TRR 22:  Pulmonary Allergies

• Subject Area: Medicine ; Biology
• Term: from 2005 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5486276

• Final Report Year: 2015

Final Report Abstract

Allergic asthma represents the most severe manifestation of allergic diseases on the airways. Prevalence and incidence of asthma are on the rise, especially since the end of World-War II. The starting point of this research consortium was the recognition that asthma represents a chronic inflammatory disease which de-velopes on the basis of complex gene-x-environment interactions. Based on an already existing long-lasting collaboration between investigators from Munich, Mar-burg and Lübeck/Borstel, this consortium was formed to provide a mechanistic explanation for the epidemiological finding that certain environmental exposures and living conditions (e.g. “traditional farming”) provide immunological stimuli that confer asthma protection. Cohort studies provide evidence that these factors operate early in life, presumably starting already in the prenatal period. During the funding period (2005 – 2014) great progress was achieved to better understand the complexity of this observation. The hallmarks include: identification and characterisation of prototypic environmental bac-teria which confer asthma-protection; “proof of principle”-experiments in animal models revealing the im-portance of prenatal exposure; identification of epigenetic mechanisms as a novel explanation for their ac-tion; a better understanding of the regulation of airway mucosal immune responses, which are the result of the interaction between epithelial cells, innate and adaptive immune cells. Three clinical studies have been successfully initiated in children and adults to examine early immune responses in childhood involved in asthma development, to assess the heterogeneity of asthma phenotypes, and to provide a better under-standing of the mechanisms of specific immuno-therapy. The combined research activities resulted in a great number of published articles, including 40 high-impact publications (impact factor > 10). Almost 50 doctorate students completed or started their doctoral theses within the SFB/TRR22.

Publications

• 2007. PCT/EP2008/004958 “Targeting recombinase activity by trans-splicing”
  Buch, Thorsten
  
• EP 1 411 977. 18.04.2007 Zusammensetzung, enthaltend bakterielle Antigene, zum Vorbeugen und Behandeln von allergischen Erkrankungen
  Holst, Otto
  
• 11.12.2008 US020080305089A1. Pharmaceutical Composition for Protection from Allergies and Inflammatory Disorders
  Ege, Markus
  
• 30.09.2008 2008/36 EP000001964570A1. Pharmazeutische Zusammensetzung zum Schutz vor Allergien und entzündlichen Erkrankungen
  Ege, Markus
  
• EP 1 637 147. Stallstaub-Extrakt zum Schutz vor Allergien, erteilt 10.12.2008
  Holst, Otto
  
• 2009 PAT053760 “Genetic Sterility”
  Buch, Thorsten
  
• Drosophila in asthma research. Am J Respir Crit Care Med. 2009 Jun 1;179(11):979-83
  Roeder T1, Isermann K, Kabesch M
  
• Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acineto-bacter lwoffii F78. J Exp Med. 2009 Dec 21;206(13):2869-77
  Conrad ML, Ferstl R, Teich R, Brand S, Blümer N, Yildirim AO, Patrascan CC, Hanuszkiewicz A, Akira S, Wagner H, Holst O, von Mutius E, Pfefferle PI, Kirschning CJ, Garn H, Renz H
  
• P627209WO/EP und P627209WO/US Sialylated antigen-specific IgGs protect from inflammatory immune responses in an antigen-specific manner” EP/PCT
  Ehlers, Marc A
  
• Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol. 2010 Jun;11(6):512-9
  Hinterberger M, Aichinger M, Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L
  
• Farm living: effects on childhood asthma and allergy. Nat Rev Immunol. 2010 Dec;10(12):861-8
  von Mutius E, Vercelli D
  
• Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity. 2010 Aug 27;33(2):192-202
  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, Bopp T
  
• Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive im-mune responses. Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20459-64
  Ritter M, Gross O, Kays S, Ruland J, Nimmerjahn F, Saijo S, Tschopp J, Layland LE, Prazeres da Costa C
  
• 31.08.2011 EP000002361632A1. Bulletin 2011/35 Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune diseases
  Ege, Markus
  
• Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection in-duced by microbes. J Allergy Clin Immunol. 2011 Sep;128(3):618-25.e1-7
  Brand S, Teich R, Dicke T, Harb H, Yildirim AÖ, Tost J, Schneider-Stock R, Waterland RA, Bauer UM, von Mutius E, Garn H, Pfefferle PI, Renz H
  
• Exposure to environmental microorganisms and childhood asthma. N Engl J Med. 2011 Feb 24;364(8):701-9
  Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrländer C, Heederik D, Piarroux R, von Mutius E; GABRIELA Transregio 22 Study Group
  
• Gene-environment interaction in chronic disease: a European Science Foundation Forward Look. J Allergy Clin Immunol. 2011 Dec;128(6 Suppl):S27-49
  Renz H, Autenrieth IB, Brandtzæg P, Cookson WO, Holgate S, von Mutius E, Valenta R, Haller D
  
• Gene-environment interaction in chronic disease: a European Science Foundation Forward Look. J Allergy Clin Immunol. 2011 Dec;128(6 Suppl):S27-49
  Renz H, Autenrieth IB, Brandtzæg P, Cookson WO, Holgate S, von Mutius E, Valenta R, Haller D
  
• MHC class I-specific antibody binding to nonhematopoietic cells drives complement activation to induce transfusion-related acute lung injury in mice. J Exp Med. 2011 Nov 21;208(12):2525-44
  Strait RT, Hicks W, Barasa N, Mahler A, Khodoun M, Köhl J, Stringer K, Witte D, Van Rooijen N, Susskind BM, Finkelman FD
  
• Mutual antagonism of T cells causing psoriasis and atopic eczema. N Engl J Med. 2011 Jul 21;365(3):231-8
  Eyerich 1, Onken AT, Weidinger S, Franke A, Nasorri F, Pennino D, Grosber M, Pfab F, Schmidt-Weber CB, Mempel M, Hein R, Ring J, Cavani A, Eyerich K
  
• The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nat Rev Immunol. 2011 Dec 9;12(1):9-23
  Renz H, Brandtzaeg P, Hornef M
  
• DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma. J Allergy Clin Immunol. 2012 Jun;129(6):1602-10.e6
  Brand S1, Kesper DA, Teich R, Kilic-Niebergall E, Pinkenburg O, Bothur E, Lohoff M, Garn H, Pfefferle PI, Renz H
  
• Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell. 2012 Jul 6;150(1):194-206
  Krautler NJ, Kana V, Kranich J, Tian Y, Perera D, Lemm D, Schwarz P, Armulik A, Browning JL, Tallquist M, Buch T, Oliveira-Martins JB, Zhu C, Hermann M, Wagner U, Brink R, Heikenwalder M, Aguzzi A
  
• Nucleic acid-sensing Toll-like receptors are essential for the control of endogenous retrovirus viremia and ERV-induced tumors. Immunity. 2012 Nov 16;37(5):867-79
  Yu P, Lübben W, Slomka H, Gebler J, Konert M, Cai C, Neubrandt L, Prazeres da Costa O, Paul S, Dehnert S, Döhne K, Thanisch M, Storsberg S, Wiegand L, Kaufmann A, Nain M, Quintanilla-Martinez L, Bettio S, Schnierle B, Kolesnikova L, Becker S, Schnare M, Bauer S
  
• Prenatal and early-life exposures alter expression of innate immunity genes: the PASTURE cohort study. J Allergy Clin Immunol. 2012 Aug;130(2):523-30.e9
  Loss G, Bitter S, Wohlgensinger J, Frei R, Roduit C, Genuneit J, Pekkanen J, Roponen M, Hirvonen MR, Dalphin JC, Dalphin ML, Riedler J, von Mutius E, Weber J, Kabesch M, Michel S, Braun-Fahrländer C, Lauener R; PASTURE study group
  
• Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs. J Allergy Clin Immunol. 2012 Jun;129(6):1647-55.e13
  Oefner CM, Winkler A, Hess C, Lorenz AK, Holecska V, Huxdorf M, Schommartz T, Petzold D, Bitterling J, Schoen AL, Stoehr AD, Vu Van D, Darcan-Nikolaisen Y, Blanchard V, Schmudde I, Laumonnier Y, Ströver HA, Hegazy AN, Eiglmeier S, Schoen CT, Mertes MM, Loddenkemper C, Löhning M, König P, Petersen A, Luger EO, Collin M, Köhl J, Hutloff A, Hamelmann E, Berger M, Wardemann H, Ehlers M
  
• IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. J Clin Invest. 2013 Jan 2;123(1):247-60
  Huber M, Heink S, Pagenstecher A, Reinhard K, Ritter J, Visekruna A, Guralnik A, Bollig N, Jeltsch K, Heinemann C, Wittmann E, Buch T, Prazeres da Costa O, Brüstle A, Brenner D, Mak TW, Mittrücker HW, Takkenberg B, Kamradt T, Lohoff M
  
• IRF4 provides rations for cytotoxic CD8(+) T cell soldiers. Immunity. 2013 Nov 14;39(5):797-9
  Huber M, Lohoff M
  
• Negative selection, not receptor editing, is a physiological response of autoreactive thymocytes. J Exp Med. 2013 Sep 23;210(10):1911-8
  Kreslavsky T, Kim HJ, Koralov SB, Ghitza D, Buch T, Cantor H, Rajewsky K, von Boehmer H
  
• TGF-β signalling is required for CD4⁺ T cell homeostasis but dispensable for regulatory T cell function. PLoS Biol. 2013 Oct;11(10):e1001674
  Sledzińska A, Hemmers S, Mair F, Gorka O, Ruland J, Fairbairn L, Nissler A, Müller W, Waisman A, Becher B, Buch T
  
• IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1. Nat Commun. 2014 May 6;5:3770
  Heinemann C, Heink S, Petermann F, Vasanthakumar A, Rothhammer V, Doorduijn E, Mitsdoerffer M, Sie C, Prazeres da Costa O, Buch T, Hemmer B, Oukka M, Kallies A, Korn T
  
• Maternal immune response to helminth infection during pregnancy determines offspring susceptibility to allergic airway inflammation. J Allergy Clin Immunol. 2014 Dec;134(6):1271-1279.e10
  Straubinger K, Paul S, Prazeres da Costa O, Ritter M, Buch T, Busch DH, Layland LE
  
• Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner. J Allergy Clin Immunol. 2014 Mar;133(3):872-9.e7
  Wambre E, DeLong JH, James EA, Torres-Chinn N, Pfützner W, Möbs C, Durham SR, Till SJ, Robin-son D, Kwok WW
  
• Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1. Nat Med. 2012 Sep;18(9):1401-6
  Karsten CM, Pandey MK, Figge J, Kilchenstein R, Taylor PR, Rosas M, McDonald JU, Orr SJ, Berger M, Petzold D, Blanchard V, Winkler A, Hess C, Reid DM, Majoul IV, Strait RT, Harris NL, Köhl G, Wex E, Lud-wig R, Zillikens D, Nimmerjahn F, Finkelman FD, Brown GD, Ehlers M, Köhl J
  
• Identification of novel immune phenotypes for allergic and nonallergic childhood asthma. J Allergy Clin Immunol. 2015 Jan;135(1):81-91
  Raedler D, Ballenberger N, Klucker E, Böck A, Otto R, Prazeres da Costa O, Holst O, Illig T, Buch T, von Mutius E, Schaub B
  
• Identification of novel immune phenotypes for allergic and nonallergic childhood asthma. J Allergy Clin Immunol. 2015 Jan;135(1):81-91
  Raedler D, Ballenberger N, Klucker E, Böck A, Otto R, Prazeres da Costa O, Holst O, Illig T, Buch T, von Mutius E, Schaub B
  
• Identification of novel immune phenotypes for allergic and nonallergic childhood asthma. J Allergy Clin Immunol. 2015 Jan;135(1):81-91
  Raedler D, Ballenberger N, Klucker E, Böck A, Otto R, Prazeres da Costa O, Holst O, Illig T, Buch T, von Mutius E, Schaub B