Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model

Yousef A. Taher, Benoit J. A. Piavaux, Renee Gras, Betty C. A. M. van Esch, Gerard A. Hofman, Nanne Bloksma, Paul A. J. Henricks, Antoon J. M. van Oosterhout*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

61 Citations (Scopus)

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 T(H)2 cytokine levels were used as a model of allergic asthma. Sensitized mice received subcutaneous optimal (1 mg) or suboptimal (100 mu g) 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 T(H)2 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 T(H)2 cytokine levels in bronchoalveolar lavage fluid, but no effects on IgE levels were detected.

Conclusion: During immunotherapy, the tryptophan metabolites kynurenine, 3-hydroxykynurenine, and xanthurenic acid generated through IDO contribute to tolerance induction regarding T(H)2-dependent allergic airway inflammation.

Original languageEnglish
Pages (from-to)983-991
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume121
Issue number4
DOIs
Publication statusPublished - Apr-2008

Keywords

  • allergic asthma
  • immunotherapy
  • indoleamine 2,3-dioxygenase
  • tryptophan
  • kynurenine
  • dendritic cell
  • regulatory T cells
  • T(H)2 lymphocytes
  • hyperresponsiveness
  • eosinophilia
  • IgE
  • IL-10
  • suppression
  • GRASS-POLLEN IMMUNOTHERAPY
  • DENDRITIC CELLS
  • T-CELL
  • AIRWAY INFLAMMATION
  • KYNURENINE PATHWAY
  • INTERFERON-GAMMA
  • ASTHMA
  • INHIBITION
  • MICE
  • LYMPHOCYTES

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