Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10

Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11810-5. doi: 10.1073/pnas.1410579111. Epub 2014 Jul 29.

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.

Keywords: allergy and asthma prevention; bacterial immunomodulation; bacterial persistence determinants; tolerogenic dendritic cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allergens / administration & dosage
  • Animals
  • Antigens, Bacterial / administration & dosage
  • Asthma / immunology
  • Asthma / microbiology*
  • Asthma / therapy*
  • Bacterial Proteins / immunology
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / immunology*
  • Dendritic Cells / immunology*
  • Disease Models, Animal
  • Helicobacter pylori / immunology*
  • Helicobacter pylori / pathogenicity*
  • Humans
  • Immune Tolerance
  • Immunologic Factors / therapeutic use*
  • Interleukin-10 / immunology*
  • Interleukin-18 / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • gamma-Glutamyltransferase / immunology

Substances

  • Allergens
  • Antigens, Bacterial
  • Bacterial Proteins
  • Basic-Leucine Zipper Transcription Factors
  • IL10 protein, mouse
  • Immunologic Factors
  • Interleukin-18
  • Repressor Proteins
  • SNFT protein, mouse
  • VacA protein, Helicobacter pylori
  • Interleukin-10
  • gamma-Glutamyltransferase