title: Dendritic cells prevent rather than promote immunity conferred by a helicobacter vaccine using a mycobacterial adjuvant.
abstract: OBJECTIVE
  Immunization against the gastric bacterium Helicobacter pylori could prevent many gastric cancers and other disorders. Most vaccination protocols used in preclinical models are not suitable for humans. New adjuvants and a better understanding of the correlates and requirements for vaccine-induced protection are needed to accelerate development of vaccines for H pylori.
  
  
  METHODS
  Vaccine-induced protection against H pylori infection and its local and systemic immunological correlates were assessed in animal models, using cholera toxin or CAF01 as adjuvants. The contribution of B cells, T-helper (Th)-cell subsets, and dendritic cells to H pylori-specific protection were analyzed in mice.
  
  
  RESULTS
  Parenteral administration of a whole-cell sonicate, combined with the mycobacterial cell-wall-derived adjuvant CAF01, protected against infection with H pylori and required cell-mediated, but not humoral, immunity. The vaccine-induced control of H pylori was accompanied by Th1 and Th17 responses in the gastric mucosa and in the gut-draining mesenteric lymph nodes; both Th subsets were required for protective immunity against H pylori. The numbers of memory CD4+ T cells and neutrophils in gastric tissue were identified as the best correlates of protection. Systemic depletion of dendritic cells or regulatory T cells during challenge infection significantly increased protection by overriding immunological tolerance mechanisms activated by live H pylori.
  
  
  CONCLUSIONS
  Parenteral immunization with a Helicobacter vaccine using a novel mycobacterial adjuvant induces protective immunity against H pylori that is mediated by Th1 and Th17 cells. Tolerance mechanisms mediated by dendritic cells and regulatory T cells impair H pylori clearance and must be overcome to improve immunity.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
authors.forename: Iris
authors.initials: I
authors.lastname: Hitzler
authors.forename: Mathias
authors.initials: M
authors.lastname: Oertli
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000494:pharmacology*; D002473:Cell Wall / Q000276:immunology; D002633:Chemotaxis / Q000187:drug effects; D002772:Cholera Toxin / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D016481:Helicobacter Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D016480:Helicobacter pylori / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009161:Mycobacterium / Q000276:immunology; D013270:Stomach / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D013274:Stomach Neoplasms / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D019496:Cancer Vaccines; D002772:Cholera Toxin