Tryptophan catabolites regulate mucosal sensitization to ovalbumin in respiratory airways

Allergy. 2009 Mar;64(3):488-92. doi: 10.1111/j.1398-9995.2008.01809.x. Epub 2008 Aug 21.

Abstract

Background: Indoleamine 2,3 dioxygenase (IDO), the rate-limiting enzyme in tryptophan catabolism, is important in generating tolerance at the foetal-maternal interface. Studies using 1-methyl-tryptophan (1-MT), the specific inhibitor of IDO, showed that this enzyme is important in interferon-gamma (IFN-gamma)-dependent inhibition of allergic inflammation in the respiratory airway during immunotherapy.

Aims of study: We investigated the role of IDO in the development of allergic sensitization, leading to allergic inflammation and airway hyper-responsiveness (AHR).

Methods: We used a mouse model to generate mucosal tolerance to lipopolysaccharide-free ovalbumin (OVA) following repeated intranasal inoculation of OVA over a 3-day period. We tested the successful induction of tolerance by subsequent intraperitoneal (i.p.) sensitization followed by intranasal challenge with OVA. A slow-release pellet of 1-MT implanted into mice was used to block IDO activity prior to repeated intranasal inoculation of OVA. We measured T-cell proliferation in response to OVA, determined airway inflammation, and measured AHR to intranasal methacholine to investigate the role of IDO in sensitization to OVA.

Results: Repeated intranasal administration of OVA generated tolerance and prevented a subsequent sensitization to OVA via the i.p. route. This response was inhibited in mice receiving a slow-release pellet of 1-MT. However, we successfully reconstituted tolerance in mice receiving 1-MT following intra-peritoneal injection of a mixture of kynurenine and hydroxyanthranilic acid.

Conclusion: Our data suggest that, in addition to their role in IFN-gamma-mediated inhibition of allergic airway inflammation, products of tryptophan catabolism play an important role in the prevention of sensitization to potential allergens in the respiratory airway.

MeSH terms

  • Allergens / immunology
  • Animals
  • Immune Tolerance / physiology*
  • Immunity, Mucosal / drug effects*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Interferon-gamma / immunology
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Ovalbumin / immunology
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism*
  • T-Lymphocytes / immunology
  • Tryptophan / analogs & derivatives*
  • Tryptophan / metabolism

Substances

  • Allergens
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interferon-gamma
  • Tryptophan
  • Ovalbumin