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2. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease

Author

Taube, C, Tertilt, C, Gyülveszi, G, Dehzad, N, Kreymborg, K, Schneeweiss, K, Michel, E, Reuter, S, Renauld, J C, Arnold-Schild, D, Schild, H, Buhl, R, Becher, B; https://orcid.org/0000-0002-1541-7867, Taube, C, Tertilt, C, Gyülveszi, G, Dehzad, N, Kreymborg, K, Schneeweiss, K, Michel, E, Reuter, S, Renauld, J C, Arnold-Schild, D, Schild, H, Buhl, R, and Becher, B; https://orcid.org/0000-0002-1541-7867

Abstract

Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22-deficiency led to increased eosinophil infiltration lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung. Mice treated with IL-22 before antigen challenge displayed reduced expression of CCL17 and IL-13 and significant amelioration of airway constriction and inflammation. We conclude that innate IL-22 limits airway inflammation, tissue damage and clinical decline in allergic lung disease.

Published
2011

3. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells

Author

Arnold, I C, Dehzad, N, Reuter, S, Martin, H, Becher, B, Taube, C, Müller, Anne; https://orcid.org/0000-0002-1368-8276, Arnold, I C, Dehzad, N, Reuter, S, Martin, H, Becher, B, Taube, C, and Müller, Anne; https://orcid.org/0000-0002-1368-8276

Abstract

Atopic asthma is a chronic disease of the airways that has taken on epidemic proportions in the industrialized world. The increase in asthma rates has been linked epidemiologically to the rapid disappearance of Helicobacter pylori, a bacterial pathogen that persistently colonizes the human stomach, from Western societies. In this study, we have utilized mouse models of allergic airway disease induced by ovalbumin or house dust mite allergen to experimentally examine a possible inverse correlation between H. pylori and asthma. H. pylori infection efficiently protected mice from airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia, which are hallmarks of asthma, and prevented allergen-induced pulmonary and bronchoalveolar infiltration with eosinophils, Th2 cells, and Th17 cells. Protection against asthma was most robust in mice infected neonatally and was abrogated by antibiotic eradication of H. pylori. Asthma protection was further associated with impaired maturation of lung-infiltrating dendritic cells and the accumulation of highly suppressive Tregs in the lungs. Systemic Treg depletion abolished asthma protection; conversely, the adoptive transfer of purified Treg populations was sufficient to transfer protection from infected donor mice to uninfected recipients. Our results thus provide experimental evidence for a beneficial effect of H. pylori colonization on the development of allergen-induced asthma.

Published
2011

6. The role of IL-22 in allergic airway disease

Author

Dehzad, N, primary, Tertilt, C, additional, Gyülveszi, G, additional, Kreymborg, K, additional, Schneeweiß, K, additional, Michel, E, additional, Reuter, S, additional, Martin, H, additional, Renauld, JC, additional, Buhl, R, additional, Becher, B, additional, and Taube, C, additional

Published
2011
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7. Immunologie I

Author

Staudt, V., primary, Bopp, T., additional, Schmitt, E., additional, Bothur, E., additional, Stein, J., additional, Raker, V., additional, Montermann, E., additional, Maxeiner, J., additional, Taube, C., additional, Grabbe, S., additional, Reske-Kunz, A., additional, Sudowe, S., additional, Reuter, S., additional, Becker, M., additional, Dehzad, N., additional, Martin, H., additional, Waisman, A., additional, Stassen, M., additional, Buhl, R., additional, Gehring, M., additional, Böhm, M., additional, Luger, T., additional, Kapp, A., additional, Raap, U., additional, Gibbs, B. F., additional, Yasinska, I., additional, Oniku, A., additional, Streatfield, C., additional, Sumbayey, V., additional, Hofmann, C., additional, Scheurer, S., additional, Vieths, S., additional, Adler, H., additional, Steinbrink, K., additional, Pföhler, C., additional, Körner, R., additional, Müller, C., additional, Madjidi, D., additional, Preuss, K., additional, Pfreundschuh, M., additional, Vogt, T., additional, Niebuhr, M., additional, Kasraie, S., additional, Baumert, K., additional, Werfel, T., additional, Klein, M., additional, Ulges, A., additional, Schild, H., additional, Seher, T., additional, Mayer, J., additional, Brockow, K., additional, Traidl-Hoffmann, C., additional, Ollert, M., additional, Gutermuth, J., additional, Schmidt-Weber, C., additional, Treudler, R., additional, Chu, C., additional, Simon, J., additional, Hipler, U.-C., additional, Goetze, S., additional, Rahmig, N., additional, Elsner, P., additional, Kamml, M., additional, Öder, S., additional, Alessandrini, F., additional, Braun, A., additional, Ernst, D., additional, Kanter, U., additional, Durner, J., additional, Hauser, M., additional, Ferreira, F., additional, Mempel, M., additional, Behrendt, H., additional, von Bubnoff, D., additional, Sell, U., additional, Hörauf, A., additional, Specht, S., additional, and Bieber, T., additional

Published
2011
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9. Immunologie II

Author

Heydenreich, B., primary, Bellinghausen, I., additional, Henmar, H., additional, Wintzen, P. Adler, additional, Saloga, J., additional, Grabbe, S., additional, Kopfnagel, V., additional, Werfel, T., additional, Wittmann, M., additional, Zopf, Y., additional, Hagel, A., additional, Konturek, P., additional, Kressel, J., additional, Neurath, M., additional, Raithel, M., additional, Kueri, S., additional, Hess, T., additional, Winter, O., additional, Mohr, E., additional, Dame, C., additional, Manz, R., additional, Lingner, S., additional, Maus, U., additional, Pabst, R., additional, Dittrich, A., additional, Martin, H., additional, Reuter, S., additional, Dehzad, N., additional, Heinz, A., additional, Korn, S., additional, Buhl, R., additional, Becker, C., additional, Taube, C., additional, Albrecht, M., additional, Lochner, M., additional, Böhm, L., additional, Übel, C., additional, Maxeiner, J., additional, Schild, H., additional, Finotto, S., additional, Hradetzky, S., additional, Balaji, H., additional, Heratizadeh, A., additional, Mittermann, I., additional, and Valenta, R., additional

Published
2011
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20. 21. Mainzer Allergie-Workshop

Author

Rennert, S., primary, Krause, S., additional, Becker, W., additional, Petersen, A., additional, Schocker, F., additional, Papenfuß, K., additional, Jappe, U., additional, Brehler, R., additional, Lange, L., additional, Riffelmann, F., additional, Nemat, K., additional, Hompes, S., additional, Holzhauser, T., additional, Lidholm, J., additional, Reese, G., additional, Vieths, S., additional, Seismann, H., additional, Blank, S., additional, Braren, I., additional, Greunke, K., additional, Cifuentes, L., additional, Grunwald, T., additional, Bredehorst, R., additional, Ollert, M., additional, Spillner, E., additional, von der Gathen, Y., additional, Sander, I., additional, Flagge, A., additional, Brüning, T., additional, Raulf-Heimsoth, M., additional, Zahradnik, E., additional, Fleischer, C., additional, Schierl, R., additional, Sültz, J., additional, Nowak, D., additional, Buters, J., additional, Weichenmeier, I., additional, Ochs, S., additional, Kreyling, W., additional, Boere, A., additional, Schober, W., additional, Behrendt, H., additional, Jaeger, T., additional, Kerzl, R., additional, Huss-Marp, J., additional, Ring, J., additional, Darsow, U., additional, Roeschmann, K., additional, Vroling, A., additional, van Drunen, C., additional, Ulmer, A., additional, Gilles, S., additional, Mariani, V., additional, Zhang, X., additional, Jakob, T., additional, Müller, M., additional, Pastore, S., additional, Traidl-Hoffmann, C., additional, Oeder, S., additional, Dietrich, S., additional, Fromme, H., additional, Schäfer, V., additional, Renne, J., additional, Werfel, T., additional, Wittmann, M., additional, Grusser, M., additional, Maurer, M., additional, Dudeck, A., additional, Suender, C., additional, Heydrich, S., additional, Bros, M., additional, Wiechmann, N., additional, Besche, V., additional, Hövelmeyer, N., additional, Reissig, S., additional, Massoumi, R., additional, Grabbe, S., additional, Waisman, A., additional, Reske-Kunz, A., additional, Gschwandtner, M., additional, Roßbach, K., additional, Bäumer, W., additional, Kietzmann, M., additional, Dijkstra, D., additional, Stark, H., additional, Gutzmer, R., additional, Höhn, Y., additional, Thamsen, M., additional, Trojandt, S., additional, Bovensiepen, C., additional, Bellinghausen, I., additional, Hilmenyuk, T., additional, Saloga, J., additional, Luxemburger, U., additional, Türeci, Ö., additional, Wiesner, H., additional, Kohlrautz, V., additional, Wahn, U., additional, Stock, P., additional, Mommert, S., additional, Köther, G., additional, Sudowe, S., additional, Barwig, C., additional, Montermann, E., additional, Milovanovic, M., additional, Koch, C., additional, Hilt, K., additional, Hartmann, B., additional, Heine, G., additional, Worm, M., additional, Ambach, A., additional, Hoefeld-Fegeler, M., additional, Besser, C., additional, Weren, A., additional, Schraven, B., additional, Bonekoh, B., additional, Gollnick, H., additional, Raap, M., additional, Bruder, M., additional, Kapp, A., additional, Raap, U., additional, Grosber, M., additional, Hausteiner, C., additional, Bubel, E., additional, Groben, S., additional, Bornschein, S., additional, Lahmann, C., additional, Zilker, T., additional, Eberlein, B., additional, Henningsen, P., additional, Huber, D., additional, Biedermann, T., additional, Kunz, J., additional, Fischer, J., additional, Kempf, W., additional, Wölbing, F., additional, Alexopoulou, A., additional, Albert, A., additional, Pfaar, O., additional, Distler, A., additional, Hörmann, K., additional, Klimek, L., additional, Wieczorek, D., additional, Büsing, M., additional, Wedi, B., additional, Rerinck, H.-C., additional, Przybilla, B., additional, Ruëff, F., additional, Weigert, C., additional, Ghoreschi, K., additional, Röcken, M., additional, Muhr, P., additional, Zeitvogel, J., additional, Ott, H., additional, Wiederholt, T., additional, Andresen-Bergström, M., additional, Skazik, C., additional, Merk, H., additional, Karlberg, A., additional, Zwadlo-Klarwasser, G., additional, Baron, J., additional, Frankenberg, U., additional, Lorenz, N., additional, Steinbrink, K., additional, Pföhler, C., additional, Dietrich, K.-A., additional, Thomas, P., additional, Baran, W., additional, Hänsel, A., additional, Meurer, M., additional, Schäkel, K., additional, Mamerow, D., additional, Niebuhr, M., additional, Bonnekoh, B., additional, Bunselmeyer, B., additional, Laubach, H., additional, Schiller, M., additional, Stanke, M., additional, Luger, T., additional, Böcking, C., additional, Köllisch, G., additional, Pfefferle, P., additional, Renz, H., additional, Conrad, M., additional, Teich, R., additional, Ferstl, R., additional, Brand, S., additional, Yildirim, A., additional, Kirschning, C., additional, Garn, H., additional, Eilbacher, I., additional, Stein, K., additional, Hanuszkiewicz, A., additional, Holst, O., additional, Heine, H., additional, Guenova, E., additional, Hoetzenecker, W., additional, Mailhammer, R., additional, Weindl, G., additional, Sauer, K., additional, Schaller, M., additional, Hiller, J., additional, Förster, S., additional, Eyerich, K., additional, Hofmann, H., additional, Ilchmann, A., additional, Burgdorf, S., additional, Waibler, Z., additional, Kurts, C., additional, Scheurer, S., additional, Kalinke, U., additional, Toda, M., additional, Adler, H. S., additional, Hofmann, C., additional, Becker, C., additional, Hemmer, W., additional, Focke, M., additional, Marzban, G., additional, Mayer, D., additional, Laimer, M., additional, Jarisch, R., additional, McIntyre, M., additional, Thiebes, V., additional, Mempel, M., additional, Jeßberger, B., additional, Vrtala, S., additional, Mauss, V., additional, Eben, R., additional, Walker, A. I., additional, Herzinger, T., additional, Berking, C., additional, Reese, I., additional, Sonar, S., additional, Ehmke, M., additional, Dietze, J., additional, Nockher, W., additional, Reuter, S., additional, Dehzad, N., additional, Martin, H., additional, Jung, M., additional, Heinz, A., additional, Stassen, M., additional, Buhl, R., additional, Taube, C., additional, Lingner, S., additional, Hennig, C., additional, Remke, J., additional, Hansen, G., additional, Dittrich, A., additional, Peters, M., additional, Bufe, A., additional, Polte, T., additional, Schütze, N., additional, Simon, J., additional, Lehmann, I., additional, Albrecht, M., additional, Preston-Hurlburt, P., additional, Bottomoly, H., additional, Pilzner, C., additional, Bühling, F., additional, Reinheckel, T., additional, Lauenstein, H., additional, Braun, A., additional, Welte, T., additional, Groneberg, D., additional, Greiner, T., additional, Zimmer, A., additional, Abram, M., additional, Fokuhl, V., additional, Luger, E., additional, Radbruch, A., additional, Zemlin, M., additional, Kilic, A., additional, Yildirim, A. Ö., additional, Alrifai, M., additional, Hagner, S., additional, Renzing, A., additional, Closs, E., additional, Bopp, T., additional, Schmitt, E., additional, Dicke, T., additional, Seyfarth, F., additional, Hipler, U., additional, Elsner, P., additional, Schliemann, S., additional, Konakovsky, V., additional, Moser, P., additional, Wantke, F., additional, Sesztak-Greinecker, G., additional, Götz, M., additional, Schmid, R., additional, and Hoffmann-Sommergruber, K., additional

Published
2009
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27. TLR3 but not TLR7/8 ligand induces allergic sensitization to inhaled allergen.

Author

Reuter S, Dehzad N, Martin H, Böhm L, Becker M, Buhl R, Stassen M, and Taube C

Subjects
Administration, Inhalation, Animals, Dendritic Cells immunology, Dendritic Cells metabolism, Disease Models, Animal, Hypersensitivity microbiology, Hypersensitivity virology, Imidazoles administration & dosage, Imidazoles metabolism, Ligands, Lipopolysaccharides administration & dosage, Lipopolysaccharides metabolism, Membrane Glycoproteins agonists, Membrane Glycoproteins deficiency, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Ovalbumin administration & dosage, Ovalbumin immunology, Poly I-C administration & dosage, Poly I-C metabolism, Toll-Like Receptor 3 deficiency, Toll-Like Receptor 7 agonists, Toll-Like Receptor 7 deficiency, Toll-Like Receptor 8 agonists, Allergens administration & dosage, Allergens immunology, Hypersensitivity immunology, Membrane Glycoproteins metabolism, Toll-Like Receptor 3 metabolism, Toll-Like Receptor 7 metabolism, Toll-Like Receptor 8 metabolism
Abstract

Epidemiological studies suggest that viral infections during childhood are a risk factor for the development of asthma. However, the role of virus-specific pattern recognition receptors in this process is not well defined. In the current study, we compare the effects of the inhaled viral TLR ligands polyinosinic-polycytidylic acid (TLR3) and resiquimod (TLR7/8) on sensitization to a model allergen (OVA) in a murine model. Both compounds enhance the migration, activation, and Ag-processing of myeloid dendritic cells from the lung to the draining lymph nodes comparable to the effects of LPS. Application of polyinosinic-polycytidylic acid [poly(I:C)] or LPS induces production of allergen-specific IgE and IgG1, whereas resiquimod (R848) had no effect. In addition, rechallenge of mice with OVA resulted in airway inflammation and mucus production in animals that received either poly(I:C) or LPS but not after application of R848. In summary, these results show that activation of TLR3 in combination with inhaled allergen results in induction of dendritic cell activation and migration similar to the effects of LPS. This leads to the development of allergic airway disease after allergen rechallenge, whereas mice treated with R848 did not develop allergic airway disease. These findings give further insight into the effects of stimulation of different TLRs on the development of asthma.

Published
2012
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28. The tick salivary protein sialostatin L inhibits the Th9-derived production of the asthma-promoting cytokine IL-9 and is effective in the prevention of experimental asthma.

Author

Horka H, Staudt V, Klein M, Taube C, Reuter S, Dehzad N, Andersen JF, Kopecky J, Schild H, Kotsyfakis M, Hoffmann M, Gerlitzki B, Stassen M, Bopp T, and Schmitt E

Subjects
Animals, Asthma metabolism, Asthma prevention & control, Cell Separation, Cystatins pharmacology, Cytokines immunology, Cytokines metabolism, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Interleukin-9 biosynthesis, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocyte Subsets metabolism, Asthma immunology, Cystatins immunology, Interleukin-9 immunology, Ixodidae immunology, T-Lymphocyte Subsets immunology
Abstract

Ticks developed a multitude of different immune evasion strategies to obtain a blood meal. Sialostatin L is an immunosuppressive cysteine protease inhibitor present in the saliva of the hard tick Ixodes scapularis. In this study, we demonstrate that sialostatin L strongly inhibits the production of IL-9 by Th9 cells. Because we could show recently that Th9-derived IL-9 is essentially involved in the induction of asthma symptoms, sialostatin L was used for the treatment of experimental asthma. Application of sialostatin L in a model of experimental asthma almost completely abrogated airway hyperresponsiveness and eosinophilia. Our data suggest that sialostatin L can prevent experimental asthma, most likely by inhibiting the IL-9 production of Th9 cells. Thus, alternative to IL-9 neutralization sialostatin L provides the basis for the development of innovative therapeutic strategies to treat asthma.

Published
2012
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29. CD4-mediated regulatory T-cell activation inhibits the development of disease in a humanized mouse model of allergic airway disease.

Author

Martin H, Reuter S, Dehzad N, Heinz A, Bellinghausen I, Saloga J, Haasler I, Korn S, Jonuleit H, Buhl R, Becker C, and Taube C

Subjects
Adult, Animals, Bronchial Hyperreactivity immunology, Bronchial Hyperreactivity pathology, Disease Models, Animal, Female, HIV Envelope Protein gp120 immunology, Humans, Interleukin-4 genetics, Interleukin-4 immunology, Male, Mice, Mice, SCID, Middle Aged, Pneumonia pathology, Recombinant Proteins immunology, Respiratory Hypersensitivity pathology, CD4 Antigens immunology, Leukocytes, Mononuclear immunology, Pneumonia immunology, Respiratory Hypersensitivity immunology, T-Lymphocytes, Regulatory immunology
Abstract

Background: Based on their potency to control allergic diseases, regulatory T (Treg) cells represent a promising target for novel strategies to interfere with allergic airway inflammation. We have previously demonstrated that stimulation of the CD4 molecule on human Treg cells activates their suppressive activity in vitro and in vivo., Objective: We sought to determine the effect of CD4-mediated Treg-cell activation on pulmonary inflammation in a humanized mouse model of allergic airway inflammation., Methods: PBMCs obtained from donors allergic to birch pollen or from healthy donors were injected into NOD-severe combined immunodeficiency γc(-/-) mice, followed by allergen airway challenges and analysis of airway responsiveness and inflammation. For Treg-cell activation, mice were treated with the CD4-binding, lck-activating recombinant HIV-1 surface protein gp120 after sensitization prior to allergen challenge. Control experiments with CD25-depleted PBMCs were performed to evaluate the role of Treg cells., Results: PBMCs from allergic donors but not from healthy donors induced airway inflammation and airway hyperresponsiveness. Treatment with gp120 prior to allergen challenge abrogated airway hyperresponsiveness and reduced the inflammatory immune response. In contrast, treatment had no effect on inflammation and airway hyperresponsiveness in mice that received CD25-depleted PBMCs, demonstrating Treg-cell dependency of disease prevention., Conclusion: Allergic airway inflammation can be prevented by stimulation of human Treg cells by CD4. These results suggest a clinical potential of Treg-cell activation by high-affinity CD4 ligands in allergic diseases., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Published
2012
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30. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells.

Author

Arnold IC, Dehzad N, Reuter S, Martin H, Becher B, Taube C, and Müller A

Subjects
Animals, Asthma complications, Bronchoalveolar Lavage, Dendritic Cells cytology, Disease Models, Animal, Hypersensitivity complications, Inflammation, Lung cytology, Mice, Mice, Inbred C57BL, Th17 Cells cytology, Th2 Cells cytology, Asthma microbiology, Helicobacter Infections complications, Helicobacter Infections metabolism, Helicobacter pylori metabolism, Hypersensitivity microbiology, T-Lymphocytes, Regulatory cytology
Abstract

Atopic asthma is a chronic disease of the airways that has taken on epidemic proportions in the industrialized world. The increase in asthma rates has been linked epidemiologically to the rapid disappearance of Helicobacter pylori, a bacterial pathogen that persistently colonizes the human stomach, from Western societies. In this study, we have utilized mouse models of allergic airway disease induced by ovalbumin or house dust mite allergen to experimentally examine a possible inverse correlation between H. pylori and asthma. H. pylori infection efficiently protected mice from airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia, which are hallmarks of asthma, and prevented allergen-induced pulmonary and bronchoalveolar infiltration with eosinophils, Th2 cells, and Th17 cells. Protection against asthma was most robust in mice infected neonatally and was abrogated by antibiotic eradication of H. pylori. Asthma protection was further associated with impaired maturation of lung-infiltrating dendritic cells and the accumulation of highly suppressive Tregs in the lungs. Systemic Treg depletion abolished asthma protection; conversely, the adoptive transfer of purified Treg populations was sufficient to transfer protection from infected donor mice to uninfected recipients. Our results thus provide experimental evidence for a beneficial effect of H. pylori colonization on the development of allergen-induced asthma.

Published
2011
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31. Regulatory T cells more effectively suppress Th1-induced airway inflammation compared with Th2.

Author

Dehzad N, Bopp T, Reuter S, Klein M, Martin H, Ulges A, Stassen M, Schild H, Buhl R, Schmitt E, and Taube C

Subjects
Acute Disease, Animals, Bronchial Hyperreactivity pathology, Bronchial Hyperreactivity prevention & control, Cells, Cultured, Coculture Techniques, Disease Susceptibility immunology, Disease Susceptibility pathology, Female, Immunity, Innate, Inflammation immunology, Inflammation pathology, Inflammation prevention & control, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, T-Lymphocytes, Regulatory pathology, Th1 Cells pathology, Th2 Cells pathology, Bronchial Hyperreactivity immunology, Disease Models, Animal, T-Lymphocytes, Regulatory immunology, Th1 Cells immunology, Th2 Cells immunology
Abstract

Asthma is a syndrome with different inflammatory phenotypes. Animal models have shown that, after sensitization and allergen challenge, Th2 and Th1 cells contribute to the development of allergic airway disease. We have previously demonstrated that naturally occurring regulatory T cells (nTregs) can only marginally suppress Th2-induced airway inflammation and airway hyperresponsiveness. In this study, we investigated nTreg-mediated suppression of Th2-induced and Th1-induced acute allergic airway disease. We demonstrate in vivo that nTregs exert their suppressive potency via cAMP transfer on Th2- and Th1-induced airway disease. A comparison of both phenotypes revealed that, despite similar cAMP transfers, Th1-driven airway hyperresponsiveness and inflammation are more susceptible to nTreg-dependent suppression, suggesting that potential nTreg-based therapeutic strategies might be more effective in patients with predominantly neutrophilic airway inflammation based on deregulated Th1 response.

Published
2011
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32. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease.

Author

Taube C, Tertilt C, Gyülveszi G, Dehzad N, Kreymborg K, Schneeweiss K, Michel E, Reuter S, Renauld JC, Arnold-Schild D, Schild H, Buhl R, and Becher B

Subjects
Allergens immunology, Animals, Biomarkers metabolism, Epithelial Cells drug effects, Epithelial Cells metabolism, Immunity, Innate drug effects, Immunization, Immunoglobulins blood, Inflammation blood, Inflammation pathology, Interleukin-13 pharmacology, Interleukins administration & dosage, Interleukins deficiency, Interleukins metabolism, Intracellular Space drug effects, Intracellular Space metabolism, Lung drug effects, Lung immunology, Lung pathology, Lymphocytes drug effects, Mice, Phosphorylation drug effects, Recombinant Proteins administration & dosage, Recombinant Proteins pharmacology, Respiratory Hypersensitivity blood, STAT3 Transcription Factor metabolism, T-Lymphocytes drug effects, T-Lymphocytes immunology, Tumor Necrosis Factor-alpha pharmacology, Interleukin-22, Immunity, Innate immunology, Inflammation complications, Inflammation immunology, Interleukins biosynthesis, Lymphocytes immunology, Respiratory Hypersensitivity complications, Respiratory Hypersensitivity immunology
Abstract

Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22-deficiency led to increased eosinophil infiltration lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung. Mice treated with IL-22 before antigen challenge displayed reduced expression of CCL17 and IL-13 and significant amelioration of airway constriction and inflammation. We conclude that innate IL-22 limits airway inflammation, tissue damage and clinical decline in allergic lung disease.

Published
2011
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33. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells.

Author

Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, and Bopp T

Subjects
Animals, Asthma genetics, Asthma immunology, Cell Differentiation, Cells, Cultured, Humans, Interferon Regulatory Factors deficiency, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Interleukin-9 biosynthesis, Interleukin-9 genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, Protein Binding, RNA, Small Interfering genetics, T-Lymphocytes, Helper-Inducer cytology, Interferon Regulatory Factors immunology, Interleukin-9 immunology, T-Lymphocytes, Helper-Inducer immunology
Abstract

Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4(+) T cell subset designated Th9. IRF4-deficient CD4(+) T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4(+) T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4(+) T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma., (Copyright 2010 Elsevier Inc. All rights reserved.)

Published
2010
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34. Mast cells induce migration of dendritic cells in a murine model of acute allergic airway disease.

Author

Reuter S, Dehzad N, Martin H, Heinz A, Castor T, Sudowe S, Reske-Kunz AB, Stassen M, Buhl R, and Taube C

Subjects
Adoptive Transfer, Allergens immunology, Animals, Bronchoalveolar Lavage Fluid immunology, Cell Separation, Flow Cytometry, Mice, Ovalbumin immunology, Bronchial Hyperreactivity immunology, Chemotaxis, Leukocyte immunology, Dendritic Cells immunology, Mast Cells immunology
Abstract

Background: The migration of dendritic cells (DCs) from the lungs to the regional lymph nodes is necessary for the development of allergic airway disease. Following activation, mast cells release a variety of stored or de novo-produced inflammatory mediators, several of them being capable of activating DCs. In this study, the role of mast cells on DC migration from the lungs to the thoracic lymph nodes was investigated in sensitized mice., Methods: Mast cell-deficient mice (Kit(W-sh/W-sh)) and their wild-type counterparts were sensitized intraperitoneally with ovalbumine (OVA) in saline and challenged by a single intranasal administration of OVA labeled with a fluorescent dye (OVA-Alexa)., Results: Following challenge, the relative and absolute amount of OVA- Alexa-positive DCs was clearly increased in sensitized wild-type mice compared to nonsensitized mice. In contrast, sensitized Kit(W-sh/W-sh) showed no increase in OVA-Alexa-positive DCs compared to nonsensitized mast cell-deficient animals. In sensitized Kit(W-sh/W-sh) mice reconstituted with bone marrow-derived mast cells (BMMCs), the number of OVA- Alexa-positive DCs was comparable to that in sensitized wild-type animals. However, transfer of allergen-exposed BMMCs to sensitized mice prior to airway challenge augmented airway inflammation similarly in wild-type and mast cell-deficient mice. In line with this, sensitization with allergen-pulsed DCs induced allergic airway disease independently of mast cells., Conclusions: This study shows an interaction between mast cells and DCs following allergen challenge in sensitized hosts. However, the function of mast cells can be bypassed in models utilizing activated allergen-exposed DCs to initiate the development of allergic airway disease.

Published
2010
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35. Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells.

Author

Becker C, Taube C, Bopp T, Becker C, Michel K, Kubach J, Reuter S, Dehzad N, Neurath MF, Reifenberg K, Schneider FJ, Schmitt E, and Jonuleit H

Subjects
Animals, CD4 Antigens immunology, CHO Cells, Cricetinae, Cricetulus, Cyclic AMP immunology, Graft vs Host Disease drug therapy, HIV Envelope Protein gp120 immunology, Humans, Immune Tolerance immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred NOD, Mice, SCID, Signal Transduction drug effects, Signal Transduction immunology, Transplantation, Heterologous, Graft vs Host Disease immunology, HIV Envelope Protein gp120 pharmacology, HIV-1, Immune Tolerance drug effects, Lymphocyte Activation drug effects, T-Lymphocytes, Regulatory immunology
Abstract

Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) represent a unique T-cell lineage that is endowed with the ability to actively suppress immune responses. Therefore, approaches to modulate Treg function in vivo could provide ways to enhance or reduce immune responses and lead to novel therapies. Here we show that the CD4 binding human immunodeficiency virus-1 envelope glycoprotein gp120 is a useful and potent tool for functional activation of human Tregs in vitro and in vivo. Gp120 activates human Tregs by binding and signaling through CD4. Upon stimulation with gp120, human Tregs accumulate cyclic adenosine monophosphate (cAMP) in their cytosol. Inhibition of endogeneous cAMP synthesis prevents gp120-mediated Treg activation. Employing a xenogeneic graft versus host disease model that has been shown to be applicable for the functional analysis of human Tregs in vivo, we further show that a single dose of gp120 is sufficient to prevent lethal graft versus host disease and that the tolerizing effect of gp120 is strictly dependent on the presence of human Tregs and their up-regulation of cAMP upon gp120-mediated activation. Our findings demonstrate that stimulation via the CD4 receptor represents a T-cell receptor-independent Treg activating pathway with potential to induce immunologic tolerance in vivo.

Published
2009
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36. Inhibition of cAMP degradation improves regulatory T cell-mediated suppression.

Author

Bopp T, Dehzad N, Reuter S, Klein M, Ullrich N, Stassen M, Schild H, Buhl R, Schmitt E, and Taube C

Subjects
Animals, Cells, Cultured, Coculture Techniques, Cyclic Nucleotide Phosphodiesterases, Type 4 drug effects, Cyclic Nucleotide Phosphodiesterases, Type 4 immunology, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Immune Tolerance drug effects, Lung Diseases drug therapy, Lung Diseases immunology, Lung Diseases pathology, Mice, Mice, Transgenic, Phosphodiesterase Inhibitors pharmacology, Rolipram pharmacology, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory metabolism, Th2 Cells immunology, Cyclic AMP immunology, Cyclic AMP metabolism, Hypersensitivity immunology, Immune Tolerance immunology, T-Lymphocytes, Regulatory immunology
Abstract

Naturally occurring regulatory T cells (nTreg cells) are crucial for the maintenance of peripheral tolerance. We have previously shown that a key mechanism of their suppressive action is based on a contact-dependent transfer of cAMP from nTreg cells to responder T cells. Herein, we further elucidate the important role of cAMP for the suppressive properties of nTreg cells. Prevention of cAMP degradation by application of the phosphodiesterase 4 inhibitor rolipram led to strongly increased suppressive potency of nTreg cells for Th2 cells in vitro and in vivo. Detailed analyses revealed that rolipram caused, in the presence of nTreg cells, a synergistic increase of cAMP in responder Th2 cells. In vivo, the application of nTreg cells in a strictly Th2-dependent preclinical model of asthma had only a marginal effect. However, the additional treatment with rolipram led to a considerable reduction of airway hyperresponsiveness and inflammation in a prophylactic as well as in a therapeutic model. This amelioration was correlated with enhanced cAMP-levels in lung Th2 cells in vivo. Collectively, these data support our observation that cAMP has a key function for nTreg cell-based suppression and they clearly demonstrate that the effect of cAMP on T responder cells can be greatly enhanced upon application of phosphodiesterase 4 inhibitors.

Published
2009
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