title: Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10.
abstract: The prevalence of allergic asthma and other atopic diseases has reached epidemic proportions in large parts of the developed world. The gradual loss of the human indigenous microbiota has been held responsible for this trend. The bacterial pathogen Helicobacter pylori is a constituent of the normal gastric microbiota whose presence has been inversely linked to allergy and asthma in humans and experimental models. Here we show that oral or i.p. tolerization with H. pylori extract prevents the airway hyperresponsiveness, bronchoalveolar eosinophilia, pulmonary inflammation, and Th2 cytokine production that are hallmarks of allergen-induced asthma in mice. Asthma protection is not conferred by extracts from other enteropathogens and requires a heat-sensitive H. pylori component and the DC-intrinsic production of IL-10. The basic leucine zipper ATF-like 3 (BATF3)-dependent CD103(+)CD11b(-) dendritic cell lineage is enriched in the lungs of protected mice and strictly required for protection. Two H. pylori persistence determinants, the γ-glutamyl-transpeptidase GGT and the vacuolating cytotoxin VacA, are required and sufficient for asthma protection and can be administered in purified form to prevent asthma. In conclusion, we provide preclinical evidence for the concept that the immunomodulatory properties of H. pylori can be exploited for tolerization strategies aiming to prevent allergen-induced asthma.
authors: Institute of Molecular Cancer Research, University of Zürich, 8057 Zürich, Switzerland;
authors: Daniela B
authors: DB
authors: Engler
authors: Medical Clinic III and.
authors: Sebastian
authors: S
authors: Reuter
authors: Department of Pulmonology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands;
authors: Yolanda
authors: Y
authors: van Wijck
authors: Institute of Molecular Cancer Research, University of Zürich, 8057 Zürich, Switzerland;
authors: Sabine
authors: S
authors: Urban
authors: Institute of Molecular Cancer Research, University of Zürich, 8057 Zürich, Switzerland;
authors: Andreas
authors: A
authors: Kyburz
authors: Medical Clinic III and.
authors: Joachim
authors: J
authors: Maxeiner
authors: Medical Clinic III and.
authors: Helen
authors: H
authors: Martin
authors: Institute for Molecular Medicine, Johannes Gutenberg University, 55131 Mainz, Germany;
authors: Nir
authors: N
authors: Yogev
authors: Institute for Molecular Medicine, Johannes Gutenberg University, 55131 Mainz, Germany;
authors: Ari
authors: A
authors: Waisman
authors: Institute of Microbiology, Immunology and Hygiene, Technical University of Munich and German Center for Infection Research, 81675 Munich, Germany; and.
authors: Markus
authors: M
authors: Gerhard
authors: Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37232-2358.
authors: Timothy L
authors: TL
authors: Cover
authors: Department of Pulmonology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands;
authors: Christian
authors: C
authors: Taube
authors: Institute of Molecular Cancer Research, University of Zürich, 8057 Zürich, Switzerland; mueller@imcr.uzh.ch.
authors: Anne
authors: A
authors: Müller
mesh_terms: D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage; D001249:Asthma / Q000276:immunology / Q000382:microbiology* / Q000628:therapy*; D001426:Bacterial Proteins / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D016480:Helicobacter pylori / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D007108:Immune Tolerance; D007155:Immunologic Factors / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D005723:gamma-Glutamyltransferase / Q000276:immunology
chemical_list: D000485:Allergens; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D050976:Basic-Leucine Zipper Transcription Factors; C556062:IL10 protein, mouse; D007155:Immunologic Factors; D020382:Interleukin-18; D012097:Repressor Proteins; C533289:SNFT protein, mouse; C074689:VacA protein, Helicobacter pylori; D016753:Interleukin-10; D005723:gamma-Glutamyltransferase
keywords: allergy and asthma prevention; bacterial immunomodulation; bacterial persistence determinants; tolerogenic dendritic cells