4886-417X, Bures, Peter, Scheurer, Stephan; https://orcid.org/0000-0002-2859-562X, Ballmer-Weber, Barbara; https://orcid.org/0000-0002-4136-5036, Vieths, Stefan, Wangorsch, Andrea; https://orcid.org/0000-0002-5184-5455, Lidholm, Jonas; https://orcid.org/0000-0002-7779-3411, Mattsson, Lars A, Larsson, Håkan, Reuter, Andreas, Gubesch, Michaela, Gadermaier, Gabriele; https://orcid.org/0000-0002-4886-417X, Bures, Peter, Scheurer, Stephan; https://orcid.org/0000-0002-2859-562X, Ballmer-Weber, Barbara; https://orcid.org/0000-0002-4136-5036, and Vieths, Stefan

Published
2022

32. Stimulation of naïve B cells with a fusion protein consisting of FlaA and Bet v 1 induces regulatory B cells ex vivo.

Author

Goretzki, Alexandra, Lin, Yen‐Ju, Meier, Clara, Dorn, Britta, Wolfheimer, Sonja, Jamin, Annette, Schott, Maike, Wangorsch, Andrea, Vieths, Stefan, Jakob, Thilo, Scheurer, Stephan, and Schülke, Stefan

Subjects
REGULATORY B cells, B cells, CHIMERIC proteins, CELL fusion, IMMUNOREGULATION, ANTIBODY formation
Abstract

Background: The experimental fusion protein rFlaA:Betv1 was shown to efficiently suppress allergen‐specific sensitization in mice. However, the detailed mechanism of rFlaA:Betv1‐mediated immune modulation is not fully understood. In this study, we investigated the effect of rFlaA:Betv1 on naïve murine B cells. Methods: Immune modulating capacity of rFlaA:Betv1 was screened in IL‐10 reporter mice. B cells were isolated from spleens of naïve C57Bl/6, TLR5−/−, or MyD88−/− mice, stimulated with rFlaA:Betv1 and controls, and monitored for the expression of the regulatory B cell markers CD1d, CD24, CD38, and surface IgM by flow cytometry. Secreted cytokines, antibodies, and reactivity of the induced antibodies were investigated by ELISA and intracellular flow cytometry. Suppressive capacity of rFlaA:Betv1‐stimulated B cells was tested in mDC:CD4+ T cell:B cell triple cultures. Results: Upon in vivo application of rFlaA:Betv1 into IL‐10‐GFP reporter mice, CD19+ B cells were shown to produce anti‐inflammatory IL‐10, suggesting B cells to contribute to the immune‐modulatory properties of rFlaA:Betv1. rFlaA:Betv1‐induced IL‐10 secretion was confirmed in human B cells isolated from buffy coats. In vitro stimulation of naïve murine B cells with rFlaA:Betv1 resulted in an mTOR‐ and MyD88‐dependent production of IL‐10 and rFlaA:Betv1 induced Bet v 1‐reactive IgG production, which was not observed for IgA. rFlaA:Betv1‐stimulated B cells formed a CD19+CD24+CD1d+IgM+CD38+ Breg subpopulation capable of suppressing Bet v 1‐induced TH2 cytokine secretion in vitro. Conclusion: rFlaA:Betv1 can act as a thymus‐independent B cell antigen, stimulating the mTOR‐ and MyD88‐dependent differentiation of B cells displaying a regulatory phenotype, IL‐10 secretion, antigen‐binding antibody production, and a suppressive capacity in vitro. [ABSTRACT FROM AUTHOR]

Published
2023
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34. Allergenic Properties and Molecular Characteristics of PR-1 Proteins

Author

Wangorsch, Andrea, scheurer, stephan, Blanca, Miguel, Blanca-lopez, Natalia, Somoza, Maria Luisa, and Martín-Pedraza, Laura

Subjects
allergy diagnosis, immune system diseases, pathogenesis-related protein-1, otorhinolaryngologic diseases, Allergie, PR-1, allergen, occupational allergy, food and beverages, Immunologic diseases. Allergy, RC581-607, respiratory system, respiratory tract diseases
Abstract

Only a small fraction of proteins in plants and animals are classified as allergens. The allergenic properties are frequently attributed to certain functional characteristics of the proteins, such as a role in the plant defense against biotic and abiotic stress, to achieve the systematic acquired resistance. In line with this, eight members out of 17 functional pathogenesis-related (PR) protein families have been characterized as allergens. The present review summarizes the molecular features and allergenic significance of allergens of the PR-1 family. Not many allergens have been identified as belonging to this protein family, with most of them having a pollen origin, like mugwort or Bermuda grass. Molecular and structural features of allergenic PR-1 proteins are discussed and attributed to their IgE-reactive properties, clinical manifestation, and cross-reactivity among different foods and inhalants.

Published
2022

35. Pru p 10: the polygalacturonase described as a new peach tree pollen allergen

Author

Laura Martín-Pedraza, Andrea Wangorsch, Stephan Scheurer, Isabel Torres Rojas, Elisa Haroun-Diaz, Maria Vazquez de La Torre, Laura Victorio Puche, Enrique Fernandez-Caldas, Jose Luis Subiza, Natalia Blanca-Lopez, Miguel Blanca, and María Luisa Somoza

Subjects
Immunology, Immunology and Allergy
Published
2023

36. Author Correction: Conjugation of wildtype and hypoallergenic mugwort allergen Art v 1 to flagellin induces IL-10-DC and suppresses allergen-specific TH2-responses in vivo

Author

Stefan Schülke, Kirsten Kuttich, Sonja Wolfheimer, Nadine Duschek, Andrea Wangorsch, Andreas Reuter, Peter Briza, Isabel Pablos, Gabriele Gadermaier, Fatima Ferreira, Stefan Vieths, Masako Toda, and Stephan Scheurer

Subjects
Medicine, Science
Abstract

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Published
2018
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37. Identification of a defensin as novel allergen in celery root: Api g 7 as a missing link in the diagnosis of celery allergy?

Author

Wangorsch, Andrea, Lidholm, Jonas, Mattsson, Lars A, Larsson, Håkan, Reuter, Andreas, Gubesch, Michaela, Gadermaier, Gabriele, Bures, Peter, Scheurer, Stephan, Ballmer-Weber, Barbara, Vieths, Stefan, University of Zurich, and Wangorsch, Andrea

Subjects
2403 Immunology, Lebensmittelallergie, Immunology, 10177 Dermatology Clinic, 610 Medicine & health, Allergens, Antigens, Plant, Cross Reactions, Defensins, Hypersensitivity, 2723 Immunology and Allergy, Humans, Immunology and Allergy, Food Hypersensitivity, Apium
Published
2021

38. Allergenicity Analysis of Pru p 9 IgE-epitope: The First Peach Aeroallergen

Author

Martín-Pedraza, Laura, primary, Wangorsch, Andrea, additional, Sanchez, Natalia Perez, additional, Luna, Laura, additional, Jamin, Annette, additional, Fernandez-Caldas, Enrique, additional, Subiza, Jose Luis, additional, Lidholm, Jonas, additional, Haroun, Elisa, additional, de la Torre, María Vazquez, additional, Blanca, Miguel, additional, Cornejo-Garcia, Jose, additional, Scheurer, Stephan, additional, and Somoza, Maria Luisa, additional

Published
2022
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39. Identification of a defensin as novel allergen in celery root: Api g 7 as a missing link in the diagnosis of celery allergy?

Author

Wangorsch, Andrea, primary, Lidholm, Jonas, additional, Mattsson, Lars A., additional, Larsson, Håkan, additional, Reuter, Andreas, additional, Gubesch, Michaela, additional, Gadermaier, Gabriele, additional, Bures, Peter, additional, Scheurer, Stephan, additional, Ballmer‐Weber, Barbara, additional, and Vieths, Stefan, additional

Published
2021
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40. Does the Food Ingredient Pectin Provide a Risk for Patients Allergic to Non-Specific Lipid-Transfer Proteins?

Author

Steigerwald, Hanna, primary, Blanco-Perez, Frank, additional, Albrecht, Melanie, additional, Bender, Caroline, additional, Wangorsch, Andrea, additional, Endreß, Hans-Ulrich, additional, Bunzel, Mirko, additional, Mayorga, Cristobalina, additional, Torres, Maria José, additional, Scheurer, Stephan, additional, and Vieths, Stefan, additional

Published
2021
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46. Aluminium in plasma and tissues after intramuscular injection of adjuvanted human vaccines in rats

Author

Jennifer D Oduro, Kay-Martin Hanschmann, Karin Weisser, Gaby Wangorsch, Thomas Göen, and Brigitte Keller-Stanislawski

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Wet weight, Health, Toxicology and Mutagenesis, medicine.medical_treatment, Aluminum Hydroxide, 010501 environmental sciences, Toxicology, Injections, Intramuscular, 01 natural sciences, Phosphates, 03 medical and health sciences, Animal data, Adjuvants, Immunologic, Whole skeleton, Internal medicine, medicine, Animals, Humans, Toxicokinetics, Tissue Distribution, Rats, Wistar, Aluminum Compounds, Saline, 0105 earth and related environmental sciences, Vaccines, Chemistry, General Medicine, Plasma levels, Rats, 030104 developmental biology, Endocrinology, Area Under Curve, Intramuscular injection, Adjuvant
Abstract

Aluminium (Al) toxicokinetics after intramuscular (IM) injection of Al-adjuvanted vaccines is unknown. Since animal data are required for modeling and extrapolation, a rat study was conducted measuring Al in plasma and tissues after IM injection of either plain Al-hydroxide (pAH) or Al-phosphate (pAP) adjuvant (Al dose 1.25 mg), single human doses of three Al-adjuvanted vaccines (V1, V2, and V3; Al doses 0.5–0.82 mg), or vehicle (saline). A significant increase in Al plasma levels compared to controls was observed after pAP (AUC(0–80 d), mean ± SD: 2424 ± 496 vs. 1744 ± 508 µg/L*d). Percentage of Al dose released from injected muscle until day 80 was higher after pAP (66.9%) and AP-adjuvanted V3 (85.5%) than after pAH and AH-adjuvanted V1 (0 and 22.3%, resp.). Estimated absolute Al release was highest for pAP (836.8 µg per rat). Al concentration in humerus bone was increased in all groups, again strongest in the pAP group [3.35 ± 0.39 vs. 0.05 ± 0.06 µg/g wet weight (ww)]. Extrapolated amounts in whole skeleton corresponded to 5–12% of the released Al dose. Very low brain Al concentrations were observed in all groups (adjuvant group means 0.14–0.29 µg/g ww; control 0.13 ± 0.04 µg/g ww). The results demonstrate systemically available Al from marketed vaccines in rats being mainly detectable in bone. Al release appears to be faster from AP- than AH-adjuvants. Dose scaling to human adults suggests that increase of Al in plasma and tissues after single vaccinations will be indistinguishable from baseline levels.

Published
2019

48. Prevention of intestinal allergy in mice by rflaA:Ova is associated with enforced antigen processing and TLR5-dependent IL-10 secretion by mDC.

Author

Stefan Schülke, Sonja Wolfheimer, Gabriele Gadermaier, Andrea Wangorsch, Susanne Siebeneicher, Peter Briza, Ingo Spreitzer, Dirk Schiller, Bettina Loeschner, Satoshi Uematsu, Bernard Ryffel, Shizuo Akira, Zoe Waibler, Stefan Vieths, Masako Toda, and Stephan Scheurer

Subjects
Medicine, Science
Abstract

Conjugated vaccines consisting of flagellin and antigen activate TLR5 and induce strong innate and adaptive immune responses. Objective of the present study was to gain further insight into the mechanisms by which flagellin fusion proteins mediate their immune modulating effects. In a mouse model of Ova-induced intestinal allergy a fusion protein of flagellin and Ova (rflaA:Ova) was used for intranasal and intraperitoneal vaccination. Aggregation status of flaA, Ova and flaA:Ova were compared by light scattering, uptake of fluorescence labeled proteins into mDC was analyzed, processing was investigated by microsomal digestion experiments. Mechanism of DC-activation was investigated using proteasome and inflammasome inhibitors. Immune responses of wildtype, IL-10(-/-), TLR5(-/-) mDCs and Ova-transgenic T cells were investigated. Mucosal and i.p.-application of rflaA:Ova were able to prevent allergic sensitization, suppress disease-related symptoms, prevent body weight loss and reduction in food uptake. Intranasal vaccination resulted in strongest suppression of Ova-specific IgE production. These protective effects were associated with increased aggregation of rflaA:Ova and accompanied by tenfold higher uptake rates into mDC compared to the mixture of both proteins. Microsomal digestion showed that stimulation with rflaA:Ova resulted in faster degradation and the generation of different peptides compared to rOva. rflaA:Ova-mediated activation of mDC could be suppressed in a dose-dependent manner by the application of both inflammasome and proteasome inhibitors. Using TLR5(-/-) mDC the rflaA:Ova induced IL-10 secretion was shown to be TLR5 dependent. In co-cultures of IL-10(-/-) mDC with DO11.10 T cells the lack of rflaA:Ova-mediated IL-10 secretion resulted in enhanced levels of both TH2 (IL-4, IL-5) and TH1 (IL-2 and IFN-y) cytokines. In summary, mucosal vaccination with flaA:Ova showed strongest preventive effect. Stimulation with rflaA:Ova results in strong immune modulation mediated by enhanced uptake of the aggregated fusion protein, likely resulting in a different processing by DC as well as stronger TLR5 mediated cell activation.

Published
2014
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49. Human monocyte-derived type 1 and 2 macrophages recognize Ara h 1, a major peanut allergen, by different mechanisms

Author

Ger van Zandbergen, Masako Toda, Martin Globisch, Andrea Wangorsch, Peter Crauwels, Jonas Lidholm, Thomas Henle, Frank Blanco-Pérez, Maren Krause, Stefan Vieths, and Stephan Scheurer

Subjects
0301 basic medicine, Small interfering RNA, Arachis, Science, medicine.medical_treatment, media_common.quotation_subject, Cell Plasticity, Monocytes, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Macrophage, Peanut Hypersensitivity, Scavenger receptor, Internalization, Receptor, Plant Proteins, media_common, Gene knockdown, Multidisciplinary, Innate immune system, Chemistry, Macrophages, Membrane Proteins, Allergens, Antigens, Plant, Macrophage Activation, Cell biology, 030104 developmental biology, Cytokine, Medicine, Immunology, Molecular biology, Lebensmittelallergie, Disease Susceptibility, Biomarkers, 030215 immunology
Abstract

Evidence has suggested that major peanut allergen Ara h 1 activates dendritic cells (DCs) via interaction with DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin), a C-type lectin receptor, and contributes to development of peanut allergy. Since macrophages, as well as DCs, play a crucial role in innate immunity, we investigated whether natural Ara h 1 (nAra h 1) activates two different subsets of macrophages, human monocyte derived macrophage type 1 (hMDM1: pro-inflammatory model) and type 2 (hMDM2: anti-inflammatory model). hMDM1 and hMDM2 predominantly produced pro-inflammatory cytokines (IL-6 and TNF-α) and an anti-inflammatory cytokine (IL-10) in response to nAra h 1, respectively. hMDM2 took up nAra h 1 and expressed DC-SIGN at higher levels than hMDM1. However, small interfering RNA knockdown of DC-SIGN did not suppress nAra h 1 uptake and nAra h 1-mediated cytokine production in hMDM2. Inhibitors of scavenger receptor class A type I (SR-AI) suppressed the response of hMDM2, but not of hMDM1, suggesting that SR-AI is a major receptor in hMDM2 for nAra h 1 recognition and internalization. nAra h 1 appears to exert stimulatory capacity on DC and macrophages via different receptors. This study advances our understanding how a major peanut allergen interacts with innate immunity.

Published
2021

50. Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility

Author

Musuamba, Flora T., primary, Skottheim Rusten, Ine, additional, Lesage, Raphaëlle, additional, Russo, Giulia, additional, Bursi, Roberta, additional, Emili, Luca, additional, Wangorsch, Gaby, additional, Manolis, Efthymios, additional, Karlsson, Kristin E., additional, Kulesza, Alexander, additional, Courcelles, Eulalie, additional, Boissel, Jean‐Pierre, additional, Rousseau, Cécile F., additional, Voisin, Emmanuelle M., additional, Alessandrello, Rossana, additional, Curado, Nuno, additional, Dall’ara, Enrico, additional, Rodriguez, Blanca, additional, Pappalardo, Francesco, additional, and Geris, Liesbet, additional

Published
2021
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