Document Detail

Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model.
MedLine Citation:
PMID:  18179817     Owner:  NLM     Status:  MEDLINE    
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. CONCLUSION: During immunotherapy, the tryptophan metabolites kynurenine, 3-hydroxykynurenine, and xanthurenic acid generated through IDO contribute to tolerance induction regarding TH2-dependent allergic airway inflammation.
Yousef A Taher; Benoit J A Piavaux; Reneé Gras; Betty C A M van Esch; Gerard A Hofman; Nanne Bloksma; Paul A J Henricks; Antoon J M van Oosterhout
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-01-07
Journal Detail:
Title:  The Journal of allergy and clinical immunology     Volume:  121     ISSN:  1097-6825     ISO Abbreviation:  J. Allergy Clin. Immunol.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-08     Completed Date:  2008-06-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1275002     Medline TA:  J Allergy Clin Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  983-91.e2     Citation Subset:  AIM; IM    
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands.
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MeSH Terms
Bronchoalveolar Lavage Fluid / cytology,  immunology
Cytokines / blood
Desensitization, Immunologic* / methods
Disease Models, Animal
Eosinophilia / immunology,  prevention & control
Immune Tolerance*
Indoleamine-Pyrrole 2,3,-Dioxygenase / physiology*
Mice, Inbred BALB C
Respiratory Hypersensitivity / enzymology*,  immunology,  pathology,  therapy*
Th2 Cells / enzymology,  immunology,  metabolism
Tryptophan / metabolism*
Reg. No./Substance:
0/Cytokines; 73-22-3/Tryptophan; EC 2,3,-Dioxygenase

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