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The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity
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Indoleamine 2, 3-dioxygenase (IDO) is the first and rate limiting catabolic enzyme in the degradation pathway of the essential amino acid tryptophan. By cleaving the aromatic indole ring of tryptophan, IDO initiates the production of a variety of tryptophan degradation products called “kynurenines” that are known to exert important immuno-regulatory functions. Because tryptophan must be supplied in the diet, regulation of tryptophan catabolism may exert profound effects by activating or inhibiting metabolism and immune responses. Important for survival, the regulation of IDO biosynthesis and its activity in cells of the immune system can critically alter their responses to immunological insults, such as infection, autoimmunity and cancer. In this review, we assess how IDO-mediated catabolism of tryptophan can modulate the immune system to arrest inflammation, suppress immunity to cancer and inhibit allergy, autoimmunity and the rejection of transplanted tissues. Finally, we examine how vaccines may enhance immune suppression of autoimmunity through the upregulation of IDO biosynthesis in human dendritic cells.
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![Figure 2 Mechanism of IDO1 induction in dendritic cells: transcription and translation. Several molecular stimuli and signaling pathways were shown to induce the transcription and translation of metabolically-active IDO1 enzyme [35,40,50]. The IDO1 promoter contains nucleotide sequences that allow regulation of transcription through interferon sequence response-like element (ISRE) upstream consensus sequences, GAS (palindromic gamma-activated sequences) and non-canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) [42,50]. In addition, the IDO1 promoter region contains three partial non-canonical RelB/p52 binding sites: AGGAGACACA, GGGAGACAGA and AGGAGAAAGA located near position −2000, which is located downstream of NF-κB-driven IDO upregulation following stimulation of the TLR4, INFGR, IFNAR, TNFR and CD40R signaling pathways [43].](/paper-figures/c748b5e2d686409aba397c4eb47122fd/the-role-of-indoleamine-2-3-dioxygenase-in-immune-suppression-and-autoimmunity-figure-2.jpg)
![Figure 3 The TGF-β-IDO-SHP axis. The TGF-β-IDO-SHP axis activates the non-canonical NF-κB pathway [49]. In splenocytes, SHP-1 inhibits the protein kinase IRAK1 and tips the balance of activation of the canonical versus non-canonical NF-κB signaling pathway in favor of the latter, resulting in upregulated production of type I interferon [49]. In addition to TGF-β, the aryl hydrocarbon receptor (AhR) has also been shown to play a role in IDO production [51,53]. Interestingly, kynurenines produced from IDO’s enzymatic activity can also bind and activate as an endogenous ligand, AhR [53,54]. Abbreviations: IFN (α β, γ,): interferon alpha, beta, gamma; TGF-β: transforming growth factor-beta; TNF: tumor necrosis factor; TLR4: toll-like receptor 4; TRAF: TNF-receptor associated factors; TRIF: TIR-domain-containing adapter-inducing interferon-β; SHP: orphan nuclear receptor small heterodimer partner; SMAD: extracellular signal transducers from TGF-β ligands to the nucleus; IRF (1, 3): and interferon regulatory factor 1,3.](/paper-figures/ded76164a88e4dc388ba105d8aa15574/the-role-of-indoleamine-2-3-dioxygenase-in-immune-suppression-and-autoimmunity-figure-3.jpg)
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“Increased IDO expression is responsible for the catabolism of TRP in the KYN degradation pathway [36] and is canonically upregulated by inflammatory mechanisms [37,38].”
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“deletion of portions of two ISRE cis-acting (ISRE1 and ISRE2) response elements resulted in decreased IDO1 expression levels [39].”
BackgroundThaker, A. I., Rao, M. S., Bishnupuri, K. S., Kerr, T. A., Foster, L. R., Marinshaw, J. M., Newberry, R. D., Stenson, W. F., & Ciorba, M. A. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.05.002 · Cited by 197
Recent Developments in Cancer Vaccines
Palucka, K., Ueno, H., & Banchereau, J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.0902539 · Cited by 193 · cited 1×
“loaded with tumor antigens were shown to improve the immune response to the cancer [109,110].”
BackgroundBoyland, E. J., & Williams, D. C. (1956) · Biochemical Journal · doi:10.1042/bj0640578 · Cited by 180
Manipulation of dendritic cell function by viruses
Cunningham, A. L., Donaghy, H., Harman, A. N., Kim, M., & Turville, S. G. (2010) · Current Opinion in Microbiology · doi:10.1016/j.mib.2010.06.002 · Cited by 179 · cited 2×
“A recent report showed that IDO1 was overexpressed in lymphoid tissues during HIV infection [83].”
BackgroundIndoleamine 2,3-Dioxygenase and Dendritic Cell Tolerogenicity
Harden, J. L., & Egilmez, N. K. (2012) · Immunological Investigations · doi:10.3109/08820139.2012.676122 · Cited by 177 · cited 1×
“Tryptophan depletion is sensed in eukaryotic cells through activation of the general control non-repressed 2 (GCN2) kinase, which directly binds uncharged tRNAs [14,58,59].”
BackgroundJürgens, B., Hainz, U., Fuchs, D., Felzmann, T., & Heitger, A. (2009) · Blood · doi:10.1182/blood-2008-12-195073 · Cited by 176
Cutting Edge: Autocrine TGF-β Sustains Default Tolerogenesis by IDO-Competent Dendritic Cells
Belladonna, M. L., Volpi, C., Bianchi, R., Vacca, C., Orabona, C., Pallotta, M. T., Boon, L., Gizzi, S., Fioretti, M. C., Grohmann, U., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.8.5194 · Cited by 169 · cited 1×
“Treatment of mouse plasmacytoid DCs with transforming growth factor- (TGF- ) conferred regulatory effects on IDO1 that were shown to be mechanistically separable from its enzymatic activity [11,49,66].”
BackgroundGeorge‐Chandy, A., Eriksson, K., Lebens, M., Nordström, I., Schön, E., & Holmgren, J. R. (2001) · Infection and Immunity · doi:10.1128/iai.69.9.5716-5725.2001 · Cited by 168 · cited 5×
“Initial oral immunization experiments showed that feeding small amounts (2–20 μg) of CTB-INS could effectively suppress -cell destruction and clinical diabetes in pre-diabetic NOD mice [123,124,141].”
BackgroundInfluentialSpectrum of Epstein-Barr virus-related diseases: a pictorial review
Maeda, E., Akahane, M., Kiryu, S., Kato, N., Yoshikawa, T., Hayashi, N., Aoki, S., Minami, M., Uozaki, H., Fukayama, M., et al. (2009) · Japanese Journal of Radiology · doi:10.1007/s11604-008-0291-2 · Cited by 168 · cited 1×
“shown to occur in HIV-infected patients [87].”
Levo- but not dextro-1-methyl tryptophan abrogates the IDO activity of human dendritic cells
Löb, S., Königsrainer, A., Schäfer, R., Rammensee, H., Opelz, G., & Terness, P. (2007) · Blood · doi:10.1182/blood-2007-10-116111 · Cited by 167 · cited 2×
“Based on the enzyme’s immunosuppressive functions, IDO1 is becoming established as a target for drug discovery in cancer immunotherapy [95,97].”
BackgroundTas, S. W., Vervoordeldonk, M. J., Hajji, N., Schuitemaker, J. H. N., van der Sluijs, K., May, M. J., Ghosh, S., Kapsenberg, M. L., Tak, P. P., & de Jong, E. C. (2007) · Blood · doi:10.1182/blood-2006-11-056010 · Cited by 167 · cited 3×
“Based on the observation that CD40 ligand (CD40L) induces IDO1 biosynthesis through non-canonical NF- B signaling in human DCs [35], NF- B signaling pathway involvement in cholera toxin B subunit-”
BackgroundAerobic and anaerobic NAD+ metabolism in Saccharomyces cerevisiae
Panozzo, C., Nawara, M., Suski, C., Kucharczyk, R., Skoneczny, M., Bécam, A. ‐., Rytka, J., & Herbert, C. J. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02585-1 · Cited by 156 · cited 1×
“While TDO is widely distributed in both eukaryotes and bacteria [5], IDO1 is restricted to mammals and yeast [6].”
BackgroundIDO expression in the brain: a double-edged sword
Kwidzinski, E., & Bechmann, I. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-007-0229-7 · Cited by 154 · cited 3×
“Two tryptophan degradation products, quinolinic acid (QUIN) and 3-hydroxyanthranilic acid (3-HAA), exhibit neurotoxic properties [26].”
BackgroundInfluentialImmunopathogenesis of multiple sclerosis: the role of T cells
Martino, G., & Hartung, H.-P. (1999) · Current Opinion in Neurology · doi:10.1097/00019052-199906000-00010 · Cited by 151 · cited 1×
“The predisposition of NOD mouse development of autoimmunity may involve defects in the mechanisms of both peripheral and central tolerance [65,112].”
BackgroundIndoleamine 2,3 dioxygenase and regulation of T cell immunity
Mellor, A. L. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.232 · Cited by 149 · cited 2×
“work by Munn, Mellor and their colleagues demonstrated that cells of the placenta express IDO1, which prevented maternal T-cell destruction of the fetus during pregnancy [12–14].”
BackgroundClements, C. S., Reid, H. H., Beddoe, T., Tynan, F. E., Perugini, M. A., Johns, T. G., Bernard, C. C. A., & Rossjohn, J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1833158100 · Cited by 148 · cited 2×
“self-antigens were shown to prevent uveitis, multiple sclerosis and type 1 diabetes in animal models of autoimmunity [124,131,132,142,153].”
BackgroundChen, J.-Y., Li, C., Kuo, C.-C., Tsai, K. K., Hou, M., & Hung, W.-C. (2014) · Breast Cancer Research · doi:10.1186/s13058-014-0410-1 · Cited by 145 · cited 2×
“One hallmark of GBM is the gradual accumulation of immunosuppressive and tumor-promoting CD4+ FoxP3+ regulatory T-cells (Tregs) [100,101].”
BackgroundLi, M., Bolduc, A. R., Hoda, M. N., Gamble, D. N., Dolisca, S.-B., Bolduc, A., Hoang, K., Ashley, C., McCall, D. C., Rojiani, A. M., et al. (2014) · Journal for ImmunoTherapy of Cancer · doi:10.1186/2051-1426-2-21 · Cited by 144 · cited 1×
“One hallmark of GBM is the gradual accumulation of immunosuppressive and tumor-promoting CD4 FoxP3+ regulatory T-cells (Tregs) [100,101].”
BackgroundIDO2 in Immunomodulation and Autoimmune Disease
Prendergast, G. C., Metz, R. A., Muller, A. J., Merlo, L. M. F., & Mandik‐Nayak, L. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00585 · Cited by 140 · cited 1×
“Both IDO1 and IDO2 genes are conserved in mammals and are present in tandem on chromosome 8 [8,9].”
BackgroundInfection of Primary Human Monocytes by Epstein-Barr Virus
Savard, M., Bélanger, C., Tardif, M. R., Gourde, P., Flamand, L., & Gosselin, J. (2000) · Journal of Virology · doi:10.1128/jvi.74.6.2612-2619.2000 · Cited by 135 · cited 1×
“The EB virus is known to infect monocytes/macrophages, intraepithelial macrophages and Langerhans dendritic cells [90,91].”
BackgroundTGF-β and kynurenines as the key to infectious tolerance
Belladonna, M. L., Orabona, C., Grohmann, U., & Puccetti, P. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2008.11.006 · Cited by 134 · cited 3×
“Vaccine-induced IDO1 biosynthesis and enzyme activity in human DCs suggest that kynurenines may be important for vaccine suppression of type 1 diabetes autoimmunity [11,34,56,61,65].”
BackgroundDendritic Cells: Arbiters of Immunity and Immunological TolerancePreprint
Lewis, K. L., & Reizis, B. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a007401 · Cited by 129 · cited 1×
“degradation of tryptophan accompanied DC suppression of arthritis, asthma, hemolytic anemia, multiple sclerosis, systemic lupus erythematosus and type 1 diabetes [116,117,146,154].”
BackgroundZhang, Y., Kang, S. A., Mukherjee, T., Bale, S., Crane, B. R., Begley, T. P., & Ealick, S. E. (2006) · Biochemistry · doi:10.1021/bi0620095 · Cited by 124 · cited 1×
“While TDO is widely distributed in both eukaryotes and bacteria [5], IDO1 is restricted to mammals and yeast [6].”
BackgroundStanford, M. R., Whittall, T., Bergmeier, L. A., Lindblad, M., LUNDIN, S., Shinnick, T. M., Mizushima, Y., Holmgren, J. R., & Lehner, T. (2004) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2004.02520.x · Cited by 121 · cited 1×
“Fusion of an uveitogenic HSP60-derived peptide (aa 336–351) with CTB resulted in significant protection against mucosally-induced uveitis and other Behcet’s disease symptoms [130].”
BackgroundKaneko, S., Suzuki, N., Yamashita, N., Nagafuchi, H., Nakajima, T., Wakisaka, S., Yamamoto, S., & Sakane, T. (1997) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.1997.3611265.x · Cited by 121
Konan, K. V., & Taylor, M. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.32.19140 · Cited by 121 · cited 2×
“expression, as the deletion of 748 bps between the elements had no effect on IDO1 synthesis [40].”
BackgroundFallarino, F., Bianchi, R., Orabona, C., Vacca, C., Belladonna, M. L., Fioretti, M. C., SERREZE, D. V., Grohmann, U., & Puccetti, P. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040942 · Cited by 120
Marrying Immunotherapy with Chemotherapy: Why Say IDO?
Muller, A. J., & Prendergast, G. C. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2213 · Cited by 115
Immunosuppression Via Tryptophan Catabolism: The Role of Kynurenine Pathway Enzymes
Belladonna, M. L., Puccetti, P., Orabona, C., Fallarino, F., Vacca, C., Volpi, C., Gizzi, S., Pallotta, M. T., Fioretti, M. C., & Grohmann, U. (2007) · Transplantation · doi:10.1097/01.tp.0000269199.16209.22 · Cited by 114 · cited 4×
“Through its expression in dendritic cells, monocytes and macrophages, IDO modulates T-cell behavior through catabolism of the essential amino acid tryptophan, which is obtained through the diet [11].”
BackgroundInfluentialNon-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation
Brandacher, G., Cakar, F., Winkler, C., Schneeberger, S., Obrist, P., Bösmüller, C., Werner‐Felmayer, G., Werner, E. R., Bonatti, H., Margreiter, R., et al. (2006) · Kidney International · doi:10.1038/sj.ki.5002023 · Cited by 112
Vogel, C. F. A., Wu, D., Goth, S. R., Baek, J., Lollies, A., Domhardt, R., Grindel, A., & Pessah, I. N. (2013) · Immunology and Cell Biology · doi:10.1038/icb.2013.43 · Cited by 111
AB Toxins: A Paradigm Switch from Deadly to Desirable
Odumosu, O., Nicholas, D., Yano, H., & Langridge, W. H. R. (2010) · Toxins · doi:10.3390/toxins2071612 · Cited by 109
Self-citationSoliman, H. H., Rawal, B., Fulp, J., Lee, J., Lopez, A. S., Bui, M. M., Khalil, F. K., Antonia, S. J., Yfantis, H. G., Lee, D. H., et al. (2013) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-013-1393-y · Cited by 109 · cited 1×
“[102] uncovering a link between IDO and the complement, pharmacologic”
BackgroundIDO Mediates TLR9-Driven Protection from Experimental Autoimmune Diabetes
Fallarino, F., Volpi, C., Zelante, T., Vacca, C., Calvitti, M., Fioretti, M. C., Puccetti, P., Romani, L. R., & Grohmann, U. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901577 · Cited by 108
Chiarugi, A., Meli, E., & Moroni, F. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00335.x · Cited by 107 · cited 1×
“At micromolar concentrations, the cytotoxic effect of QUIN can be mimicked in primary cortical neuronal cell cultures [30].”
BackgroundImmune Activation and Decreased Tryptophan in Patients with HIV-1 Infection
Fuchs, D., FORSMAN, A., Hagberg, L., LARSSON, M., Norkrans, G., Reibnegger, G. J., Werner, E. R., & WACHTER, H. (1990) · Journal of Interferon Research · doi:10.1089/jir.1990.10.599 · Cited by 102 · cited 1×
“HIV is a lentivirus (retrovirus subgroup) that infects CD4+ T-cells, macrophages and dendritic cells [84,85].”
BackgroundIndoleamine 2,3-dioxygenase, immunosuppression and pregnancy
Mellor, A. L., Chandler, P., Lee, G. K., Johnson, T. S., Keskin, D. B., Lee, J. R., & Munn, D. H. (2002) · Journal of Reproductive Immunology · doi:10.1016/s0165-0378(02)00040-2 · Cited by 101 · cited 1×
“The discovery of IDO function first occurred in mammals, which owe their continued existence to IDO-mediated immunosuppressive processes that prevent fetal rejection in utero [12].”
BackgroundNewell, B., Dilly, S., Finlayson, C., Gandhi, M., & Lakhani, S. (2009) · CRC Press eBooks · doi:10.1201/b13541-43 · Cited by 100
Suh, H.-S., Zhao, M., Rivieccio, M. A., Choi, S., Connolly, E. C., Zhao, Y., Takikawa, O., Brosnan, C. F., & Lee, S. C. (2007) · Journal of Virology · doi:10.1128/jvi.00792-07 · Cited by 99 · cited 3×
“and suppression of the antiviral T-cell response in HIV-generated encephalitis (HIVE) [27].”
BackgroundThe Role of Dendritic Cells in Tissue-Specific Autoimmunity
Mbongue, J. C., Nicholas, D., Firek, A. F., & Langridge, W. H. R. (2014) · Journal of Immunology Research · doi:10.1155/2014/857143 · Cited by 96 · cited 6×
“Demonstrating the adjuvant capability of the cholera toxin B subunit, the linkage of CTB to an autoantigen (ovalbumin) was shown to provide up to a 10,000-fold reduction in the amount of autoantigen required for generating immune tolerance [59,122,125,126].”
BackgroundInfluentialSelf-citationActivation of the STING Adaptor Attenuates Experimental Autoimmune Encephalitis
Lemos, H. D. P., Huang, L., Chandler, P., Mohamed, E. T., de Souza, G. R., Li, L., Pacholczyk, G. A., Barber, G. N., Hayakawa, Y., Munn, D. H., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1303258 · Cited by 96 · cited 11×
“Based on their immunosuppressive properties, human mesenchymal stem cells (hMSC) provide a promising tool for cell-based therapies of autoimmune diseases, including MS. Murine MSCs (mMSC) were used to characterize and optimize the route of administration, motility, cellular targets and immunosuppressive mechanisms in…”
BackgroundInfluentialThe Jak-STAT Pathway Stimulated by Interferon γ
Horvath, C. M. (2004) · Science s STKE · doi:10.1126/stke.2602004tr8 · Cited by 96
Liu, H., Liu, L., Liu, K., Bizargity, P., Hancock, W. W., & Visner, G. A. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900408 · Cited by 94 · cited 1×
“resulting in the induction of a long-lasting allograft tolerance in combination with a locally-restricted immunosuppressive environment [78].”
BackgroundTugizov, S. M., Herrera, R., Veluppillai, P., Greenspan, J. S., Greenspan, D., & Palefsky, J. M. (2007) · Journal of Virology · doi:10.1128/jvi.00171-07 · Cited by 92 · cited 2×
“The herpesvirus 4 strain is best known as the cause of infectious mononucleosis (glandular fever) [88].”
BackgroundZaher, S. S., Germain, C., Fu, H., Larkin, F., & George, A. J. T. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-5793 · Cited by 89 · cited 2×
“biosynthesis and enzyme activity in human DCs suggest that kynurenines may be important for vaccine suppression of type 1 diabetes autoimmunity [11,34,56,61,65].”
BackgroundPloix, C. C., Bergerot, I., Durand, A., Czerkinsky, C. C., Holmgren, J. R., & Thivolet, C. H. (1999) · Diabetes · doi:10.2337/diabetes.48.11.2150 · Cited by 88 · cited 1×
“hyperglycemia can result in neural and circulatory complications that lead to amputation, loss of kidney function, blindness, heart attack and stroke, resulting in early mortality [34,138,139].”
BackgroundPhipps, P. A., Stanford, M. R., Sun, J., Xiao, B., Holmgren, J. R., Shinnick, T. M., Hasan, A., Mizushima, Y., & Lehner, T. (2003) · European Journal of Immunology · doi:10.1002/immu.200390025 · Cited by 84 · cited 1×
“Behcet’s disease (BD) is an inflammatory tissue-specific autoimmune disorder characterized by uveitis, oral and genital ulcers, as well as cutaneous, vascular, joint and neurological inflammation [128,129].”
BackgroundSucher, R., Fischler, K., Oberhuber, R., Kronberger, I. E., Margreiter, C., Öllinger, R., Schneeberger, S., Fuchs, D., Werner, E. R., Watschinger, K., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002777 · Cited by 83 · cited 1×
“Current treatments employ a general immunosuppressive regimen, which leaves the patient vulnerable to common pathogens, and immuno-suppressive therapy usually must be administered lifelong with potentially severe side effects [75,76].”
BackgroundLiu, W., Lin, Y., Han, X., Xing, S., Chen, H., Chi, P., & Zhang, G. (2014) · Journal of Virology · doi:10.1128/jvi.03678-13 · Cited by 81
Dendritic Cells: A Critical Player in Cancer Therapy?
Palucka, A. K., Ueno, H., Fay, J. W., & Banchereau, J. (2008) · Journal of Immunotherapy · doi:10.1097/cji.0b013e31818403bc · Cited by 80 · cited 1×
“For some time, the significance of IDO promotion of cancer survival was questioned by its observed function in the prevention of allogenic rejection and by the evidence that IDO is overexpressed in most tumors and tumor draining lymph nodes [106,107].”
BackgroundChon, S. Y., Hassanain, H. H., Pine, R. I., & Gupta, S. L. (1995) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.1995.15.517 · Cited by 79 · cited 1×
“promoter contains nucleotide sequences that allow regulation through interferon sequence response-like elements (ISRE), GAS (palindromic gamma-activated sequences) and non-canonical NF- B (nuclear factor kappa-light-chain-enhancer of activated B-cells) consensus sequences [36–38].”
BackgroundNon-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation.
Brandacher, G., Cakar, F., Winkler, C., Schneeberger, S., Obrist, P., Bösmüller, C., Werner-Felmayer, G., Werner, E. R., Bonatti, H., Margreiter, R., et al. (2007) · Kidney International · doi:10.1016/s0090-3671(08)79105-5 · Cited by 74 · cited 1×
“In vivo experiments have shown that IDO1 gene knockout mice experience acute rejection of transplanted MHC mismatched grafts, while wild-type mice with high tryptophan catabolism experienced long-term graft survival [77].”
BackgroundRobinson, C. M., Hale, P. T., & Carlin, J. M. (2006) · Cytokine · doi:10.1016/j.cyto.2006.07.007 · Cited by 73
Characterization and evolution of vertebrate indoleamine 2, 3-dioxygenases
Yuasa, H. J., Ball, H. J., Ho, Y. F., Austin, C., Whittington, C. M., Belov, K., Maghzal, G. J., Jermiin, L. S., & Hunt, N. H. (2009) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2009.02.002 · Cited by 72 · cited 1×
“The first and rate-limiting step in this pathway is the conversion of tryptophan to N-formyl kynurenine, and until recently, this reaction was thought to be performed by either tryptophan 2, 3-dioxygenase (TDO) or indoleamine 2, 3-dioxygenase (IDO1) [2–4].”
BackgroundManches, O., Fernandez, M. V., Plumas, J., Chaperot, L., & Bhardwaj, N. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1204032109 · Cited by 70
Grant, R., Naif, H. M., Thuruthyil, S. J., Nasr, N., Littlejohn, T. K., Takikawa, O., & Kapoor, V. (2000) · Journal of Virology · doi:10.1128/jvi.74.9.4110-4115.2000 · Cited by 69 · cited 1×
“The impaired cytotoxic function seen in the IDO-treated CD8+ T-cells was accompanied by defects in the production of granule cytotoxic proteins, including perforin and granzyme A and B [79,80].”
BackgroundAnalysis of Transcription Factors Regulating Induction of Indoleamine 2,3-Dioxygenase by IFN- gamma
Du, M. X., Sotero-Esteva, W. D., & Taylor, M. W. (2000) · Journal of Interferon & Cytokine Research · doi:10.1089/107999000312531 · Cited by 67 · cited 1×
“In murine 3B6A cells, a cell line with a defect in IDO1 activity, Stat 1 was shown to bind to GAS and to restore IDO1 induction [36].”
BackgroundBock, F., Rößner, S., Onderka, J., Lechmann, M., Pallotta, M. T., Fallarino, F., Boon, L., Nicolette, C. A., Debenedette, M. A., Tcherepanova, I. Y., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1201531 · Cited by 66 · cited 1×
“Current treatments employ a general immunosuppressive regimen, which leaves the patient vulnerable to common pathogens, and immuno-suppressive therapy usually must be administered lifelong with potentially severe side effects [75,76].”
BackgroundAspord, C., & Thivolet, C. H. (2002) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2002.01988.x · Cited by 64 · cited 1×
“Disease onset begins when insulin-presenting DCs bind T-cell receptors of cognate naive T helper cells and guide their differentiation into pro-inflammatory T helper and cytotoxic T-cells that attack the insulin producing islet -cells [13,149–152].”
BackgroundThe significance of tryptophan in human nutrition
Heine, W. E., Radke, M. H., & Wutzke, K. D. (1995) · Amino Acids · doi:10.1007/bf00805951 · Cited by 64 · cited 2×
“amino acids in protein metabolism, tryptophan (TRP) serves as a precursor for the synthesis of the neurotransmitters serotonin and tryptamine, as well as for the synthesis of the anti-pellagra vitamin nicotinic acid and the hormone melatonin [32].”
BackgroundPallotta, M. T., Orabona, C., Bianchi, R., Vacca, C., Fallarino, F., Belladonna, M. L., Volpi, C., Mondanelli, G., Gargaro, M., Allegrucci, M., et al. (2014) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12360 · Cited by 63 · cited 4×
“cytokine IFN , one of the most potent inducers of IDO expression and catalytic function [65,113].”
BackgroundInfluentialFukui, T., Tabata, M., Taguri, M., Manabe, S., Morita, S., & Takanashi, S. (2011) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2010.10.002 · Cited by 62 · cited 1×
“Tregs, as well as highlighting the central importance of IDO’s signaling capabilities [72–74].”
BackgroundMultiple sclerosis, seizures, and antiepileptics: role of IL-18, IDO, and melatonin
Anderson, G., & Rodriguez, M. (2010) · European Journal of Neurology · doi:10.1111/j.1468-1331.2010.03257.x · Cited by 62 · cited 2×
“self-antigens were shown to prevent uveitis, multiple sclerosis and type 1 diabetes in animal models of autoimmunity [124,131,132,142,153].”
BackgroundDendritic Cells Require the NF-κB2 Pathway for Cross-Presentation of Soluble Antigens
Lind, E. F., Ahonen, C. L., Wasiuk, A., Kosaka, Y., Becher, B., Bennett, K. A., & Noelle, R. J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.1.354 · Cited by 60 · cited 1×
“Tregs, as well as highlighting the central importance of IDO’s signaling capabilities [72–74].”
BackgroundRegulation of Expression and Function of IDO in Human Dendritic Cells
Heitger, A. (2011) · Current Medicinal Chemistry · doi:10.2174/092986711795656018 · Cited by 58 · cited 1×
“basis for reducing the effect of IDO2 in cancer progression [2].”
BackgroundWalling, D. M., Ray, A. J., Nichols, J. E., Flaitz, C. M., & Nichols, C. M. (2007) · Journal of Virology · doi:10.1128/jvi.02754-06 · Cited by 52 · cited 1×
“lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma and HIV-associated conditions, including hairy leukoplakia and central nervous system lymphomas [88,89].”
BackgroundLanz, T. V., Opitz, C. A., Ho, P. P.-K., Agrawal, A., Lutz, C., Weller, M., Mellor, A. L., Steinman, L., Wick, W., & Platten, M. (2009) · Stem Cells and Development · doi:10.1089/scd.2009.0385 · Cited by 52 · cited 1×
“cytokine IFN , one of the most potent inducers of IDO expression and catalytic function [65,113].”
BackgroundEBV Suppresses Prostaglandin E2 Biosynthesis in Human Monocytes
Savard, M., Bélanger, C., Tremblay, M. J., Dumais, N., Flamand, L., Borgeat, P., & Gosselin, J. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.12.6467 · Cited by 51 · cited 1×
“The EB virus is known to infect monocytes/macrophages, intraepithelial macrophages and Langerhans dendritic cells [90,91].”
BackgroundB-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase
Johnson, B. A., Kahler, D. J., Baban, B., Chandler, P., Kang, B., Shimoda, M., Koni, P. A., Pihkala, J. P. S., Vilagos, B., Busslinger, M., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914347107 · Cited by 51 · cited 2×
“In the same line, a discrete population of splenocytes with attributes of dendritic cells (DCs) and co-expressing the B-cell marker CD19 is uniquely competent to express the T-cell regulatory enzyme indoleamine 2, 3-dioxygenase (IDO) in mice treated with TLR9 ligands (CpGs) [69].”
BackgroundIdo (indolamine 2,3-dioxygenase) Expression and Function in the CNS
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“Particularly, soluble mediator IDO promotes the degradation of tryptophan to generate kynurenine and numerous other catabolites, which have been shown to contribute greatly to suppressing T cell proliferation and inducing Treg cells [117, 118].”
Background
Metadata
- Authors
- Mbongue, J., Nicholas, D., Torrez, T., Kim, N.-S., Firek, A., & Langridge, W.
- Affiliations
- Loma Linda University (US)
- California Baptist University (US)
- Jerry L. Pettis Memorial VA Medical Center (US)
- Corresponding author
- Langridge, William
- Venue
- Vaccines
- Publisher
- MDPI AG
- Published
- 2015-09-10
- Volume
- 3
- Issue
- 3
- Pages
- 703-729
- ISSN
- 2076-393X (ISSN-L)
- PMC
- PMC4586474
- OpenAlex
- W2101376945
- Cited by
- 351
- References
- 165
- Citations by year
- 2026: 18 · 2025: 32 · 2024: 32 · 2023: 39 · 2022: 43 · 2021: 39 · 2020: 47 · 2019: 34 · 2018: 39 · 2017: 16 · 2016: 11 · 2015: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Vaccines (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Loma Linda University
- National Institutes of Health (DK-99-013)
- National Institute of General Medical Sciences (R25GM060507)
- National Institute on Minority Health and Health Disparities (P20MD006988)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- indoleamine 2,3-dioxygenase, tryptophan catabolism, kynurenine, immunosuppression, autoimmunity, dendritic cells, tumor immunosuppression, allergy, graft rejection, inflammation, vaccine adjuvants, tryptophan metabolism
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