Tryptophan catabolites regulate mucosal sensitization to ovalbumin in respiratory airways

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.