Short communication Tryptophan catabolites regulate mucosal sensitization to ovalbumin in respiratory airways The oxidative catabolism of tryptophan via the kynure- nine (KYN) pathway in peripheral tissues generates a host of neuroactive compounds called KYN. The rate- limiting step in this pathway is catalyzed by an interferon- (IFN)-inducible enzyme, indoleamine 2,3 dioxygenase (IDO) (1). Infiltration of lymphoid tissue by IDO- expressing dendritic cells (DCs) inhibited the develop- ment of antigen-specific immune response even when the ratio of IDO + to IDO ) DCs was extremely low (2). Epidemiological studies in cancer patients positively correlated escape of tumor cells from tumor-specific immune response with a switch to IDO expression by those cells (3). Thus, IDO expression, leading to tryptophan catabolism and depletion from cellular microenvironment, is a very potent tolerogenic mecha- nism, in vivo. While some studies suggested a role for tryptophan depletion, others ascribed a role to the accumulation of KYN following the initial, IDO- catalyzed, rate-limiting step (4, 5). In the airways, induction of IFN-c using a toll-like receptor-9 (TLR-9) agonist, ISSN-ODN, or ovalbumin (OVA) containing a high level of lipopolysaccharide (LPS) inhibited OVA-induced inflammation through the induction of IDO (6). This inhibitory effect was subse- quently shown to be on account of the IDO-mediated induction of apoptosis in Th2 cells through 3-hydroxy- anthranilic acid (3-HAA) (7). A recent study confirmed this observation and suggested that Th1-mediated induction of IDO and tryptophan capabilities is the basis of successful immunotherapy for atopic airway disease (8). Although these studies clearly established a role for IDO in the generation of a Th1 response in the airway, the precise role of IDO and tryptophan catab- olites in the development of mucosal tolerance or 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-c)-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 lipopoly- saccharide-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-c-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. S. O. Odemuyiwa 1 *, C. Ebeling 2 *, V. Duta 2 *, M. Abel 2 , L. Puttagunta 3 , O. Cravetchi 2 , C. Majaesic 1 , H. Vliagoftis 2† , R. Moqbel 2† Pulmonary Research Group, Departments of 1 Paediatrics and 2 Medicine; 3 Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada Key words: airway; indoleamine 2,3 dioxygenase; sensitization; tolerance; tryptophan. Redwan Moqbel, PhD, FRCPath Pulmonary Research Group Department of Medicine 574 Heritage Medical Research Centre University of Alberta Edmonton AB T6G 2S2 Canada *These authors contributed equally to this work.   This work was jointly supervised by these authors. Accepted for publication 1 May 2008 Allergy 2009: 64: 488–492 Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Munksgaard DOI: 10.1111/j.1398-9995.2008.01809.x 488