Current Opinion in Allergy & Clinical Immunology:
RHINITIS, SINUSITIS AND UPPER AIRWAY DISEASE: Edited by Ruby Pawankar and David P. Skoner
Indoleamine 2,3-dioxygenase expression is associated with chronic rhinosinusitis: review of the evidence
Luukkainen, Annikaa; Toppila-Salmi, Sannab,c
aDepartment of Otorhinolaryngology, University of Tampere, Tampere
bHelsinki University Central Hospital, Skin and Allergy Hospital
cTransplantation laboratory, Haartman Institute, Haartmaninkatu 3 University of Helsinki, Helsinki, Finland
Correspondence to Sanna Toppila-Salmi, MD, PhD, Helsinki University Central Hospital, Skin and Allergy Hospital, PO BOX 160 (Meilahdentie 2), 00029 Hospital District of Helsinki and Uusimaa, Helsinki, Finland. Tel: +358 9 4711; fax: +358 9 1912 5155; e-mail: email@example.com
Purpose of review: Indoleamine 2,3 dioxygenase (IDO), the key metabolic enzyme implicated in tryptophan catabolism has been studied extensively during the past years in cancer, infections and autoimmunity. This review summarizes the findings of the immunomodulatory effects of IDO. In addition, the possible role of IDO in chronic rhinosinusitis (CRS) is discussed.
Recent findings: Epithelial and leukocyte IDO expression is pronounced in CRS with nasal polyps and antrochoanal polyps. Although IDO associates with atopic disorders of the lower respiratory tract, we were not able to find an association between IDO and allergic rhinitis in the sinonasal mucosa.
Summary: IDO might have a distinct role in the upper and lower respiratory tract. Future studies need to identify whether the IDO found in sinonasal mucosa is active and if it is a cause or a reason in the development of CRS with nasal polyps.
Chronic rhinosinusitis (CRS) is a versatile, multifactorial immunological disease of the nose and paranasal sinuses with a prevalence of about 10%. It is a significant health problem, with a large financial burden on our society and with an increasing incidence . Several diseases have been reported to coexist with CRS by partly unknown mechanisms: asthma, aspirin sensitivity, atopy, chronic rhinitis, depression, anxiety, fatigue, fibromyalgia, immunodeficiency, cystic fibrosis, and primary ciliary dyskinesia [2–4]. CRS can be subdivided into chronic rhinosinusitis with nasal polyps (CRSwNP) and without (CRSsNP). Nasal polyps appear as oedematous masses originating from the middle meatus and affect between 1 and 4% of the general population. CRS may develop in individuals with a certain genetic and/or epigenetic background as an outcome of unbalanced barrier-environment interactions. The exacerbations, triggered by viruses, allergens or other factors, might be both infective and hyperinflammatory in nature. The majority of patients with CRS have mild or moderate disease and can obtain adequate control of symptoms through conservative therapy, added occasionally by sinus surgery. However, patients with difficult-to-treat CRS might experience considerable morbidity and organ-threatening complications. There is a need to explore biomarkers and tools for preventing progressing of CRS.
Indoleamine 2,3 dioxygenase (IDO) is an intracellular enzyme that initiates the first and rate-limiting step of tryptophan (Trp) breakdown along the kynurenine pathway. The role of IDO has evolved throughout time. IDO is induced in dendritic cells, which restricts infection and prevents exaggerated host responses [5,6]. In noninflammatory states, IDO seems to mediate tolerance to self [7,8]. IDO also seems to mediate the transition from innate to acquired immunity. The role of IDO is traditionally recognized in autoimmunity, infection, cancer and pregnancy in a murine model. The scope of this review is to go over the evidence on the putative role of IDO in CRS and other respiratory disorders.
TRYPTOPHAN DEGRADATION PATHWAYS
Trp is present in relatively low amounts in the body. Unlike other amino acids, Trp circulates in blood and plasma mainly bound to albumin . Only 10–20% of Trp is present as free form in the plasma. Factors, such as nonesterified fatty acids or some drugs modify the binding of Trp to albumin. Whether or not Trp binding to albumin may modify the availability of Trp for tissue metabolism remains controversial [10,11]. Trp is also the precursor of N-formylkynurenine that is converted into kynurenine by kynurenine formamidase. N-formylkynurenine and kynurenine are the first metabolites of a complex metabolic pathway ending in quinolic acid, niacin, kynurenic and xanthurenic acid. Two enzymes are able to catalyse the conversion of Trp into N-formylkynurenine: Trp 2,3-dioxygenase (TDO) and IDO. These two enzymes differ in their tissue localisation, structure, substrate specificity, cofactor requirement and function. Whereas IDO is widespread in numerous tissues, TDO is mainly located in the liver . The liver through TDO activity is responsible for maintaining Trp homeostasis.
THE IMMUNOREGULATORY ROLE OF INDOLEAMINE 2,3-DIOXYGENASE
IDO is more than a metabolic enzyme. At first, its role seemed to be antimicrobial by restricting Trp availability. Munn showed in mice that inhibition of IDO by 1-methyl-DL-Trp (1-ML) in pregnancy causes rejection of semi-allogeneic, but not syngeneic fetuses . IDO is widely expressed in a variety of cell types, including leukocytes, antigen-presenting cells and tumour cells [14–16]. IDO is known to be induced by both type I and II interferons (IFN) [17,18]. In a murine model, macrophages and monocytes seem to express IDO messenger RNA (mRNA) transcripts only when activated by IFN-γ . On the contrary, IDO is expressed constitutively in CD8− and CD8+ dendritic cells, as well as eosinophils, even in the absence of IFN-γ. To date, two isoforms of IDO, IDO1 and IDO2 have been identified. Both differ in local expression, activity and organ specificity .
The putative mechanisms of action
The downstream metabolites of Trp suppress immune reactivity by directly interacting with effector T lymphocytes and other types of immune cells [21,22]; however, not all T cells are susceptible to the toxic effects of Trp metabolites . Kynurenine metabolites regulate the production of type I IFNs by decreasing the number of macrophages . Another hypothesis proposes that the breakdown of Trp suppresses T-cell proliferation by reducing the availability of this essential amino acid in local tissue microenvironments.
Indoleamine 2,3-dioxygenase in hypersensitivity responses
The function of IDO in eosinophils is either stimulatory or inhibitory on Th1 (T-helper 1 cell) and Th2 (T-helper 2 cell) cells depending on the inflammatory model and previous sensitization [23,25]. IDO induction in eosinophils might mediate a Th2 polarization in-vitro and in-vivo eosinophils displayed intracellular IDO immunoreactivity . The abundance and persistence of IDO-expressing eosinophils in lymphoid tissue may accentuate or, at a minimum, potentiate the apoptotic effect on Th1 cells previously thought to be associated only with IDO-expressing tolerogenic dendritic cells and thus maintain Th2 bias .
Indoleamine 2,3-dioxygenase in induction of tolerance
IDO seems to provide a potential mechanism for the development of dendritic cell-mediated T-cell tolerance . The effects of IDO are selective and narrowly focused on specific forms of acquired peripheral tolerance or unresponsiveness to novel antigens. Classically antigen presentation to resting T cells occurs in draining lymph nodes and this is thought to lead to T-cell activation, but studies have shown that this can also lead to potent, antigen-specific tolerance induction, particularly when antigens are presented in lymph nodes draining normal uninflamed tissues or mucosal surfaces. These studies emphasize that it is the nature of the lymph node, rather than the antigen, which dictates the choice between tolerance and immunity. Systemic inactivation of IDO does not appear to cause severe autoimmunity . Yet, IDO might mediate tolerance to self by transforming growth factor-beta (TGF-β) [7,8]. In this pathway, IDO is phosphorylated and acts as a signalling mediator [29▪,30]. IDO also seems to mediate the transition from innate to acquired immunity. IDO has signalling activity in dendritic cells, which are stably turned into regulatory dendritic cells [29▪]. Dendritic cells have functional plasticity. They can present antigens in an immunogenic or tolerogenic fashion, depending on environmental factors . In certain pathways, antigen-presenting cells and regulatory T cells (Tregs) are involved in an interplay which results in further upregulation of IDO and also four other amino acid-consuming enzymes, capable of restraining T-cell proliferation and promoting Treg expansion [29▪].
Indoleamine 2,3-dioxygenase in infection: a tolerogenic pathogen strategy
When pathogens invade host cells, they activate the innate immune system and elicit the production of cytokines and chemokines, which recruit immune cells that mediate pathogen clearance. Type I IFNs especially are important mediators of innate immunity that limit the adverse effects of many viruses. IFN-γ-induced IDO has an antiviral effect in measles virus infection of epithelial and endothelial cells in vitro. On the contrary, IFN-γ has shown to induce IDO's enzymatical functions in dendritic cells, which restricts infection and prevents exaggerated host responses [5,6]. Hoshi et al. found in a murine acute viral myocarditis model that IDO was induced by encephalomyocarditis virus, which promoted viral replication and tissue damage. IDO-deficient and inhibitor-treated mice had higher survival rates and had greater suppression of encephalomyocarditis virus replication. Disadvantageous effects of IDO have also been reported in other viral infections [33,34]. Bacterial infection with Mycobacterium tuberculosis strongly upregulated the expression of IDO1 in human monocyte derived dendritic cells and macrophages . In a murine model, Loughman and Hunstad [36▪] observed that uropathogenic Escherichia coli attenuated innate responses to epithelial infection by inducing expression of IDO. Bacteria such as uropathogenic E. coli seem to stimulate IDO expression as a pathogen strategy to create local immune privilege at epithelial surfaces, thus attenuating innate responses to promote colonization and the establishment of infection. Moreover, the authors observed that IFN was not necessary for IDO induction.
INDOLEAMINE 2,3-DIOXYGENASE IN AIRWAY DISEASES
Several studies propose that IDO has a role in the control of atopic and infective airway diseases, as summarized in Table 1[23,25,26,35,37–53].
Table 1-a Original a...Image Tools
Indoleamine 2,3-dioxygenase in asthma
Table 1-b Original a...Image Tools
Table 1-c Original a...Image Tools
In a murine asthma model, IDO inhibits eosinophilic inflammation . In an OVA-sensitized mouse model, An et al. found that immature dendritic cells (imDCs)-expressing IDO relieved allergic airway inflammation, as measured by decreased eosinophil and total cell counts, as well as by improved pulmonary histopathology. The authors also observed that increased CD4+ T-cell apoptosis was observed in mice receiving IDO-expressing imDCs, in comparison to the control groups. Paveglio et al. showed in a transgenic mouse model that overexpression of IDO in the lungs might cause an antiasthmatic effect by diminishing proliferation, numbers and cytokine production of CD4+ T cells. It has been shown that IDO in lung dendritic cells promoted Th2-mediated allergic airway inflammation, but was not essential for immune tolerance via inhibition of Th1 response [40,54]. Toll-like receptor-9-ligand-induced pulmonary IDO activity inhibits Th2-driven experimental asthma . When exposing in vitro monocyte-derived dendritic cells with house dust mite Dermatophagoides pteronyssinus 1, functionally active IDO decreased in cells from patients with house dust mite-sensitive asthma compared with nonatopic asthmatics . In studies with asthmatic patients, von Bubnoff et al. showed that after in-vivo aeroallergen exposure, serum IDO activity was increased in asymptomatic atopics compared with either symptomatic atopic or nonatopic individuals. In an asthma cohort study , lower IDO activity has been observed in atopics in comparison to nonatopics. Maneechotesuwan et al. showed that asthmatics have low baseline IDO activity in sputum. They also showed that IDO activity could be enhanced by treatment with inhaled corticosteroids .
Indoleamine 2,3-dioxygenase in chronic rhinosinusitis
CRS without nasal polyps (CRSsNP) is characterized by a Th1 polarization with high levels of IFN-γ and TGF-β . In comparison to CRSsNP, nasal polyps of Caucasian patients are characterized by pronounced local eosinophilia  and systemically by increased blood eosinophilia . CRSwNP is characterised by a Th2 polarization with high interleukin-5 (IL-5) and immunoglobulin E (IgE) concentrations . A deficit in Treg capacity in CRSwNP might lead to a strong increase in Th1 and Th2 effector cell signals . Antrochoanal polyps originate (unilaterally) from the maxillary sinus mucosa and protrude into the choana. They are considered to have a predominance of neutrophils .
We found that in comparison to control inferior turbinate, IDO is strongly expressed in nasal polyp tissue in the vicinity of the Golgi apparatus of epithelial cells, but not on the supraepithelial mucus . Moreover, IDO is weakly expressed in submucosal leukocytes and intraepithelial glands. Also, epithelial IDO expression seems to correlate with higher eosinophil numbers as well as with leukocyte IDO expression . Epithelial IDO expression associates also with higher amounts of supraepithelial mucus. The maxillary sinus mucosa from patients with CRSwNP showed a higher IDO expression level in leukocytes but not in the epithelium when compared with healthy controls. However, the patients suffering from CRSsNP did not have different expression levels of IDO in the maxillary sinus mucosa in comparison to controls. The findings of IDO expression in sinonasal biopsies were independent of allergic rhinitis, acetyl salicylic acid (aspirin) intolerance, asthma, smoking, use of intranasal or peroral corticosteroids, or antihistamines, previous operations, recurrence of polyps, sex and age . Sekigawa et al. showed that the INDO genotype found in nasal polyp specimens seems to have a role in the genetic risk for aspirin-intolerant asthma. Our unpublished results show that serum IDO activity is significantly lower in patients with nasal polyps (NP), independently of asthma, atopy, aspirin intolerance and smoking. NP might thus affect immunity on a system level independently of asthma, atopy or acetylsalicylic acid intolerance [61–63]. The fact that patients with CRSwNP might have a high level of epithelial IDO locally, but low serum activity of IDO, requires further elucidation. The explanation could partly be that active epithelial IDO does not affect or affects serum kyn/trp concentrations little. Moreover, local and systemically acting IDO probably have different immunoregulatory functions in patients with CRSwNP.
Indoleamine 2,3-dioxygenase in allergic rhinitis
IDO seems to associate with atopic asthma, yet there is still a lack of evidence whether IDO promotes allergic inflammation also in the upper airways. When we observed patients with CRS, the expression of epithelial and leukocyte IDO was independent of the allergic rhinitis diagnosis . We also took nasal biopsies from controls and patients with birch pollen allergic rhinitis, both in winter and spring. As expected, patients with birch pollen allergic rhinitis had increased serum IgE levels. During spring, atopic patients showed increased mucosal eosinophilia and symptom score. Yet, the expression of IDO in the nasal mucosa remained at the control level . Thus, in the upper airways, IDO could associate with CRSwNP but not with allergic rhinitis.
INDOLEAMINE 2,3-DIOXYGENASE IN OTHER DISEASES
During the past year, reviews on the role of IDO in allergy [64▪▪], cancer , antitumour immunity [66▪], HIV infection , the induction of IDO activity and signalling [29▪], therapeutic potentials , posttranslational modifications , allogeneic engraftment of skin substitute  have been made. In allografts, IDO-mediated T-cell inhibition has shown to be rapidly reversed once IDO activity ceases . The pharmacologic inhibition of IDO causes marked exacerbation of inflammation and worsened symptoms of disease in a murine model of inflammatory bowel disease . In cancer, IDO seems to decrease recruitment of antitumour immune cells, induce tolerance towards tumour antigens and thus facilitate immune escape. In addition, increased IDO expression correlates with diverse tumour progression parameters and shorter patient survival. IDO helps create a tolerogenic milieu in the tumour and the tumour-draining lymph nodes, both by direct suppression of T cells and enhancement of local Treg-mediated immunosuppression. It can also function as an antagonist to other activators of antitumour immunity . Immunologic tolerance to tumours is not simply a passive event; the immune system, in some cases, seems to be aware of tumour antigens but is somehow rendered tolerant to them. Once this acquired tolerance has been established, immunization with tumour-associated antigens can intensify antigen-specific immunosuppression . Preclinical studies with 1-methyltryptophan and other approaches in cancer immunotherapy are in progress .
IDO has variable functions in several diseases, such as atopic lower respiratory diseases. By this review, we were able to add a putative role of IDO also in CRSwNP. Before considering IDO as a biomarker or potent tool for management of airways diseases, further studies on the distinct roles of IDO in the respiratory system are needed. Moreover, the elucidation of its role in the pathomechanisms of CRSwNP demands more studies.
Conflicts of interest
There are no conflicts of interest.
The authors declare not having received any funding for this work from any of the following organizations: National Institutes of Health (NIH); Wellcome Trust; Howard Hughes Medical Institute (HHMI) or other(s).
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 120).
1. Fokkens WJ, Lund VJ, Mullol J, et al.
European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl 2012; 23:3 p preceding table of contents, 1–298.
2. Jarvis D, Newson R, Lotvall J, et al. Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe. Allergy 2012; 67:91–98.
3. Bousquet J, Bachert C, Canonica GW, et al. Unmet needs in severe chronic upper airway disease (SCUAD). J Allergy Clin Immunol 2009; 124:428–433.
4. Rudmik L, Smith TL. Quality of life in patients with chronic rhinosinusitis. Curr Allergy Asthma Rep 2011; 11:247–252.
5. Daubener W, MacKenzie CR. IFN-gamma activated indoleamine 2,3-dioxygenase activity in human cells is an antiparasitic and an antibacterial effector mechanism. Adv Exp Med Biol 1999; 467:517–524.
6. Yuasa HJ, Takubo M, Takahashi A, et al. Evolution of vertebrate indoleamine 2,3-dioxygenases. J Mol Evol 2007; 65:705–714.
7. Belladonna ML, Orabona C, Grohmann U, Puccetti P. TGF-beta and kynurenines as the key to infectious tolerance. Trends Mol Med 2009; 15:41–49.
8. Pallotta MT, Orabona C, Volpi C, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol 2011; 12:870–878.
9. Pardridge WM. Tryptophan transport through the blood-brain barrier: in vivo measurement of free and albumin-bound amino acid. Life Sci 1979; 25:1519–1528.
10. Smith SA, Pogson CI. The metabolism of L-tryptophan by isolated rat liver cells: effect of albumin binding and amino acid competition on oxidatin of tryptophan by tryptophan 2,3-dioxygenase. Biochem J 1980; 186:977–986.
11. Pardridge WM. Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev 1983; 63:1481–1535.
12. Le Floc’h N, Otten W, Merlot E. Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 2011; 41:1195–1220.
13. Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998; 281:1191–1193.
14. Munn DH, Shafizadeh E, Attwood JT, et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 1999; 189:1363–1372.
15. Mellor AL, Sivakumar J, Chandler P, et al. Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol 2001; 2:64–68.
16. Mellor AL, Keskin DB, Johnson T, et al. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J Immunol 2002; 168:3771–3776.
17. Popov A, Schultze JL. IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med (Berl) 2008; 86:145–160.
18. Scheler M, Wenzel J, Tuting T, et al. Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation? Am J Pathol 2007; 171:1936–1943.
19. Fallarino F, Vacca C, Orabona C, et al. Functional expression of indoleamine 2,3-dioxygenase by murine CD8 alpha(+) dendritic cells. Int Immunol 2002; 14:65–68.
20. Ball HJ, Sanchez-Perez A, Weiser S, et al. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene 2007; 396:203–211.
21. Frumento G, Rotondo R, Tonetti M, et al. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 2002; 196:459–468.
22. Terness P, Bauer TM, Rose L, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 2002; 196:447–455.
23. Swanson KA, Zheng Y, Heidler KM, et al. CDllc+ cells modulate pulmonary immune responses by production of indoleamine 2,3-dioxygenase. Am J Respir Cell Mol Biol 2004; 30:311–318.
24. Hoshi M, Matsumoto K, Ito H, et al. L-tryptophan-kynurenine pathway metabolites regulate type I IFNs of acute viral myocarditis in mice. J Immunol 2012; 188:3980–3987.
25. Grohmann U, Volpi C, Fallarino F, et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med 2007; 13:579–586.
26. Odemuyiwa SO, Ghahary A, Li Y, et al. Cutting edge: human eosinophils regulate T cell subset selection through indoleamine 2,3-dioxygenase. J Immunol 2004; 173:5909–5913.
27. Sharma MD, Baban B, Chandler P, et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 2007; 117:2570–2582.
28. Mellor AL, Munn DH. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev Immunol 2008; 8:74–80.
29▪. Fallarino F, Grohmann U. Indoleamine 2,3-dioxygenase: from catalyst to signaling function 2012; 42:1932–1937.
This review summarises various pathways, which induce IDO's functions.
30. Fujigaki H, Seishima M, Saito K. Posttranslational modification of indoleamine 2,3-dioxygenase. Anal Bioanal Chem 2012; 403:1777–1782.
31. Grohmann U, Bianchi R, Orabona C, et al. Functional plasticity of dendritic cell subsets as mediated by CD40 versus B7 activation. J Immunol 2003; 171:2581–2587.
32. Heseler K, Spekker K, Schmidt SK, et al. Antimicrobial and immunoregulatory effects mediated by human lung cells: role of IFN-gamma-induced tryptophan degradation. FEMS Immunol Med Microbiol 2008; 52:273–281.
33. Boasso A, Herbeuval JP, Hardy AW, et al. HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood 2007; 109:3351–3359.
34. Hryniewicz A, Boasso A, Edghill-Smith Y, et al. CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Blood 2006; 108:3834–3842.
35. Weiner J 3rd, Parida SK, Maertzdorf J, et al. Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients. PLoS One 2012; 7:e40221.
36▪. Loughman JA, Hunstad DA. Induction of indoleamine 2,3-dioxygenase by uropathogenic bacteria attenuates innate responses to epithelial infection. J Infect Dis 2012; 205:1830–1839.
The study presents interesting findings on IDO's role in the induction of local immune privilege at epithelial surfaces in response to infection.
37. Hayashi T, Beck L, Rossetto C, et al. Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest 2004; 114:270–279.
38. An XJ, Bai CX, Xia JB, et al. Immature dendritic cells expressing indoleamine 2,3-dioxygenase suppress ovalbumin-induced allergic airway inflammation in mice. J Investig Allergol Clin Immunol 2011; 21:185–192.
39. Paveglio SA, Allard J, Foster Hodgkins SR, et al. Airway epithelial indoleamine 2,3-dioxygenase inhibits CD4+ T cells during Aspergillus fumigatus antigen exposure. Am J Respir Cell Mol Biol 2011; 44:11–23.
40. Xu H, Oriss TB, Fei M, et al. Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation. Proc Natl Acad Sci U S A 2008; 105:6690–6695.
41. Maneechotesuwan K, Wamanuttajinda V, Kasetsinsombat K, et al. Der p 1 suppresses indoleamine 2, 3-dioxygenase in dendritic cells from house dust mite-sensitive patients with asthma. J Allergy Clin Immunol 2009; 123:239–248.
42. von Bubnoff D, Fimmers R, Bogdanow M, et al. Asymptomatic atopy is associated with increased indoleamine 2,3-dioxygenase activity and interleukin-10 production during seasonal allergen exposure. Clin Exp Allergy 2004; 34:1056–1063.
43. Maneechotesuwan K, Supawita S, Kasetsinsombat K, et al. Sputum indoleamine-2, 3-dioxygenase activity is increased in asthmatic airways by using inhaled corticosteroids. J Allergy Clin Immunol 2008; 121:43–50.
44. Honkanen T, Luukkainen A, Lehtonen M, et al. Indoleamine 2,3-dioxygenase expression is associated with chronic rhinosinusitis with nasal polyps and antrochoanal polyps. Rhinology 2011; 49:356–363.
45. Luukkainen A, Karjalainen J, Honkanen T, et al. Indoleamine 2,3-dioxygenase expression in patients with allergic rhinitis: a case-control study. Clin Transl Allergy 2011; 1:17.
46. Ciprandi G, De Amici M, Tosca M, Fuchs D. Tryptophan metabolism in allergic rhinitis: the effect of pollen allergen exposure. Hum Immunol 2010; 71:911–915.
47. Maneechotesuwan K, Ekjiratrakul W, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ. Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase. J Allergy Clin Immunol 2010; 126:754,762.e1.
48. Taher YA, Piavaux BJ, Gras R et al.
Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model. J Allergy Clin Immunol 2008; 121:983,991.e2.
49. Kositz C, Schroecksnadel K, Grander G, et al. High serum tryptophan concentration in pollinosis patients is associated with unresponsiveness to pollen extract therapy. Int Arch Allergy Immunol 2008; 147:35–40.
50. van der Marel AP, Samsom JN, Greuter M, et al. Blockade of IDO inhibits nasal tolerance induction. J Immunol 2007; 179:894–900.
51. Suzuki Y, Suda T, Asada K, et al. Serum indoleamine 2,3-dioxygenase activity predicts prognosis of pulmonary tuberculosis. Clin Vaccine Immunol 2012; 19:436–442.
52. Suzuki Y, Suda T, Yokomura K, et al. Serum activity of indoleamine 2,3-dioxygenase predicts prognosis of community-acquired pneumonia. J Infect 2011; 63:215–222.
53. Yoshida R, Urade Y, Tokuda M, Hayaishi O. Induction of indoleamine 2,3-dioxygenase in mouse lung during virus infection. Proc Natl Acad Sci U S A 1979; 76:4084–4086.
54. Xu H, Zhang GX, Ciric B, Rostami A. IDO: a double-edged sword for T(H)1/T(H)2 regulation. Immunol Lett 2008; 121:1–6.
55. Raitala A, Karjalainen J, Oja SS, et al. Indoleamine 2,3-dioxygenase (IDO) activity is lower in atopic than in nonatopic individuals and is enhanced by environmental factors protecting from atopy. Mol Immunol 2006; 43:1054–1056.
56. Van Zele T, Claeys S, Gevaert P, et al. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy 2006; 61:1280–1289.
57. Nakayama T, Yoshikawa M, Asaka D, et al. Mucosal eosinophilia and recurrence of nasal polyps: new classification of chronic rhinosinusitis. Rhinology 2011; 49:392–396.
58. Ebbens FA, Toppila-Salmi SK, Renkonen JA, et al. Endothelial L-selectin ligand expression in nasal polyps. Allergy 2010; 65:95–102.
59. Van Bruaene N, Perez-Novo CA, Basinski TM et al.
T-cell regulation in chronic paranasal sinus disease. J Allergy Clin Immunol 2008; 121:1435,41, 1441.e1–e3.
60. Sekigawa T, Tajima A, Hasegawa T, et al. Gene-expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma. Clin Exp Allergy 2009; 39:972–981.
61. Keseroglu K, Banoglu E, Kizil Y, et al. Serum interleukin-16 levels in patients with nasal polyposis. Laryngoscope 2012; 122:961–964.
62. Ahn Y, An SY, Won TB, et al. Nasal polyps: An independent risk factor for bronchial hyperresponsiveness in patients with allergic rhinitis. Am J Rhinol Allergy 2010; 24:359–363.
63. Han DH, Kim SW, Cho SH, et al. Predictors of bronchial hyperresponsiveness in chronic rhinosinusitis with nasal polyp. Allergy 2009; 64:118–122.
64▪▪. von Bubnoff D, Bieber T. The indoleamine 2,3-dioxygenase (IDO) pathway controls allergy. Allergy 2012; 67:718–725.
This review summarizes the role of IDO in allergy.
65. Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res 2011; 17:6985–6991.
66▪. Munn DH. Blocking IDO activity to enhance antitumor immunity. Front Biosci (Elite Ed) 2012; 4:734–745.
This review goes over the role of IDO in tolerance to tumours and the possible inhibition of IDO in the future, pharmacologically, in the treatment of cancer patients.
67. Boasso A. Wounding the immune system with its own blade: HIV-induced tryptophan catabolism and pathogenesis. Curr Med Chem 2011; 18:2247–2256.
68. Bahar MA, Nabai L, Ghahary A. Immunoprotective role of indoleamine 2,3-dioxygenase in engraftment of allogenic skin substitute in wound healing. J Burn Care Res 2012; 33:364–370.
69. Hainz U, Jurgens B, Heitger A. The role of indoleamine 2,3-dioxygenase in transplantation. Transpl Int 2007; 20:118–127.
70. Gurtner GJ, Newberry RD, Schloemann SR, et al. Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice. Gastroenterology 2003; 125:1762–1773.
71. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 2007; 117:1147–1154.
asthma; chronic rhinosinusitis; indoleamine 2,3-dioxygenase; kynurenine; tryptophan
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