mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2017-3-225-240mimmun-1257Research ArticleОБЗОРЫREVIEWSТРИПТОФАН И INDOLEAMINE-2,3-DIOXYGENASE (IDO) В ПАТОГЕНЕЗЕ ИММУНОКОМПРОМЕТИРОВАННЫХ ЗАБОЛЕВАНИЙTRYPTOPHAN AND INDOLEAMINE-2,3-DIOXYGENASE (IDO) IN PATHOGENESIS OF IMMUNOSUPPRESSIVE CLINICAL CONDITIONSКозловВ. А.KozlovV. A.

д.м.н., профессор, академик РАН, научный руководитель

PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sciences, Director for Research

vakoz40@yandex.ruДеминаД. В.DeminaD. V.

к.м.н., заведующая отделением аллергологии клиники иммунопатологии

PhD (Medicine), Head, Department of Allergology, The Immunopathology Clinics

vakoz40@yandex.ruФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии», г. НовосибирскРоссияResearch Institute of Fundamental and Clinical Immunology, Novosibirsk, Russian FederationRussian Federation201704072017193225240Copyright © Козлов В.А., Демина Д.В., 20172017Козлов В.А., Демина Д.В.Kozlov V.A., Demina D.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1257

Резюме. Все больше и больше литературных данных свидетельствуют о ведущей роли в формировании иммуносупрессорных механизмов фермента indoleamin 2,3-deoxygenase (IDO), которая продуцируется в основном дендритными клетками, в индукции которой участвует в основном IFNγ и функции которой состоят в индукции катаболизма незаменимой аминокислоты триптофана. Уже одно снижение уровня триптофана в околоклеточной среде обуславливает подавление ряда функций клеток иммунной системы и индукцию регуляторных Т-клеток. Появление ряда катаболитов триптофана еще более усугубляет иммунодепрессивное состояние, индуцированное повышенной экспрессией IDO. Предполагается, что цепочка из IDO, триптофана и его катаболитов в значительной степени определяет формирование гиперсупрессорного состояния при опухолевом росте и гипо- (или недостаточного) супрессорного состояния при аутоиммунных и аллергических заболеваниях. Отсюда вытекают и новые задачи в терапии: найти способы терапии, направленные на снижение активности фермента IDO, участвующего в индукции клеток-супрессоров при опухолевом росте, и в то же время направленные на стимуляцию активности данного фермента для повышения супрессорной активности регуляторных клеток. 

Increasing amounts of literature data suggest the leading role of indoleamine 2,3-deoxygenase (IDO) enzyme in regulation of immunosuppressive mechanisms. IDO is produced, mostly, by dendritic cells, being induced, e.g., under IFNγ involvement. Its function is to provide catabolism of tryptophan, an essential amino acid. Any reduction of tryptophan levels in extracellular environment was shown to cause functional suppression of certain immune cells, and induction of T regulatory cells. Accumulation of different tryptophan catabolites may exacerbate the immunosuppressive status induced by increased IDO expression. It is assumed that the interactions between IDO, tryptophan and its catabolites largely determine a development of hypersuppressor state in tumor growth and a hypo- (or lack of) suppressor status in autoimmune and allergic diseases. This implies some novel tasks for the therapy, including a treatment aimed for reduction of the IDO activity since the latter is involved in suppressor cell induction during tumor growth. Respectively, stimulation of IDO activity may augment suppressor activity of the regulatory cells.

 

иммунопатологияиммуносупрессиятриптофанindoleamine 23-dioxygenaseкинуренинimmunopathologyimmunosuppressiontryptophanindoleamine 2.3-dioxygenasekynurenineReferencesAndersen M.H. CD4 responses against IDO. Oncoimmunology, 2012, Vol. 1, pp. 1211-1212.Andersen M.H. CD4 responses against IDO. Oncoimmunology, 2012, Vol. 1, pp. 1211-1212.Andersen M.H. Anti-regulatory T cells. Semin. Immunopathol., 2016.Andersen M.H. Anti-regulatory T cells. Semin. Immunopathol., 2016.Baban B., Chandler P.R., Sharma M.D., Pinkala J., Koni P.A., Munn D.H., Mellor A.L. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol., 2009, Vol. 183, no. 4, pp. 2475-2483.Baban B., Chandler P.R., Sharma M.D., Pinkala J., Koni P.A., Munn D.H., Mellor A.L. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol., 2009, Vol. 183, no. 4, pp. 2475-2483.Belladonna M.L., Grohmann U., Guidetti P., Volpi C., Bianchi R., Fioretti M.C., Schwarcz R. Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO. J. Immunol., 2006, Vol. 177, pp. 130-137.Belladonna M.L., Grohmann U., Guidetti P., Volpi C., Bianchi R., Fioretti M.C., Schwarcz R. Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO. J. Immunol., 2006, Vol. 177, pp. 130-137.Bennett M.K., Kirk C.J. Development of proteasome inhibitor in oncology and autoimmune diseases. Curr. Opin. Drug. Discov. Devel., 2008, Vol. 11, pp. 616-625.Bennett M.K., Kirk C.J. Development of proteasome inhibitor in oncology and autoimmune diseases. Curr. Opin. Drug. Discov. Devel., 2008, Vol. 11, pp. 616-625.Bernardo M.E., Fibbe W.E. Mesenchymal stromal cells: sensor and switchers of inflammation. Cell Stem Cell, 2013, Vol. 13, pp. 392-402.Bernardo M.E., Fibbe W.E. Mesenchymal stromal cells: sensor and switchers of inflammation. Cell Stem Cell, 2013, Vol. 13, pp. 392-402.Bhutia Y.D., Babu E., Ganapathy V. Interferon-γ induces a tryptophan-selective amino acid transporter in human colonic epithelial cells and mouse dendritic cells. Biochimica et Biophysika Acta, 2015, Vol. 1848, pp. 453-462.Bhutia Y.D., Babu E., Ganapathy V. Interferon-γ induces a tryptophan-selective amino acid transporter in human colonic epithelial cells and mouse dendritic cells. Biochimica et Biophysika Acta, 2015, Vol. 1848, pp. 453-462.Boasso A., Herbeuval J.-P., Hardy A.W., Winker C., Shearer G.M. Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthtase by CTLA-4-Fc in human CD4+ N cells. Blood, 2005, Vol. 105, no. 4, pp. 1574-1581.Boasso A., Herbeuval J.-P., Hardy A.W., Winker C., Shearer G.M. Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthtase by CTLA-4-Fc in human CD4+ N cells. Blood, 2005, Vol. 105, no. 4, pp. 1574-1581.Brenk M., Scheler M., Koch S., Neumann J., Takikawa O., Hacker G., Bieber T., von Bubnoff D. Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+Foxp3 T regulatory cells. J. Immunol., 2009, Vol. 183, no. 1, pp. 145-154.Brenk M., Scheler M., Koch S., Neumann J., Takikawa O., Hacker G., Bieber T., von Bubnoff D. Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+Foxp3 T regulatory cells. J. Immunol., 2009, Vol. 183, no. 1, pp. 145-154.Brok H.P., Vossen J.M., Heidt P.J. IFN-gamma-mediated prevention of graft-versus-host disease: pharmacodynamic studies and influence on proliferative capacity of chimeric spleen cells. Bone Marrow Transplant., 1998, Vol. 22, no. 10, pp. 1005-1010.Brok H.P., Vossen J.M., Heidt P.J. IFN-gamma-mediated prevention of graft-versus-host disease: pharmacodynamic studies and influence on proliferative capacity of chimeric spleen cells. Bone Marrow Transplant., 1998, Vol. 22, no. 10, pp. 1005-1010.Chevolet I., Speeckaert R., Schreuer M., Neyns B., Krysko O., Bachert C., Hennart B., Allorge D., van Geel N., Van Gele M., Brochez L. Characterization of the in vivo immune network of IDO, tryptopan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma. Oncoimmunology, 2015, Vol. 4, no. 3, doi: 10.4161/2162402X.2014.982382.Chevolet I., Speeckaert R., Schreuer M., Neyns B., Krysko O., Bachert C., Hennart B., Allorge D., van Geel N., Van Gele M., Brochez L. Characterization of the in vivo immune network of IDO, tryptopan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma. Oncoimmunology, 2015, Vol. 4, no. 3, doi: 10.4161/2162402X.2014.982382.Chung D.J., Rossi M., Romano E., Ghith J., Yuan J., Munn D.H. and Young J.W. Indoleamine 2,3-dioxygenaseexpressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood, 2009, Vol. 114, no. 3, pp. 555-563.Chung D.J., Rossi M., Romano E., Ghith J., Yuan J., Munn D.H. and Young J.W. Indoleamine 2,3-dioxygenaseexpressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood, 2009, Vol. 114, no. 3, pp. 555-563.Curran T.A., Jalili R.B., Farrokhi A., Grahary A. IDO expressing fibroblasts promote the expression of antigen specific regulatory T cells. Immunobiology, 2014, Vol. 219, no. 1, pp. 17-24.Curran T.A., Jalili R.B., Farrokhi A., Grahary A. IDO expressing fibroblasts promote the expression of antigen specific regulatory T cells. Immunobiology, 2014, Vol. 219, no. 1, pp. 17-24.Darcy C.J., Davis J.S., Woodberry T., McNeil Y.R., Stephens D.P., Yeo T.W., Anstey N.M. An observational cohort study of the kynurenine to tryptophan ratio on sepsis association with impaired immune and microvascular fuction. PLoS One, 2011, Vol. 6, no. 6. doi: 10.1371/journal.pone.0021185.Darcy C.J., Davis J.S., Woodberry T., McNeil Y.R., Stephens D.P., Yeo T.W., Anstey N.M. An observational cohort study of the kynurenine to tryptophan ratio on sepsis association with impaired immune and microvascular fuction. PLoS One, 2011, Vol. 6, no. 6. doi: 10.1371/journal.pone.0021185.Fallarino F., Grohmann U., Vacca C., Bianchi R., Orabona C., Spreca A., Orabona C., Spreca A., Fioretti M.C. and Puccetti P. T cell apoptosis by tryptophan catabolism. Cell Death and Differntiation, 2002, Vol. 9, no. 10, pp. 1069- 1077.Fallarino F., Grohmann U., Vacca C., Bianchi R., Orabona C., Spreca A., Orabona C., Spreca A., Fioretti M.C. and Puccetti P. T cell apoptosis by tryptophan catabolism. Cell Death and Differntiation, 2002, Vol. 9, no. 10, pp. 1069- 1077.Fallarino F., Grohmann U., Hwang K.W., Orabona C., Vacca C., Bianchi R., Belladonna M.L., Fioretti M.C., Alegre M.-L. & Puccetti P. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunology, 2003, Vol. 4, no. 12, pp. 1206-1212.Fallarino F., Grohmann U., Hwang K.W., Orabona C., Vacca C., Bianchi R., Belladonna M.L., Fioretti M.C., Alegre M.-L. & Puccetti P. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunology, 2003, Vol. 4, no. 12, pp. 1206-1212.Fallarino F., Grohman U., You S., McGrath B.C., Cavener D.R., Vacca C., Orabona C., Bianchi R., Belladonna M.L., Volpi C., Santamaria P., Fioretti M.C., Puccetti P. The combined effect of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J. Immunol., 2006, Vol. 176, no. 11, pp. 6752-6761.Fallarino F., Grohman U., You S., McGrath B.C., Cavener D.R., Vacca C., Orabona C., Bianchi R., Belladonna M.L., Volpi C., Santamaria P., Fioretti M.C., Puccetti P. The combined effect of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J. Immunol., 2006, Vol. 176, no. 11, pp. 6752-6761.Fallarino F., Grohman U., You S., McGrath B.C., Cavener D.R., Vacca C., Orabona C., Bianchi R., Belladonnaa M.L., Volpia C., Fiorettia M.C., Puccettia P. Tryptophan catabolism generates autoimmune-preventive regulatory T cells. Transplant Immunology, 2006, Vol. 17, no. 1, pp. 58-60.Fallarino F., Grohman U., You S., McGrath B.C., Cavener D.R., Vacca C., Orabona C., Bianchi R., Belladonnaa M.L., Volpia C., Fiorettia M.C., Puccettia P. Tryptophan catabolism generates autoimmune-preventive regulatory T cells. Transplant Immunology, 2006, Vol. 17, no. 1, pp. 58-60.Fallarino F., Puccetti P. Toll-like receptor 9-mediated induction of the immunosuppressive pathway of tryptophan catabolism. Eur. J. Immunol., 2006, Vol. 36, no. 1, pp. 8-11.Fallarino F., Puccetti P. Toll-like receptor 9-mediated induction of the immunosuppressive pathway of tryptophan catabolism. Eur. J. Immunol., 2006, Vol. 36, no. 1, pp. 8-11.Fallarino F., Grohmann U., Puccetti P. Indoleamine 2,3-dioxygenase: From catalyst to signaling function. Eur. J. Immunol, 2012, Vol. 42, no. 8, pp. 1932-1937.Fallarino F., Grohmann U., Puccetti P. Indoleamine 2,3-dioxygenase: From catalyst to signaling function. Eur. J. Immunol, 2012, Vol. 42, no. 8, pp. 1932-1937.Feunou P., Vanwetswinkel S., Gaudray F., Goldman M., Matthys P., Braun M.Y. Foxp3+CD25+ T regulatory cells stimulate IFN-gamma-independent CD152-mediated activation of tryptophan catabolism that provides dendritic cells with immune regulatory activity in mice unresponsive to staphylococcal enterotoxin B. J. Immunol., 2007, Vol. 179, no. 2, pp. 910-917.Feunou P., Vanwetswinkel S., Gaudray F., Goldman M., Matthys P., Braun M.Y. Foxp3+CD25+ T regulatory cells stimulate IFN-gamma-independent CD152-mediated activation of tryptophan catabolism that provides dendritic cells with immune regulatory activity in mice unresponsive to staphylococcal enterotoxin B. J. Immunol., 2007, Vol. 179, no. 2, pp. 910-917.Furuzawa-Carballeda J., Lima G., Jakez-Ocampo J., Llorente L. Indoleamine 2,3-dioxygenase-expressing peripheral cells in rheumatoid arthritis and systemic lupus erythematosis: a cross-selectional study. Eur. J. Clin. Invest., 2011, Vol. 41, no. 10, pp. 1037-1046.Furuzawa-Carballeda J., Lima G., Jakez-Ocampo J., Llorente L. Indoleamine 2,3-dioxygenase-expressing peripheral cells in rheumatoid arthritis and systemic lupus erythematosis: a cross-selectional study. Eur. J. Clin. Invest., 2011, Vol. 41, no. 10, pp. 1037-1046.Grohmann U., Fallariono F., Bianchi R., Belladonna ML., Vacca C., Orabona C., Uyttenhove C., Fioretti M.C., Puccetti P. IL-6 inhibits the tolerogenic function of CD8 alpha+ dendritic cells expressing indoleamine 2,3-deoxygenase. J. Immunol., 2001, Vol. 106, pp. 708-714.Grohmann U., Fallariono F., Bianchi R., Belladonna ML., Vacca C., Orabona C., Uyttenhove C., Fioretti M.C., Puccetti P. IL-6 inhibits the tolerogenic function of CD8 alpha+ dendritic cells expressing indoleamine 2,3-deoxygenase. J. Immunol., 2001, Vol. 106, pp. 708-714.Grohmann U., Fallarino F., Bianchi R., Orabona C., Vacca C., Fioretti M.C., Puccetti P. A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice. J. Exp. Med., 2003, Vol. 198, no. 1, pp. 153-160.Grohmann U., Fallarino F., Bianchi R., Orabona C., Vacca C., Fioretti M.C., Puccetti P. A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice. J. Exp. Med., 2003, Vol. 198, no. 1, pp. 153-160.Higashitani K., Kanto T., Kuroda S., Yoshio S., Matsubara T., Kakia N., Oze T., Miyazaki M., Sakakibara M., Hiramatsu N., Mita E., Imai Y., Kasahara A., Okuno A., Takikawa O., Hayashi N., Takehara T. Association of enhanced activity of indoleamine 2,3-dioxugenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection. J. Gastroenterol., 2013, Vol. 48, pp. 660-670.Higashitani K., Kanto T., Kuroda S., Yoshio S., Matsubara T., Kakia N., Oze T., Miyazaki M., Sakakibara M., Hiramatsu N., Mita E., Imai Y., Kasahara A., Okuno A., Takikawa O., Hayashi N., Takehara T. Association of enhanced activity of indoleamine 2,3-dioxugenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection. J. Gastroenterol., 2013, Vol. 48, pp. 660-670.Holmgaard R.B., Zamarin D., Munn D.H., Wolchok J.D., Allison J.P. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med., 2013, Vol. 210, no. 7, pp. 1389-1402.Holmgaard R.B., Zamarin D., Munn D.H., Wolchok J.D., Allison J.P. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med., 2013, Vol. 210, no. 7, pp. 1389-1402.Holmgaard R.B., Zamarin D., Li Y., Gasmi B., Munn D.H., Allison J.P., Merghoub T., Wolchok J.D. Tumorexpressed IDO recruits and activates MDSC in a Treg-dependent manner. Cell Reports, 2015, Vol. 13, pp. 412-424.Holmgaard R.B., Zamarin D., Li Y., Gasmi B., Munn D.H., Allison J.P., Merghoub T., Wolchok J.D. Tumorexpressed IDO recruits and activates MDSC in a Treg-dependent manner. Cell Reports, 2015, Vol. 13, pp. 412-424.Holmgaard R.B., Zamarin D., Lesokin A., Merghoub T., Wolchok J.D. Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance tumors immunotherapy in indoleamine 2.3-dioxygenase-expressing tumors. EBioMedicine, 2016, Vol. 6, pp. 50-58.Holmgaard R.B., Zamarin D., Lesokin A., Merghoub T., Wolchok J.D. Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance tumors immunotherapy in indoleamine 2.3-dioxygenase-expressing tumors. EBioMedicine, 2016, Vol. 6, pp. 50-58.Hosseini-Tabatabael A., Baradar R., Li Y., Killani T., Rezakhanlou M.A., Ghahary A. Mechanism underlying interferon gamma-induced IDO expression in Non-obese diabetic mouse fibroblasts. PloS ONE, 2012, Vol. 7, no. 5, pp. 1-11.Hosseini-Tabatabael A., Baradar R., Li Y., Killani T., Rezakhanlou M.A., Ghahary A. Mechanism underlying interferon gamma-induced IDO expression in Non-obese diabetic mouse fibroblasts. PloS ONE, 2012, Vol. 7, no. 5, pp. 1-11.Hsu W.T., Lin C.-H., Chiang B.-L., Jui H.Y., Wu K. Kun-Yu, Lee C.-M. Prostaglandin E2 potentiates Mesenchymal stem cell-induced IL-10+IFN-γ+CD4+ regulatory T cells to control transplant arteriosclerosis. J. Immunol., 2013, Vol. 190, pp. 2372-2380.Hsu W.T., Lin C.-H., Chiang B.-L., Jui H.Y., Wu K. Kun-Yu, Lee C.-M. Prostaglandin E2 potentiates Mesenchymal stem cell-induced IL-10+IFN-γ+CD4+ regulatory T cells to control transplant arteriosclerosis. J. Immunol., 2013, Vol. 190, pp. 2372-2380.Inglis J.J., Criado G., Andrews M., Feldman M., Williams R.O., Selley M.L. The anti-allergic drug, N-(3’,4’-dimethoxycinnamonyl) anthranilic acid, exhibit anti-inflammatory and analgestic properties in arthritis. Rheumatology (Oxford), 2007, Vol. 46, no. 9, pp. 1428-1432.Inglis J.J., Criado G., Andrews M., Feldman M., Williams R.O., Selley M.L. The anti-allergic drug, N-(3’,4’-dimethoxycinnamonyl) anthranilic acid, exhibit anti-inflammatory and analgestic properties in arthritis. Rheumatology (Oxford), 2007, Vol. 46, no. 9, pp. 1428-1432.Jui H.Y., Lin C.H., Hsu W.T., Liu Y.R., Hsu R.B., Chiang B.L., Tseng W.Y., Wu K.K., Lee C.M. Autologous Mesenchymal stem cells prevent transplant arteriosclerosis by enhancing local expression of interleukin-10, interferon-γ, and indoleamine 2,3-dioxygenase. Cell Transplant., 2012, Vol. 21, no. 5, pp. 971-984.Jui H.Y., Lin C.H., Hsu W.T., Liu Y.R., Hsu R.B., Chiang B.L., Tseng W.Y., Wu K.K., Lee C.M. Autologous Mesenchymal stem cells prevent transplant arteriosclerosis by enhancing local expression of interleukin-10, interferon-γ, and indoleamine 2,3-dioxygenase. Cell Transplant., 2012, Vol. 21, no. 5, pp. 971-984.Larrea E., Riezu-Boj J.I., Gil-Guerrero L., Casares N., Aldabe R., Sarobe P., Civeira M.P., Heeney J.L., Rollier C., Verstrepen B., Wakita T., Borrás-Cuesta F., Lasarte J.J., and Prieto J. Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection. J. Virol., 2007, Vol. 81, pp. 3662-3666.Larrea E., Riezu-Boj J.I., Gil-Guerrero L., Casares N., Aldabe R., Sarobe P., Civeira M.P., Heeney J.L., Rollier C., Verstrepen B., Wakita T., Borrás-Cuesta F., Lasarte J.J., and Prieto J. Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection. J. Virol., 2007, Vol. 81, pp. 3662-3666.Li Q., Harden J.L., Anderson C.D., Egilmez N.K. Tolerogenic phenotype of IFN-γ-induced IDO+ dendritic cells is maintained via an autocrine IDO-kynurenine/AhR-IDO loop. J. Immunol., 2016, Vol. 197, no. 3, pp. 962-970.Li Q., Harden J.L., Anderson C.D., Egilmez N.K. Tolerogenic phenotype of IFN-γ-induced IDO+ dendritic cells is maintained via an autocrine IDO-kynurenine/AhR-IDO loop. J. Immunol., 2016, Vol. 197, no. 3, pp. 962-970.Lim J.-Y., Im K.I., Lee E.S., Kim N., Nam Y.S., Jeon Y.W., Cho S.G. Enhanced immunoregulation of mesenchymal stem cells by IL-10-producing type 1 regulatory T cells in collagen-induced arthritis. Scientific Reports, 2016, Vol. 6. doi: 10.1038/srep26851..Lim J.-Y., Im K.I., Lee E.S., Kim N., Nam Y.S., Jeon Y.W., Cho S.G. Enhanced immunoregulation of mesenchymal stem cells by IL-10-producing type 1 regulatory T cells in collagen-induced arthritis. Scientific Reports, 2016, Vol. 6. doi: 10.1038/srep26851..Lood C., Tyden H., Gullstrana B., Klint C., Wenglen C., Nielsen C.T., Heegaard N.H.H., Jönsen A., Kahn R., Bengtsson A.A.Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus. PLoS ONE, 2015, Vol. 10, no. 4, eO125.Lood C., Tyden H., Gullstrana B., Klint C., Wenglen C., Nielsen C.T., Heegaard N.H.H., Jönsen A., Kahn R., Bengtsson A.A.Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus. PLoS ONE, 2015, Vol. 10, no. 4, eO125.Manches O., Munn D., Fallahi A., Lifson J., Chaperot L., Plumas J., Bhardwaj N. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J. Clin. Invest., 2008, Vol. 118, no. 10, pp. 3431-3439.Manches O., Munn D., Fallahi A., Lifson J., Chaperot L., Plumas J., Bhardwaj N. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J. Clin. Invest., 2008, Vol. 118, no. 10, pp. 3431-3439.Mancuso R., Hernis A., Agostini S., Rovaris M., Caputo D., Fichs D., Clerici M. Indoleamine 2,3 dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis. PLoS ONE, 2015, Vol. 10, no. 6. doi: 10.1371/ journal.pone.0130715.Mancuso R., Hernis A., Agostini S., Rovaris M., Caputo D., Fichs D., Clerici M. Indoleamine 2,3 dioxygenase (IDO) expression and activity in relapsing-remitting multiple sclerosis. PLoS ONE, 2015, Vol. 10, no. 6. doi: 10.1371/ journal.pone.0130715.Mao R., Zhag J., Jiang D., Cai D., Levy J.M., Cuconati A., Block T.M., Guo J.-T., and Guo H. Indoleamine 2,3-dioxugenase mediates the antiviral effect gamma interferon against hepatitis B virus in human hepatocytederived cells. J. Virol., 2011, Vol. 85, no. 2, pp. 1048-1057.Mao R., Zhag J., Jiang D., Cai D., Levy J.M., Cuconati A., Block T.M., Guo J.-T., and Guo H. Indoleamine 2,3-dioxugenase mediates the antiviral effect gamma interferon against hepatitis B virus in human hepatocytederived cells. J. Virol., 2011, Vol. 85, no. 2, pp. 1048-1057.Mbongue J.C., Nicholas D.A., Torrez T.W., Kim N.S., Firek A.A., Langridge W.H.R. The role of indoleamine 2,3-dioxygenase in immune suppression and autoimmunity. Vaccines, 2015, Vol. 3, no. 3, pp. 703-729.Mbongue J.C., Nicholas D.A., Torrez T.W., Kim N.S., Firek A.A., Langridge W.H.R. The role of indoleamine 2,3-dioxygenase in immune suppression and autoimmunity. Vaccines, 2015, Vol. 3, no. 3, pp. 703-729.Mcllroy D., Tanguy-Royer S., Le Meur N., Guisle I., Royer P.J., Leger J., Meflah K., Gregoire M. Profiling dendritic cell maturation with dedicated microarrays. J. Leukocyte Biol., 2005, Vol. 78, no. 3, pp.794-803.Mcllroy D., Tanguy-Royer S., Le Meur N., Guisle I., Royer P.J., Leger J., Meflah K., Gregoire M. Profiling dendritic cell maturation with dedicated microarrays. J. Leukocyte Biol., 2005, Vol. 78, no. 3, pp.794-803.Moon Y.W., Hajjar J., Hwu P., Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunotherapy of Cancer, 2015, Vol. 3, pp. 51-56.Moon Y.W., Hajjar J., Hwu P., Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunotherapy of Cancer, 2015, Vol. 3, pp. 51-56.Movahedi K., Guilliams M., Van den Bossche J., Van den Bergh R., Gysemans C., Beschin A., De Baetselier P and Van Ginderachter J.A. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-cell-suppressive activity. Blood, 2008, Vol. 111, no. 8, pp. 4233-4244.Movahedi K., Guilliams M., Van den Bossche J., Van den Bergh R., Gysemans C., Beschin A., De Baetselier P and Van Ginderachter J.A. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-cell-suppressive activity. Blood, 2008, Vol. 111, no. 8, pp. 4233-4244.Munn D.H., Zhou M., Attwood J.T., Bondarev I., Conway S.J., Marshal B., Brown C., Mellor A.L. Prevention of allogenic fetal rejection by tryptophan catabolism. Science, 1998, Vol. 281, no. 5380, pp. 1191-1193.Munn D.H., Zhou M., Attwood J.T., Bondarev I., Conway S.J., Marshal B., Brown C., Mellor A.L. Prevention of allogenic fetal rejection by tryptophan catabolism. Science, 1998, Vol. 281, no. 5380, pp. 1191-1193.Ogata M., Ito T., Shimamoto K., Nakanishi T., Satsutani N., Miyamoto R., Nomura S. Plasmacytoid dendritic cells have a cytokine-producing capacity to enhance ICOS ligand-mediated IL-10 production during T-cell priming. International Immunology, 2013, Vol. 25, no. 3, pp. 171-182.Ogata M., Ito T., Shimamoto K., Nakanishi T., Satsutani N., Miyamoto R., Nomura S. Plasmacytoid dendritic cells have a cytokine-producing capacity to enhance ICOS ligand-mediated IL-10 production during T-cell priming. International Immunology, 2013, Vol. 25, no. 3, pp. 171-182.Okamoto A., Nikaido T., Ochiai K., Takakura S., Saito M., Aoki Y., Ishii N., Yanaihara N., Yamada K., Takikawa O., Kawaguchi R., Isonishi S., Tanaka T., Urashima M. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serious ovarian cancer cells. Clin. Cancer Res., 2005, Vol. 11, no. 16, pp. 6030-6039.Okamoto A., Nikaido T., Ochiai K., Takakura S., Saito M., Aoki Y., Ishii N., Yanaihara N., Yamada K., Takikawa O., Kawaguchi R., Isonishi S., Tanaka T., Urashima M. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serious ovarian cancer cells. Clin. Cancer Res., 2005, Vol. 11, no. 16, pp. 6030-6039.Orabona C., Pallotta M.T., Volpi C., Fallarino F., Vacca C., Bianchi R., Belladonna M.L., Fioretti M.C., Grohmann U., Puccetti P. SOCS3 drives proteasomal degradation of indileamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. PNAS, 2008, Vol. 105, no. 52, pp. 20828-20833.Orabona C., Pallotta M.T., Volpi C., Fallarino F., Vacca C., Bianchi R., Belladonna M.L., Fioretti M.C., Grohmann U., Puccetti P. SOCS3 drives proteasomal degradation of indileamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. PNAS, 2008, Vol. 105, no. 52, pp. 20828-20833.Orabona C., Pallotta M.T., Grohmann U. Different partness, opposite outcomes: a new perspective of the immunobiology of indoleamine 2,3-dioxygenase. Mol. Med, 2012, Vol. 18, pp. 834-842.Orabona C., Pallotta M.T., Grohmann U. Different partness, opposite outcomes: a new perspective of the immunobiology of indoleamine 2,3-dioxygenase. Mol. Med, 2012, Vol. 18, pp. 834-842.Palego L., Betti L., Rossi A., Giannaccini G. Tryptophan biochemistry: structural, nutritional, metabolic, and medical aspects in humans. J. Amino Acids, 2016, Vol. 2016, 13 p.Palego L., Betti L., Rossi A., Giannaccini G. Tryptophan biochemistry: structural, nutritional, metabolic, and medical aspects in humans. J. Amino Acids, 2016, Vol. 2016, 13 p.Pallotta M.T., Orabona C., Volpi C., Grohman U., Puccetti P., Fallarino F. Proteasomal degradation of indoleamine 2,3-dioxygenase in CD8+ dendritic cells is mediated by suppressor of cytokine signaling 3 (SOCS3). International J. Tryptophan Res., 2010, Vol. 3, pp. 91-97.Pallotta M.T., Orabona C., Volpi C., Grohman U., Puccetti P., Fallarino F. Proteasomal degradation of indoleamine 2,3-dioxygenase in CD8+ dendritic cells is mediated by suppressor of cytokine signaling 3 (SOCS3). International J. Tryptophan Res., 2010, Vol. 3, pp. 91-97.Pallotta M.P., Orabona C., Volpi C., Vacca C., Belladonna M.L., Bianchi R., Servillo G., Brunacci C., Calvitti M., Bicciato S., Mazza E.M., Boon L., Grassi F., Fioretti M.C., Fallarino F., Puccetti P., Grohmann U. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat. Immunol., 2011, Vol. 12, no. 9, pp. 870-878.Pallotta M.P., Orabona C., Volpi C., Vacca C., Belladonna M.L., Bianchi R., Servillo G., Brunacci C., Calvitti M., Bicciato S., Mazza E.M., Boon L., Grassi F., Fioretti M.C., Fallarino F., Puccetti P., Grohmann U. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat. Immunol., 2011, Vol. 12, no. 9, pp. 870-878.Pallotta M.T., Orabona C., Bianchi R., Vacca C., Francesca Fallarino F., Belladonna M.L., Volpi C., Mondanelli G., Gargaro M., Allegrucci M., Talesa V.N., Puccetti P., Grohmann U. Forced IDO1 expression in dendritic cells restores immunoregula- tory signalling in autoimmune diabetes. J. Cell. Mol. Med., 2014, Vol. 18, no. 10, pp. 2082-2091.Pallotta M.T., Orabona C., Bianchi R., Vacca C., Francesca Fallarino F., Belladonna M.L., Volpi C., Mondanelli G., Gargaro M., Allegrucci M., Talesa V.N., Puccetti P., Grohmann U. Forced IDO1 expression in dendritic cells restores immunoregula- tory signalling in autoimmune diabetes. J. Cell. Mol. Med., 2014, Vol. 18, no. 10, pp. 2082-2091.Pedersen E.R., Svingen G.F., Schartum-Hansen N., Ueland P.M., Ebbing M., Nordrehaug J.E., Igland J., Seifert R., Nilsen R.M., Nygård O. Urinary excretion of kynurenine and tryptophanan, cardiovascular events, and mortality after elective coronary angiography. Eur. Heart J., 2013, Vol. 34, no. 34, pp. 2689-2726.Pedersen E.R., Svingen G.F., Schartum-Hansen N., Ueland P.M., Ebbing M., Nordrehaug J.E., Igland J., Seifert R., Nilsen R.M., Nygård O. Urinary excretion of kynurenine and tryptophanan, cardiovascular events, and mortality after elective coronary angiography. Eur. Heart J., 2013, Vol. 34, no. 34, pp. 2689-2726.Pedersen E.R., Tuseth N., Eussen S.J., Ueland P.M., Strand E., Svingen G.F., Midttun O., Meyer K., Mellgren G., Ulvik A., Nordrehaug J.E., Nilsen D.W., Nygård O. Association of plasma kynurenine with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler. Thromb. Vasc. Biol., 2015, Vol. 35, no. 2, pp. 455-462.Pedersen E.R., Tuseth N., Eussen S.J., Ueland P.M., Strand E., Svingen G.F., Midttun O., Meyer K., Mellgren G., Ulvik A., Nordrehaug J.E., Nilsen D.W., Nygård O. Association of plasma kynurenine with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler. Thromb. Vasc. Biol., 2015, Vol. 35, no. 2, pp. 455-462.Pfefferkorn E.R. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc. Natl. Acad. Sci. USA, 1984, Vol. 81, no. 3, pp. 908-912.Pfefferkorn E.R. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc. Natl. Acad. Sci. USA, 1984, Vol. 81, no. 3, pp. 908-912.Platten M., Ho P.P., Youssef S., Fontoura P., Garren H., Hur E.M., Gupta R., Lee L.Y., Kidd B.A., Robinson W.H., Sobel R.A., Selley M.L., Steinman L. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science, 2005, Vol. 310, no. 5749, pp. 850-855.Platten M., Ho P.P., Youssef S., Fontoura P., Garren H., Hur E.M., Gupta R., Lee L.Y., Kidd B.A., Robinson W.H., Sobel R.A., Selley M.L., Steinman L. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science, 2005, Vol. 310, no. 5749, pp. 850-855.Popov A., Abdullah Z., Wickenhauser C., Saric T., Driesen J., Hanisch F.G., Domann E., Raven E.L., Dehus O., Hermann C., Eggle D., Debey S., Chakraborty T., Krönke M., Utermöhlen O., Schultze J.L. Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection. J. Clin. Invest., 2006, Vol. 116, no. 12, pp. 3160-3170.Popov A., Abdullah Z., Wickenhauser C., Saric T., Driesen J., Hanisch F.G., Domann E., Raven E.L., Dehus O., Hermann C., Eggle D., Debey S., Chakraborty T., Krönke M., Utermöhlen O., Schultze J.L. Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection. J. Clin. Invest., 2006, Vol. 116, no. 12, pp. 3160-3170.Prendergast G.C., Metz R., Muller A.J., Merto L.M.F., Mandik-Nayak L. IDO2 in immunomodilation and autoimmune disease. Frontiers in Immunology, 2014, Vol. 5, pp. 1-6.Prendergast G.C., Metz R., Muller A.J., Merto L.M.F., Mandik-Nayak L. IDO2 in immunomodilation and autoimmune disease. Frontiers in Immunology, 2014, Vol. 5, pp. 1-6.Puccetti P. On watching the watchers: IDO and type I/II IFN. Eur. J. Immunol., 2007, Vol. 37, no. 4, pp. 876- 879.Puccetti P. On watching the watchers: IDO and type I/II IFN. Eur. J. Immunol., 2007, Vol. 37, no. 4, pp. 876- 879.Radhakrishan S., Cabrera R., Schenk E.L., Nava-Parada P., Bell M.P., Van Keulen V.P., Marler R.J., Felts S.J., Pease L.R. Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo. J. Immunol., 2008, Vol. 181, no. 5, pp. 3137-3147.Radhakrishan S., Cabrera R., Schenk E.L., Nava-Parada P., Bell M.P., Van Keulen V.P., Marler R.J., Felts S.J., Pease L.R. Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo. J. Immunol., 2008, Vol. 181, no. 5, pp. 3137-3147.Ravishankar B., Liu H., Shinde R., Chandler P., Baban B., Tanaka M., Munn D.H., Mellora A.L., Karlssonf M.C.I., McGaha T.L. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. PNAS, 2012, Vol. 109, no. 10, pp. 3909-3914.Ravishankar B., Liu H., Shinde R., Chandler P., Baban B., Tanaka M., Munn D.H., Mellora A.L., Karlssonf M.C.I., McGaha T.L. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. PNAS, 2012, Vol. 109, no. 10, pp. 3909-3914.Robinson C.M., Hale P.T., Carlin J.M. The role of IFN-γ and TNF-α-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase. J. Interferon Cytokine Res., 2005, Vol. 25, no. 1, pp. 20-30. 63. Rubin B.Y., Andersen D.L., Xing L., Powell R.J., Tate W.P. Interferon ibduces tryptophanyl-tRNA synthetase expression in human fibroblasts. J. Biol. Chemistry, 1991, Vol. 266, no. 36, pp. 24245-24248.Robinson C.M., Hale P.T., Carlin J.M. The role of IFN-γ and TNF-α-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase. J. Interferon Cytokine Res., 2005, Vol. 25, no. 1, pp. 20-30. 63. Rubin B.Y., Andersen D.L., Xing L., Powell R.J., Tate W.P. Interferon ibduces tryptophanyl-tRNA synthetase expression in human fibroblasts. J. Biol. Chemistry, 1991, Vol. 266, no. 36, pp. 24245-24248.Samikkannu T., Rao K.V., Gandhi N., Saxena S.K., Nair M.P. Human immunodeficiency virus type 1 clade B and C Tat differentially induce indoleamine 2,3-dioxygenase and serotonin in immature dendritic cells implications for neuroAIDS. J. Neuroviral., 2010, Vol. 16, no. 4, pp. 255-263.Samikkannu T., Rao K.V., Gandhi N., Saxena S.K., Nair M.P. Human immunodeficiency virus type 1 clade B and C Tat differentially induce indoleamine 2,3-dioxygenase and serotonin in immature dendritic cells implications for neuroAIDS. J. Neuroviral., 2010, Vol. 16, no. 4, pp. 255-263.Sarkhosh K., Tredget E.E., Karami A., Uludag H., Iwashina T., Kilani R.T., Ghahary A. Immune cell proliferation is suppressed by the interferon-y-induced indoleamine 2,3-dioxgenase expression of fibroblasts populated in collagen gel (FPCG). J. Cell Biochem., 2003, Vol. 90, no. 1, pp. 206-217.Sarkhosh K., Tredget E.E., Karami A., Uludag H., Iwashina T., Kilani R.T., Ghahary A. Immune cell proliferation is suppressed by the interferon-y-induced indoleamine 2,3-dioxgenase expression of fibroblasts populated in collagen gel (FPCG). J. Cell Biochem., 2003, Vol. 90, no. 1, pp. 206-217.Sasaki E., Ohta Y., Shinohara R., Ishiguro I. Contribution of serum albumin to the transport of orally administered L-tryptophan into liver of rats with L-tryptophan depletion. Amino Acids, 1999, Vol. 16, no. 1, pp. 29-39.Sasaki E., Ohta Y., Shinohara R., Ishiguro I. Contribution of serum albumin to the transport of orally administered L-tryptophan into liver of rats with L-tryptophan depletion. Amino Acids, 1999, Vol. 16, no. 1, pp. 29-39.Schmidt S.V., Schultze J.L. New insight into IDO biology in bacterial and viral infections. Frontiers in Immunology, 2014, Vol. 5, pp. 1-12.Schmidt S.V., Schultze J.L. New insight into IDO biology in bacterial and viral infections. Frontiers in Immunology, 2014, Vol. 5, pp. 1-12.Schroecksnadel K., Winkler B., Wirleitner B., Schennach H., Fuchs D. Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro. Clinical and Experimental Immunology, 2005, Vol. 140, no. 1, pp. 41-45.Schroecksnadel K., Winkler B., Wirleitner B., Schennach H., Fuchs D. Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro. Clinical and Experimental Immunology, 2005, Vol. 140, no. 1, pp. 41-45.Schroecksnadel K., Winkler C., Duftner C., Wirleitner B., Schirmer M., Fuchs D. Tryptophan degradation increases with stage in patients with rheumatoid arthritis. Clin. Rheumatol., 2006, Vol. 25, no. 3, pp. 334-337.Schroecksnadel K., Winkler C., Duftner C., Wirleitner B., Schirmer M., Fuchs D. Tryptophan degradation increases with stage in patients with rheumatoid arthritis. Clin. Rheumatol., 2006, Vol. 25, no. 3, pp. 334-337.Sharma R., Di Dalmazi G., Caturegli P. Exacerbation of autoimmune thyroiditis by CTLA-4 blockade: a role for IFN-γ-induce indoleamine 2,3-dioxygenase. Thyroid., 2016, Vol. 26, no. 8, pp. 1117-1124.Sharma R., Di Dalmazi G., Caturegli P. Exacerbation of autoimmune thyroiditis by CTLA-4 blockade: a role for IFN-γ-induce indoleamine 2,3-dioxygenase. Thyroid., 2016, Vol. 26, no. 8, pp. 1117-1124.Strasser B., Becker K., Fuchs D., Gostner J.M. Kynurenine pathway metabolism and immune activation: peripheral measurement in psychiatric and co-morbid conditions. Neuropharmacology, 2016, pii: S0028- 3908(16)30065-X.Strasser B., Becker K., Fuchs D., Gostner J.M. Kynurenine pathway metabolism and immune activation: peripheral measurement in psychiatric and co-morbid conditions. Neuropharmacology, 2016, pii: S0028- 3908(16)30065-X.Su J., Chen X., Huang Y., Li W., Cao K., Cao G., Zhang L., Li F., Roberts A.I., Kang H., Yu P., Ren G., Ji W., Wang Y., Shi Y. Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species. Cell Death Differ., 2014, Vol. 21, no. 3, pp. 388-396.Su J., Chen X., Huang Y., Li W., Cao K., Cao G., Zhang L., Li F., Roberts A.I., Kang H., Yu P., Ren G., Ji W., Wang Y., Shi Y. Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species. Cell Death Differ., 2014, Vol. 21, no. 3, pp. 388-396.Suarez-Fuentetaja N., Domenech-Garcia N., Paniagua-Martin M.J., Marzoa-Rivas R., Barge-Caballero E., Grille-Cancela Z., Pombo-Oteroa J., Muñiz-Garcíab J., Castro-Beirasa A., Crespo-Leiro M.G. Indoleamine 2-3 dioxygenase activity could be early marker of graft rejection in heart transplantation. Transplantation Proc., 2012, Vol. 44, no. 9, pp. 2645-2648.Suarez-Fuentetaja N., Domenech-Garcia N., Paniagua-Martin M.J., Marzoa-Rivas R., Barge-Caballero E., Grille-Cancela Z., Pombo-Oteroa J., Muñiz-Garcíab J., Castro-Beirasa A., Crespo-Leiro M.G. Indoleamine 2-3 dioxygenase activity could be early marker of graft rejection in heart transplantation. Transplantation Proc., 2012, Vol. 44, no. 9, pp. 2645-2648.Suzuki Y., Suda T., Yokomura K., Suzuki M., Fujie M., Furuhafhi K. Serum activity of indoleamine 2.3-dioxygenase predicts prognosis of community-acquired pneumonia. J. Infect., 2011, Vol. 63, no. 3, pp. 215-222.Suzuki Y., Suda T., Yokomura K., Suzuki M., Fujie M., Furuhafhi K. Serum activity of indoleamine 2.3-dioxygenase predicts prognosis of community-acquired pneumonia. J. Infect., 2011, Vol. 63, no. 3, pp. 215-222.Tattevin P., Monnier D., Tribut O., Dulong J., Bescher N., Mourcin F. Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock. J. Infect. Dis., 2010, Vol. 201, no. 6, pp. 956-966.Tattevin P., Monnier D., Tribut O., Dulong J., Bescher N., Mourcin F. Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock. J. Infect. Dis., 2010, Vol. 201, no. 6, pp. 956-966.Taylor M.W., Feng G.S. Relationship between interferon-gamma, indoleamine 2,3-dioxugenase, and tryptophan catabolism. FASEB J., 1991, Vol. 5, no. 16, pp. 2516-2522.Taylor M.W., Feng G.S. Relationship between interferon-gamma, indoleamine 2,3-dioxugenase, and tryptophan catabolism. FASEB J., 1991, Vol. 5, no. 16, pp. 2516-2522.Theate I., van Baren N., Pilotte L., Moulin P., Larrieu P., Renauld J.C., Hervé C., Gutierrez-Roelens I., Marbaix E., Sempoux C., Van den Eynde B.J. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol. Res., 2015, Vol. 3, no. 2, pp. 161-172.Theate I., van Baren N., Pilotte L., Moulin P., Larrieu P., Renauld J.C., Hervé C., Gutierrez-Roelens I., Marbaix E., Sempoux C., Van den Eynde B.J. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol. Res., 2015, Vol. 3, no. 2, pp. 161-172.Thomas S.R., Mohr D., Stocker R. Nitric oxide inhibits indoleamine 2,3-dioxygenase activity in interferongamma primed mononuclear phagocytes. J. Biol. Chem., 1994, Vol. 269, no. 20, pp. 14457-14464.Thomas S.R., Mohr D., Stocker R. Nitric oxide inhibits indoleamine 2,3-dioxygenase activity in interferongamma primed mononuclear phagocytes. J. Biol. Chem., 1994, Vol. 269, no. 20, pp. 14457-14464.von Bubnoff D., Scheler M., Wilms H., von Bubnoff N., Häcker G., Schultze J., Popov A., Racz P., Bieber T., Wickenhauser C. Indoleamine 2.3-dioxygenase-expressing myeloid dendritic cells and macrophages in infectious and noninfectious cutaneous granulomas. J. Am. Acad. Dermatol., 2011, Vol. 65, no. 4, pp. 819-832.von Bubnoff D., Scheler M., Wilms H., von Bubnoff N., Häcker G., Schultze J., Popov A., Racz P., Bieber T., Wickenhauser C. Indoleamine 2.3-dioxygenase-expressing myeloid dendritic cells and macrophages in infectious and noninfectious cutaneous granulomas. J. Am. Acad. Dermatol., 2011, Vol. 65, no. 4, pp. 819-832.von Bubnoff D., Wilms H., Scheler M., Brenk M., Koch S., Bieber T. Human myeloid dendritic cells are refractory to tryptophan metabolitis. Human Immunology, 2011, Vol. 72, no. 10, pp. 791-797.von Bubnoff D., Wilms H., Scheler M., Brenk M., Koch S., Bieber T. Human myeloid dendritic cells are refractory to tryptophan metabolitis. Human Immunology, 2011, Vol. 72, no. 10, pp. 791-797.Wainwright D.A., Chang A.L., Dey M., Balyasnikova I.V., Kim C.K., Tobias A., Cheng Y., Kim J.W., Qiao J., Zhang L., Han Y., Lesniak M.S. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin. Cancer Res., 2014, Vol. 20, no. 20, pp. 5290-5301.Wainwright D.A., Chang A.L., Dey M., Balyasnikova I.V., Kim C.K., Tobias A., Cheng Y., Kim J.W., Qiao J., Zhang L., Han Y., Lesniak M.S. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin. Cancer Res., 2014, Vol. 20, no. 20, pp. 5290-5301.Wan S., Xia C., Moral L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J. Immunol., 2007, Vol. 178, no. 1, pp. 271-279.Wan S., Xia C., Moral L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J. Immunol., 2007, Vol. 178, no. 1, pp. 271-279.Werner E.R., Bitterlich G., Fuchs D., Hausen A., Reibnegger G., Szabo G., Dierich M.P., Wachter H. Human macrophages degrade tryptophan upon induction by interferon-gamma. Life Sci., 1987, Vol. 41, no. 3, pp. 273-280.Werner E.R., Bitterlich G., Fuchs D., Hausen A., Reibnegger G., Szabo G., Dierich M.P., Wachter H. Human macrophages degrade tryptophan upon induction by interferon-gamma. Life Sci., 1987, Vol. 41, no. 3, pp. 273-280.Widner B., Laich A., Sperner-Unterweger B., Ledochowski M., Fuchs D. Neopterin production, tryptophan degradation, and mental depression – What is the link? Brain, Behavior, and Immunity, 2002, Vol. 16, no. 5, pp. 590- 595.Widner B., Laich A., Sperner-Unterweger B., Ledochowski M., Fuchs D. Neopterin production, tryptophan degradation, and mental depression – What is the link? Brain, Behavior, and Immunity, 2002, Vol. 16, no. 5, pp. 590- 595.Williams RO. Exploitation of the IDO pathway in the therapy of rheumatoid arthritis. International J. Tryptophan. Res., 2013, Vol. 6, no. 1, pp. 67-73.Williams RO. Exploitation of the IDO pathway in the therapy of rheumatoid arthritis. International J. Tryptophan. Res., 2013, Vol. 6, no. 1, pp. 67-73.Xu H., Zhang G.-X., Ciric B., Rostami A. IDO: a double-edged sword for T(H)1/T(H)2 regulation. Immunol. Lett., 2008, Vol, 121, no. 1, pp. 1-6.Xu H., Zhang G.-X., Ciric B., Rostami A. IDO: a double-edged sword for T(H)1/T(H)2 regulation. Immunol. Lett., 2008, Vol, 121, no. 1, pp. 1-6.Xu S.Q., Wang C.Y., Zhu X.J., Dong X.Y., Shi Y., Peng J., Qin P., Sun J.-Z., Guo C., Ni H., Hou M. Decreased indoleamine 2,3-dioxygenase expression in dendritic cells and role of indoleamine 2,3-dioxygenase-expressing dendritic cells in immune thrombocytopenia. Annals of Hematology, 2012, Vol. 91, no.10, pp. 1623-1631.Xu S.Q., Wang C.Y., Zhu X.J., Dong X.Y., Shi Y., Peng J., Qin P., Sun J.-Z., Guo C., Ni H., Hou M. Decreased indoleamine 2,3-dioxygenase expression in dendritic cells and role of indoleamine 2,3-dioxygenase-expressing dendritic cells in immune thrombocytopenia. Annals of Hematology, 2012, Vol. 91, no.10, pp. 1623-1631.Xu J., Wei J., Zhu X., Zhang X., Guan J., Wang J., Yin J., Xiao Y., Zhang Y. Increased plasma indoleamine 2,3-deoxygenase activity and interferon-γ levels correlate with the severity of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant., 2013, Vol. 19, no. 2, pp. 196-201.Xu J., Wei J., Zhu X., Zhang X., Guan J., Wang J., Yin J., Xiao Y., Zhang Y. Increased plasma indoleamine 2,3-deoxygenase activity and interferon-γ levels correlate with the severity of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant., 2013, Vol. 19, no. 2, pp. 196-201.Xue Z.T., Sjogren H.O., Salford L.G., Widergren B. An epigenetic mechanism for high, synergistic expression of indoleamine 2,3-deoxugenase 1 (IDO1) by combined treatment with zebularine and IFN-gamma potential therapeutic use in autoimmune diseases. Mol. Immunol., 2012, Vol. 51, no. 2, pp. 101-111.Xue Z.T., Sjogren H.O., Salford L.G., Widergren B. An epigenetic mechanism for high, synergistic expression of indoleamine 2,3-deoxugenase 1 (IDO1) by combined treatment with zebularine and IFN-gamma potential therapeutic use in autoimmune diseases. Mol. Immunol., 2012, Vol. 51, no. 2, pp. 101-111.Yang X.O., Nurieva R., Martinez G.J., Kang H.S., Chung Y., Pappu B.P., Shah B., Chang S.H., Schluns K.S., Watowich S.S., Feng X.H., Jetten A.M., Dong C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity, 2008, Vol. 29, no. 1, pp. 44-56.Yang X.O., Nurieva R., Martinez G.J., Kang H.S., Chung Y., Pappu B.P., Shah B., Chang S.H., Schluns K.S., Watowich S.S., Feng X.H., Jetten A.M., Dong C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity, 2008, Vol. 29, no. 1, pp. 44-56.Zhu L., Ji F., Wang Y., Zhang Y., Liu Q., Zhang J.Z., Matsushima K., Cao Q., Zhang Y. Synovial autoreactive T cells in rheumatoid arthritis resist IDO-mediated inhibition. J. Immunol., 2015, Vol. 177, no. 11, pp. 8226-8233.Zhu L., Ji F., Wang Y., Zhang Y., Liu Q., Zhang J.Z., Matsushima K., Cao Q., Zhang Y. Synovial autoreactive T cells in rheumatoid arthritis resist IDO-mediated inhibition. J. Immunol., 2015, Vol. 177, no. 11, pp. 8226-8233.Zoso A., Mazza E.M.C., Bicciato S., Mandruzzato S., Bronte V., Serafini P., Inverardi L. Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion. Eur. J. Immunol., 2014, Vol. 44, no. 11, pp. 3307-3319.Zoso A., Mazza E.M.C., Bicciato S., Mandruzzato S., Bronte V., Serafini P., Inverardi L. Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion. Eur. J. Immunol., 2014, Vol. 44, no. 11, pp. 3307-3319.

The authors declare that there are no conflicts of interest present.