title: Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model.
abstract: BACKGROUND
  The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in immune suppression and tolerance induction.
  
  
  OBJECTIVE
  We examined (1) whether IDO activity is required during tolerance induction by allergen immunotherapy or for the subsequent suppressive effects on asthma manifestations and (2) whether tryptophan depletion or generation of its downstream metabolites is involved.
  
  
  METHODS
  Ovalbumin (OVA)-sensitized and OVA-challenged BALB/c mice that display increased airway responsiveness to methacholine, serum OVA-specific IgE levels, bronchoalveolar eosinophilia, and TH2 cytokine levels were used as a model of allergic asthma. Sensitized mice received subcutaneous optimal (1 mg) or suboptimal (100 microg) OVA immunotherapy.
  
  
  RESULTS
  Inhibition of IDO by 1-methyl-DL-tryptophan during immunotherapy, but not during inhalation challenge, partially reversed the suppressive effects of immunotherapy on airway eosinophilia and TH2 cytokine levels, whereas airway hyperresponsiveness and serum OVA-specific IgE levels remained suppressed. Administration of tryptophan during immunotherapy failed to abrogate its beneficial effects toward allergic airway inflammation. Interestingly, administration of tryptophan or its metabolites, kynurenine, 3-hydroxykynurenine, and xanthurenic acid, but not 3-hydroxyanthranilinic acid, quinolinic acid, and kynurenic acid, during suboptimal immunotherapy potentiated the reduction of eosinophilia. These effects coincided with reduced TH2 cytokine levels in bronchoalveolar lavage fluid, but no effects on IgE levels were detected.
  
  
  CONCLUSIONS
  During immunotherapy, the tryptophan metabolites kynurenine, 3-hydroxykynurenine, and xanthurenic acid generated through IDO contribute to tolerance induction regarding TH2-dependent allergic airway inflammation.
authors.affiliation: Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands.
authors.forename: Yousef A
authors.initials: YA
authors.lastname: Taher
authors.forename: Benoit J A
authors.initials: BJ
authors.lastname: Piavaux
authors.forename: Reneé
authors.initials: R
authors.lastname: Gras
authors.forename: Betty C A M
authors.initials: BC
authors.lastname: van Esch
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Hofman
authors.forename: Nanne
authors.initials: N
authors.lastname: Bloksma
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Henricks
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: van Oosterhout
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003888:Desensitization, Immunologic / Q000379:methods; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology / Q000517:prevention & control; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012130:Respiratory Hypersensitivity / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan