The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity
Open accessAbstract
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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Increased IDO expression is responsible for the catabolism of TRP in the KYN degradation pathway and is canonically upregulated by inflammatory mechanisms.
“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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BackgroundJürgens, B., Hainz, U., Fuchs, D., Felzmann, T., & Heitger, A. (2009) · Blood · doi:10.1182/blood-2008-12-195073 · Cited by 176 · see citing works
George‐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× · see citing works
“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× · see citing works
“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× · see citing works
“Based on the enzyme’s immunosuppressive functions, IDO1 is becoming established as a target for drug discovery in cancer immunotherapy [95,97].”
BackgroundCutting 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 164 · cited 1× · see citing works
“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].”
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 162 · cited 3× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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 148 · cited 2× · see citing works
“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× · see citing works
“self-antigens were shown to prevent uveitis, multiple sclerosis and type 1 diabetes in animal models of autoimmunity [124,131,132,142,153].”
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× · see citing works
“One hallmark of GBM is the gradual accumulation of immunosuppressive and tumor-promoting CD4 FoxP3+ regulatory T-cells (Tregs) [100,101].”
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 137 · cited 2× · see citing works
“One hallmark of GBM is the gradual accumulation of immunosuppressive and tumor-promoting CD4+ FoxP3+ regulatory T-cells (Tregs) [100,101].”
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× · see citing works
“The EB virus is known to infect monocytes/macrophages, intraepithelial macrophages and Langerhans dendritic cells [90,91].”
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 133 · cited 1× · see citing works
“Both IDO1 and IDO2 genes are conserved in mammals and are present in tandem on chromosome 8 [8,9].”
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 127 · cited 3× · see citing works
“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 125 · cited 1× · see citing works
“degradation of tryptophan accompanied DC suppression of arthritis, asthma, hemolytic anemia, multiple sclerosis, systemic lupus erythematosus and type 1 diabetes [116,117,146,154].”
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 · see citing works
Fallarino, 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 · see citing works
Stanford, 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 120 · cited 1× · see citing works
“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].”
BackgroundZhang, Y., Kang, S. A. W., Mukherjee, T., Bale, S., Crane, B. R., Begley, T. P., & Ealick, S. E. (2006) · Biochemistry · doi:10.1021/bi0620095 · Cited by 118 · cited 1× · see citing works
“While TDO is widely distributed in both eukaryotes and bacteria [5], IDO1 is restricted to mammals and yeast [6].”
BackgroundKonan, K. V., & Taylor, M. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.32.19140 · Cited by 116 · cited 2× · see citing works
“expression, as the deletion of 748 bps between the elements had no effect on IDO1 synthesis [40].”
BackgroundImmunosuppression 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 115 · cited 4× · see citing works
“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].”
BackgroundInfluentialMarrying 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 · see citing works
Non-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 · see citing works
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 · see citing works
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 107 · cited 1× · see citing works
“[102] uncovering a link between IDO and the complement, pharmacologic”
BackgroundChiarugi, A., Meli, E., & Moroni, F. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00335.x · Cited by 106 · cited 1× · see citing works
“At micromolar concentrations, the cytotoxic effect of QUIN can be mimicked in primary cortical neuronal cell cultures [30].”
BackgroundVogel, 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 106 · see citing works
IDO 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 105 · see citing works
Immune 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× · see citing works
“HIV is a lentivirus (retrovirus subgroup) that infects CD4+ T-cells, macrophages and dendritic cells [84,85].”
BackgroundNewell, B., Dilly, S., Finlayson, C., Gandhi, M., & Lakhani, S. (2009) · CRC Press eBooks · doi:10.1201/b13541-43 · Cited by 100 · see citing works
Indoleamine 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 100 · cited 1× · see citing works
“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].”
BackgroundSuh, 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 98 · cited 3× · see citing works
“and suppression of the antiviral T-cell response in HIV-generated encephalitis (HIVE) [27].”
BackgroundThe Jak-STAT Pathway Stimulated by Interferon γ
Horvath, C. M. (2004) · Science s STKE · doi:10.1126/stke.2602004tr8 · Cited by 96 · see citing works
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× · see citing works
“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× · see citing works
“The herpesvirus 4 strain is best known as the cause of infectious mononucleosis (glandular fever) [88].”
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 91 · cited 6× · see citing works
“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 91 · cited 11× · see citing works
“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…”
BackgroundInfluentialPloix, 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× · see citing works
“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].”
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 86 · cited 2× · see citing works
“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].”
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× · see citing works
“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].”
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 · see citing works
Sucher, 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 79 · cited 1× · see citing works
“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].”
BackgroundDendritic 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 79 · cited 1× · see citing works
“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 77 · cited 1× · see citing works
“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].”
BackgroundCharacterization 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× · see citing works
“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 · see citing works
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× · see citing works
“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 66 · cited 1× · see citing works
“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].”
BackgroundRobinson, C. M., Hale, P. T., & Carlin, J. M. (2006) · Cytokine · doi:10.1016/j.cyto.2006.07.007 · Cited by 65 · see citing works
Aspord, C., & Thivolet, C. H. (2002) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2002.01988.x · Cited by 64 · cited 1× · see citing works
“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× · see citing works
“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 62 · cited 4× · see citing works
“cytokine IFN , one of the most potent inducers of IDO expression and catalytic function [65,113].”
BackgroundInfluentialBock, 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 62 · cited 1× · see citing works
“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].”
BackgroundFukui, 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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“The EB virus is known to infect monocytes/macrophages, intraepithelial macrophages and Langerhans dendritic cells [90,91].”
BackgroundIdo (indolamine 2,3-dioxygenase) Expression and Function in the CNS
Kwidzinski, E., Bunse, J., Kovac, A. D., Ullrich, O., Zipp, F., Nitsch, R., & Bechmann, I. (2003) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-0135-0_13 · Cited by 50 · see citing works
Amino Acid Metabolism Inhibits Antibody-Driven Kidney Injury by Inducing Autophagy
Chaudhary, K., Shinde, R. S., Liu, H., Gnana‐Prakasam, J. P., Veeranan‐Karmegam, R., Huang, L., Ravishankar, B., Bradley, J., Kvirkvelia, N., McMenamin, M., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500277 · Cited by 48 · cited 1× · see citing works
“critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy [60].”
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 48 · cited 2× · see citing works
“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].”
BackgroundDiagnosis of Epstein-Barr virus-related diseases.
Linde, A. (1996) · PubMed · Cited by 42 · see citing works
Role of human brain microvascular endothelial cells during central nervous system infection
Adam, R., Rüßing, D., Adams, O., Ailyati, A., Kim, K. S., Schroten, H., & Däubener, W. (2005) · Thrombosis and Haemostasis · doi:10.1160/th05-01-0053 · Cited by 41 · cited 1× · see citing works
“Endothelial cells that make up the blood brain barrier catabolize L-tryptophan due to IDO1 stimulation of the kynurenine pathway [25].”
BackgroundMerTK regulates thymic selection of autoreactive T cells
Wallet, M. A., Flores, R. R., Wang, Y., Yi, Z., Kroger, C. J., Mathews, C. E., Earp, H. S., Matsushima, G. K., Wang, B., & Tisch, R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900683106 · Cited by 39 · cited 1× · see citing works
“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].”
BackgroundSun, J.-B., Czerkinsky, C., & Holmgren, J. (2012) · Journal of Immunology · doi:10.4049/jimmunol.1101771 · Cited by 38 · see citing works
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“degradation of tryptophan accompanied DC suppression of arthritis, asthma, hemolytic anemia, multiple sclerosis, systemic lupus erythematosus and type 1 diabetes [116,117,146,154].”
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“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].”
BackgroundInfluentialSelf-citationD’Ambrosio, A., Colucci, M., Pugliese, O., Quintieri, F., & Boirivant, M. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.1207850 · Cited by 30 · cited 2× · see citing works
“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].”
BackgroundNajfeld, V., Menninger, J. C., Muhleman, D. R., Comings, D. E., & Gupta, S. (2008) · Cytogenetics and Cell Genetics · doi:10.1159/000133584 · Cited by 30 · see citing works
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“Oral administration of the CTB subunit coupled with insulin or the GAD35 autoantigen was shown to induce immunological tolerance and suppression of type 1 diabetes in NOD mice [125,127].”
BackgroundSelf-citationLi, W., Katz, B. P., & Spinola, S. M. (2011) · Infection and Immunity · doi:10.1128/iai.05021-11 · Cited by 27 · cited 15× · see citing works
“Deletion of the Bin1 gene from mammalian cells resulted in an increased IDO1 gene expression stimulated by IFN- .”
BackgroundInfluentialOdumosu, O., Payne, K. J., Báez, I., Jutzy, J. M. S., Wall, N. R., & Langridge, W. H. R. (2010) · Immunobiology · doi:10.1016/j.imbio.2010.09.008 · Cited by 27 · cited 3× · see citing works
“self-antigens were shown to prevent uveitis, multiple sclerosis and type 1 diabetes in animal models of autoimmunity [124,131,132,142,153].”
BackgroundSelf-citationVaccine Therapies for the Prevention of Type 1 Diabetes Mellitus
Petrovsky, N., Silva, D. A. S., & Schatz, D. (2003) · Pediatric Drugs · doi:10.2165/00148581-200305090-00001 · Cited by 26 · cited 1× · see citing works
“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].”
BackgroundDendritic cells enhance the antigen sensitivity of T cells
Garbi, N., & Kreutzberg, T. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00389 · Cited by 23 · cited 1× · see citing works
“Dendritic cells (DCs) recognize and process self-antigens and are the first immune cells to surround pancreatic islets, indicating a prominent role in type 1 diabetes development [15,58,59,146–148].”
BackgroundSuppression of hyperglycemia in NOD mice after inoculation with recombinant vaccinia viruses
Denes, B. S., Yu, J., Fodor, N., Takátsy, Z., Fodor, I., & Langridge, W. H. R. (2006) · Molecular Biotechnology · doi:10.1385/mb:34:3:317 · Cited by 22 · cited 1× · see citing works
“Increased cellular oxidative stress and chronic inflammation generated by 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].”
BackgroundSelf-citationPrevention of type 1 diabetes: today and tomorrow
Cernea, S., Dobreanu, M., & Raz, I. (2010) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.1138 · Cited by 22 · cited 1× · see citing works
“degradation of tryptophan accompanied DC suppression of arthritis, asthma, hemolytic anemia, multiple sclerosis, systemic lupus erythematosus and type 1 diabetes [116,117,146,154].”
BackgroundCorrection: IDO Mediates Tlr9-Driven Protection From Experimental Autoimmune Diabetes
Fallarino, F., Volpi, C., Zelante, T., Vacca, C., Calvitti, M., Fioretti, M., Puccetti, P., Romani, L., & Grohmann, U. (2010) · Journal of Immunology · doi:10.4049/jimmunol.1090041 · Cited by 21 · cited 1×
“The aryl hydrocarbon receptor may be central to naive T-cell differentiation into Foxp3+ regulatory T-cells (Tregs) rather than pro-inflammatory Th17 lymphocytes [71].”
BackgroundThe Prospect of Vaccination to Prevent Type 1 Diabetes
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“Approximately 20% (one in five) Americans suffer from terminal autoimmunity because no cure is available [119,143].”
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“Prevention is, however, more applicable to early preclinical disease than to recent onset clinical disease, in which pancreatic islet beta cell destruction is more advanced [34,121].”
BackgroundSelf-citationProtection against Autoimmune Diabetes by Silkworm-Produced GFP-Tagged CTB-Insulin Fusion Protein
Meng, Q., Wang, W., Shi, X., Jin, Y., & Zhang, Y. (2011) · Clinical and Developmental Immunology · doi:10.1155/2011/831704 · Cited by 16 · cited 1× · see citing works
“Linkage of CTB to insulin (CTB-INS) provided a protective effect against the onset of type 1 diabetes in NOD mice [123,126,140].”
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The Potential Role of Dendritic Cells in the Therapy of Type 1 Diabetes
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“TRP is the only amino acid that binds high levels of serum albumin [32,33].”
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Vaccines for type 1 diabetes in the late stage of clinical development
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“1980s, prevention, following disease initiation, has been the focus of attention with many candidate therapeutic agents, mainly immunosuppressive drugs [117–120].”
BackgroundAdsorption technologies and blood purification procedures: honoring Horst Klinkmann
Courtney, J., Falkenhagen, D., Ivanovich, P., & Schuett, W. (2002) · doi:10.1046/j.1525-1594.2002.00901.x · Cited by 1
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Targeting macrophages: therapeutic approaches in cancer
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Navigating metabolic pathways to enhance antitumour immunity and immunotherapy
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Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders
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Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance
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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].”
BackgroundCancer immunotherapy: a brief review of the history, possibilities, and challenges ahead
Oiseth, S. J., & Aziz, M. S. (2017) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2017.41 · Cited by 372 · see citing works
“Some may be expressed by the cell in a free soluble form, such as indoleamine 2,3-dioxygenase (IDO1), an enzyme produced by some activated macrophages and also overexpressed by many tumors[94].”
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Castro-Portuguez, R., & Sutphin, G. L. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.110841 · Cited by 282 · see citing works
Immune and Inflammatory Cells in Thyroid Cancer Microenvironment
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“IDO catabolizes Tryptophan (Trp) to kynurenine (Kyn) and other metabolites, and acts to suppress the immune response, particularly the CD4 T cell production of IFN-γ (6).”
BackgroundInfluentialSalminen, A. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101573 · Cited by 197 · see citing works
“There are observations indicating that the activation of SHP-1 stimulated IKKα which induced the non-canonical NF-κB signaling through the p52/RelB pathway (Pallotta et al., 2011; Mbongue et al., 2015) (Fig.”
BackgroundBiomarkers for Immune Checkpoint Inhibitor-Mediated Tumor Response and Adverse Events
Nakamura, Y. (2019) · Frontiers in Medicine · doi:10.3389/fmed.2019.00119 · Cited by 184 · see citing works
“Enzymes Related to Immune Response Indoleamine 2,3-dioxygenase (IDO) IDO is an enzyme that converts the essential amino acid ltryptophan into kynurenine and carries an immunosuppressive effect through multiple mechanisms (80).”
BackgroundBiomarkers associated with checkpoint inhibitors
Manson, G., Norwood, J., Marabelle, A., Kohrt, H. E. K., & Houot, R. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw181 · Cited by 164 · see citing works
Turn Back the TIMe: Targeting Tumor Infiltrating Myeloid Cells to Revert Cancer Progression
Awad, R. M., Vlaeminck, Y. D., Maebe, J., Goyvaerts, C., & Breckpot, K. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01977 · Cited by 153 · see citing works
IDO1: An important immunotherapy target in cancer treatment
Li, F., Zhang, R., Li, S., & Liu, J. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.03.024 · Cited by 160 · see citing works
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Gendelman, H. E., Zhang, Y., Santamaria, P. M., Olson, K. E., Schutt, C. R., Bhatti, D., Shetty, B. L. D., Lu, Y., Estes, K. A., Standaert, D. G., et al. (2017) · npj Parkinson s Disease · doi:10.1038/s41531-017-0013-5 · Cited by 147 · see citing works
Metabolic modulation of immune checkpoints and novel therapeutic strategies in cancer
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Intestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury
Rath, E., & Haller, D. (2022) · Mucosal Immunology · doi:10.1038/s41385-022-00514-x · Cited by 149 · see citing works
Regulatory T cells in the tumour microenvironment
Imianowski, C. J., Chen, Q., Workman, C. J., & Vignali, D. A. A. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00832-9 · Cited by 117 · see citing works
“IDO is the rate-limiting catabolic enzyme in the degradation pathway of tryptophan, an essential amino acid with degradation products that exert multiple important immunoregulatory functions including limiting T cell proliferation by kynurenine 146,147 .”
Indoleamine 2, 3-dioxygenase regulation of immune response (Review)
Wu, H., Gong, J., & Liu, Y. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.8537 · Cited by 126 · see citing works
“The B7 receptors on DCs expressing IDO bind to cytotoxic T-lymphocyte antigen 4 (CTLA4) on Tregs, resulting in their proliferation and antigen‑specific anergy (5,11).”
BackgroundInfluentialDarragh, L. B., Oweida, A. J., & Karam, S. D. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03154 · Cited by 131 · see citing works
Immune Landscape of Breast Cancers
Nagarajan, D., & McArdle, S. (2018) · Biomedicines · doi:10.3390/biomedicines6010020 · Cited by 132 · see citing works
“In addition to PD1 and PD-L1, Indoleamine 2,3-dioxygenase-1 and -2 (IDO1,2) an intracellular enzyme overexpressed by many cancers, have also been shown to be involved in immune suppression via the depletion of tryptophan from the microenvironment and the production of metabolites, such as kynurenines [42].”
BackgroundImmune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment
Pearson, J. R. D., Cuzzubbo, S., McArthur, S., Durrant, L. G., Adhikaree, J., Tinsley, C. J., Pockley, A. G., & McArdle, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.582106 · Cited by 118 · see citing works
Wei, F., Wang, D., Wei, J., Tang, N., Tang, L. M., Xiong, F., Guo, C. J., Zhou, M., Li, X., Li, G., et al. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03581-0 · Cited by 128 · see citing works
Examining Chronic Inflammation, Immune Metabolism, and T Cell Dysfunction in HIV Infection
Mu, W., Patankar, V., Kitchen, S. G., & Zhen, A. (2024) · Viruses · doi:10.3390/v16020219 · Cited by 108 · see citing works
“For example, Indoleamine 2,3-dioxygenase (IDO) is an enzyme that is upregulated during inflammation and degrades tryptophan [147].”
BackgroundMasenga, S. K., Mweene, B. C., Luwaya, E. L., Muchaili, L., Chona, M., & Kirabo, A. (2023) · Cells · doi:10.3390/cells12101351 · Cited by 106 · see citing works
Immune Checkpoint Targeted Therapy in Glioma: Status and Hopes
Qi, Y., Liu, B., Sun, Q., Xiong, X., & Chen, Q. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.578877 · Cited by 132 · see citing works
Immunometabolism of Phagocytes During Mycobacterium tuberculosis Infection
Kumar, R., Singh, P., Kolloli, A., Shi, L., Bushkin, Y., Tyagi, S., & Subbian, S. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00105 · Cited by 99 · see citing works
“It also suppresses the host immune response, particularly IFNγ production by CD4+ T cells (Mbongue et al., 2015).”
BackgroundTargeting indoleamine-2,3-dioxygenase in cancer: Scientific rationale and clinical evidence
Ricciuti, B., Leonardi, G. C., Puccetti, P., Fallarino, F., Bianconi, V., Sahebkar, A., Baglivo, S., Chiari, R., & Pirro, M. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.12.004 · Cited by 96 · see citing works
“, pathogens, cytokines and lipopolysaccharides) (Mbongue et al., 2015).”
BackgroundInfluentialLipid-based nanosystems: the next generation of cancer immune therapy
Cheng, Z., Fobian, S., Gurrieri, E., Amin, M., D’Agostino, V., Falahati, M., Zalba, S., Debets, R., Garrido, M. J., Saeed, M., et al. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01574-1 · Cited by 90 · see citing works
“It is often overexpressed in tumors, degrading tryptophan to kynurenines, which increase immune regulatory and evasion functions, and promote metastasis [237, 238].”
BackgroundThe evolving landscape of ‘next-generation’ immune checkpoint inhibitors: A review
Mazzarella, L., Duso, B. A., Trapani, D., Belli, C., D’Amico, P., Ferraro, E., Viale, G., & Curigliano, G. (2019) · European Journal of Cancer · doi:10.1016/j.ejca.2019.04.035 · Cited by 98 · see citing works
Singh, A. K., Praharaj, M., Lombardo, K. A., Yoshida, T., Matoso, A., Baras, A. S., Zhao, L., Srikrishna, G., Huang, J., Prasad, P., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28509-z · Cited by 103 · see citing works
RetractedCommitment to Aerobic Glycolysis Sustains Immunosuppression of Human Mesenchymal Stem Cells
Liu, Y., Yuan, X., Munoz, N. M., Logan, T. M., & Ma, T. (2018) · Stem Cells Translational Medicine · doi:10.1002/sctm.18-0070 · Cited by 97 · see citing works
Mycobacterium tuberculosis: Pathogenesis and therapeutic targets
Yang, J.-X., Zhang, L., Qiao, W., & Luo, Y. (2023) · MedComm · doi:10.1002/mco2.353 · Cited by 80 · see citing works
Immune checkpoint molecules. Possible future therapeutic implications in autoimmune diseases
Huang, C., Zhu, H., Yao, Y., Bian, Z.-H., Zheng, Y.-J., Li, L., Moutsopoulos, H. Μ., Gershwin, M. E., & Lian, Z. (2019) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.102333 · Cited by 91 · see citing works
The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma.
Sordillo, P., Sordillo, L. A., & Helson, L. (2017) · Anticancer Research · doi:10.21873/anticanres.11551 · Cited by 79 · see citing works
Polyphenols as Immunomodulatory Compounds in the Tumor Microenvironment: Friends or Foes?
Focaccetti, C., Izzi, V., Benvenuto, M., Fazi, S., Ciuffa, S., Giganti, M. G., Potenza, V., Manzari, V., Modesti, A., & Bei, R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071714 · Cited by 84 · see citing works
Photobiomodulation of the microbiome: implications for metabolic and inflammatory diseases
Bicknell, B. T., Liebert, A. D., Johnstone, D. M., & Kiat, H. (2018) · Lasers in Medical Science · doi:10.1007/s10103-018-2594-6 · Cited by 89 · see citing works
Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma.
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“(66,67) Tumors that utilize IDO deplete tryptophan from T cells forming kynurenines, which predispose an exhausted and regulatory T cell phenotype.(66,67) IDO blockers have been developed and are currently evaluated in children in early phase studies (phase I, clinical trials.”
BackgroundMetabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond
Teoh, S. T., & Lunt, S. Y. (2017) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1406 · Cited by 73 · see citing works
“The expression of indoleamine 2,3dioxygenase (IDO), which catalyzes the rate-limiting first step of tryptophan degradation via the kynurenine pathway, is frequently elevated in tumor cells.(252) IDO overexpression has a dual effect on T cells: IDO overexpression: (1) depletes tryptophan from the microenvironment to ha…”
BackgroundTryptophan metabolism as a target in gut microbiota, ageing and kidney disease
Miao, H., Zhang, S.-J., Wu, X., Li, P., & Zhao, Y.-L. (2025) · International Journal on Biological Sciences · doi:10.7150/ijbs.115359 · Cited by 71
“The two enzymes are not constitutively expressed in most cells but can be induced by different inflammatory stimuli such as lipopolysaccharides, cytokines and pathogens [21].”
Interferons: Reprogramming the Metabolic Network against Viral Infection
Raniga, K., & Liang, C. (2018) · Viruses · doi:10.3390/v10010036 · Cited by 69 · see citing works
“While exerting antiviral effects against numerous viruses, long-term consequences of induction could contribute to disease progression, as seen with the promotion of an immunosuppressive environment during chronic viral infections [106].”
BackgroundEsmaeili, S., Mahmoudi, M., Rezaieyazdi, Z., Sahebari, M., Tabasi, N., Sahebkar, A., & Rastin, M. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.27203 · Cited by 68 · see citing works
“Our observation of higher expression of IDO and IL‐10 in c‐MDC‐DEL, c‐MDC‐RAM, and c‐MDC‐ MIX could signify the capability of these DCs to show modulatory responses and shift to tolerogenic manner.(26) MDC‐DEL, MDC‐RAM, and MDC‐MIX in SLE donors, following treatment with probiotics, showed lower expression of HLA‐DR,…”
ResultTargeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma
Truxová, I., Cibula, D., Špíšek, R., & Fucikova, J. P. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005968 · Cited by 74 · see citing works
Parra, E. R., Villalobos, P. A., Zhang, J., Behrens, C., Mino, B., Swisher, S. G., Sepesi, B., Weissferdt, A., Kalhor, N., Heymach, J. V., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.03.002 · Cited by 74 · see citing works
Granhøj, J. S., Jensen, A. W. P., Presti, M., Met, Ö., Svane, I. M., & Donia, M. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2064711 · Cited by 74 · see citing works
Tumor-Mediated Neutrophil Polarization and Therapeutic Implications
Raftopoulou, S., Valadez-Cosmes, P., Mihalič, Z. N., Schicho, R., & Kargl, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063218 · Cited by 68 · see citing works
The Black Hole: CAR T Cell Therapy in AML
Atilla, E., & Benabdellah, K. (2023) · Cancers · doi:10.3390/cancers15102713 · Cited by 64 · see citing works
“The high expression of Indoleamine 2,3-dioxygenase (IDO) has been reported to promote Treg conversion and enhance the immunosuppressive ability [50].”
BackgroundGonzalez‐Pujana, A., Vining, K. H., Zhang, D. K. Y., Santos‐Vizcaíno, E., Igartúa, M., Hernández, R. M., & Mooney, D. J. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120266 · Cited by 69 · see citing works
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The Role of Tryptophan Metabolism in Alzheimer’s Disease
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“IDO1 is produced in many different tissues as an anti-inflammatory immune-downregulating signal pathway; IDO-2 is less common [36].”
BackgroundMyeloid-Derived Suppressor Cells in Prostate Cancer: Present Knowledge and Future Perspectives
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“IDO catalyzes the degradation of tryptophan, leading to accumulation of metabolites such as kynurenine [48,49], that suppress T cells via inhibition of their expansion and recruitment of T regs [50,51].”
BackgroundImmunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway
Boros, F. A., & Vécsei, L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02570 · Cited by 58 · see citing works
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“Therefore, we chose an inhibitor of IDO2: 1-D-MT for further research (Novak et al., 1995; Metz et al., 2007).”
MethodIDO Immune Status after Chemoradiation May Predict Survival in Lung Cancer Patients
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“Patients in Group 1 achieved extremely long-term OS (the median OS has not been reached after up to 57 months of median follow-up), but a relatively low PFS of 14 (10-17) months.”
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“IDO degrades tryptophan and creates tryptophan-degrading kynurenines, which have an immuno-regulatory impact [100].”
BackgroundGuenin‐Macé, L., Morel, J., Doisne, J., Schiavo, A., Boulet, L., Mayau, V., Gonçalves, P., Duchatelet, S., Hovnanian, A., Bondet, V., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.140598 · Cited by 60 · see citing works
Metabolic Reprogramming in Cancer is Induced to Increase Proton Production.
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Gasotransmitters and the immune system: Mode of action and novel therapeutic targets
Fagone, P., Mazzon, E., Bramanti, P., Bendtzen, K., & Nicoletti, F. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.07.026 · Cited by 63 · see citing works
Immunosuppressive Amino-Acid Catabolizing Enzymes in Multiple Sclerosis
Correale, J. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.600428 · Cited by 54 · see citing works
“IDO1-dependent suppression of T cell responses has been proposed as an immunoregulatory pathway implicated in maternal tolerance of allogeneic fetuses during mammalian gestation, as well as in tumor tolerance, and protective regulation in autoimmune disease (9, 15, 18).”
BackgroundCancer Vaccine Immunotherapy with RNA-Loaded Liposomes
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Protracted immune disorders at one year after ICU discharge in patients with septic shock
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“IDO is stimulated by lipopolysaccharide (LPS), TNFα, IFN-γ, transforming growth factor (TGF)ß and activation of toll-like receptor (TLR)3, TLR4, TLR7, and TLR8 [30].”
BackgroundIlić, N., Gruden-Movsesijan, A., Cvetković, J., Tomić, S., Vučević, D., Aranzamendi, C., Čolić, M., Pinelli, E., & Sofronić-Milosavljević, L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00011 · Cited by 52
The prognostic value of IDO expression in solid tumors: a systematic review and meta-analysis
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“Page 3/31 regulate the differentiation direction of Th17/Treg cells, thereby promoting the balanced differentiation of Th17/Treg to Treg cells [3-5].”
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“T cells can modulate the activity of endothelial cells through the release of specific cytokines such as theTh1 cytokines IFN-γ and TNF-α, theTh2 cytokines IL-4 and IL-13, and theTreg cytokines IL-10 and TGF-β.”
BackgroundInfluentialTargeting the Kynurenine Pathway for the Treatment of Cisplatin-Resistant Lung Cancer
Nguyen, D. J. M., Theodoropoulos, G., Li, Y.-Y., Wu, C., Sha, W., Feun, L. G., Lampidis, T. J., Savaraj, N., & Wangpaichitr, M. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-19-0239 · Cited by 58 · see citing works
Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis
Guler, R., Ozturk, M., Sabeel, S., Motaung, B., Parihar, S. P., Thienemann, F., & Brombacher, F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.733853 · Cited by 46 · see citing works
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Amino Acid Catabolism in Multiple Sclerosis Affects Immune Homeostasis
Negrotto, L., & Correale, J. (2017) · Journal of Immunology · doi:10.4049/jimmunol.1601139 · Cited by 44 · see citing works
“defense against infectious agents, in maternal–fetal tolerance, in oncologic processes as well as in autoimmune diseases (7).”
BackgroundHazrati, A., Malekpour, K., Khorramdelazad, H., Rajaei, S., & Hashemi, S. M. (2024) · Biomarker Research · doi:10.1186/s40364-024-00580-2 · Cited by 43 · see citing works
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“Moreover, it promotes cancer cell survival through enhanced suppression of immunity (99).”
BackgroundTargeting immune checkpoints in malignant glioma
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“In return, when CTLA-4 is induced in Tregs, CTLA-4 mediates the down-regulating of co-stimulatory molecules, CD80 and CD86 on DCs, and thus reduces the potency of APCs to activate other T cells, critically controlling the immunosuppressive activity of Tregs (Figure 2B) [76].”
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“tryptophan is taken up by the host (18), thereby limiting tryptophan availability to the”
BackgroundIntegration of multiple networks and pathways identifies cancer driver genes in pan-cancer analysis
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Switch of NAD Salvage to de novo Biosynthesis Sustains SIRT1-RelB-Dependent Inflammatory Tolerance
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“Interestingly, although IDO1-NAD pathway plays an important role in sustaining tolerance, it is not required for tolerance induction (26, 31).”
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“MSCs exert an immunosuppressive function in the human body and the molecular mechanisms underlying the MSC-mediated immunosuppression were shown to be species dependent [81–84].”
Therapeutic Liposomal Vaccines for Dendritic Cell Activation or Tolerance
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“This depletion has been demonstrated to trigger anergy and apoptosis in effector T cells [104].”
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Adoptive T cell therapy: Boosting the immune system to fight cancer
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Extracellular vesicles from IFN-γ-primed mesenchymal stem cells repress atopic dermatitis in mice
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“This IFN-γ-IDO1 axis is responsible for the immunomodulatory function of MSCs [73].”
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Immunotherapy for Pediatric Brain Tumors
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“Tumors that utilize IDO deplete tryptophan from T cells forming kynurenines, which predispose an exhausted and regulatory T cell phenotype [70,71].”
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Unraveling the role of M2 TAMs in ovarian cancer dynamics: a systematic review
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“…TAMS mediated immunosuppression is to directly inhibit its tumor-promoting function, including inhibiting the production of IDO and thereby inhibiting CTL proliferation [186, 187], and has been associated with peritoneal dissemination and poor survival outcomes in patients with ovarian cancer.”
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“Engineered NPs allowed immune suppression to be reversed by blocking the IDO pathways (Mbongue et al., 2015).”
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Stem Cells Therapy as a Possible Therapeutic Option in Treating COVID-19 Patients
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Functional and metabolic targeting of natural killer cells to solid tumors
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“TGF-β can further suppress NK cell activity by recruiting or activating a variety of cancer-promoting immune cells, including Tregs [134], MDSCs [135, 136], CD11bLy6G neutrophils [137], and indoleamine 2,3dioxygenase 1 (IDO1)-expressing dendritic cells (DCs) [138].”
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Rusty Microglia: Trainers of Innate Immunity in Alzheimer's Disease
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Navarro‐Barriuso, J., Mansilla, M. J., & Martínez-Cáceres, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02062 · Cited by 39 · see citing works
Takamori, S., Ishikawa, S., Suzuki, J., Oizumi, H., Uchida, T., Ueda, S., Edamatsu, K., Iino, M., & Sugimoto, M. (2021) · Thoracic Cancer · doi:10.1111/1759-7714.14282 · Cited by 30 · see citing works
“Trp, a precursor of kynurenine, is metabolized to kynurenine by the action of indoleamine 2,3-dioxygenase (IDO).(22,23) Under normal physiological conditions, IDO expression is modulated; however, it is often upregulated in several cancer types.”
Background
- 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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