Annals of Hematology

, Volume 91, Issue 10, pp 1623–1631 | Cite as

Decreased indoleamine 2,3-dioxygenase expression in dendritic cells and role of indoleamine 2,3-dioxygenase-expressing dendritic cells in immune thrombocytopenia

  • Shu-qian Xu
  • Chun-yan Wang
  • Xiao-juan Zhu
  • Xiao-yuan Dong
  • Yan Shi
  • Jun Peng
  • Ping Qin
  • Jian-zhi Sun
  • Chengshan Guo
  • Heyu Ni
  • Ming Hou
Original Article

Abstract

Indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells (DCs) can induce or maintain peripheral immune tolerance. Impaired IDO-mediated tryptophan catabolism has been observed in autoimmune diseases. In order to investigate the effects of IDO-mediated tryptophan catabolism and IDO-expressing DCs in immune thrombocytopenia, the concentrations of kynurenine were detected by high-pressure liquid chromatography. The expressions of IDO were analyzed by flow cytometry and western blot analysis. The effects of IDO+ DCs stimulated with CTLA-4-Ig on T cells proliferation and activation, lymphocyte apoptosis, and Tregs were measured by flow cytometry. We found that the expression of IDO in DCs of immune thrombocytopenia (ITP) patients was significantly decreased. CTLA-4-Ig significantly increased the expression of functional IDO in DCs of ITP patients. IDO+ DCs stimulated with CTLA-4-Ig suppressed T cells proliferation and activation, promoted lymphocyte apoptosis, and increased the percentage of Tregs. These results suggest that decreased IDO expression in DCs may play a critical role in ITP. CTLA-4-Ig successfully corrected the disorder of IDO expression in ITP. IDO+ DCs stimulated with CTLA-4-Ig inhibited immune responses by an IDO-dependent mechanism. Increasing the expression and activity of IDO in DCs might be a promising therapeutic approach for ITP.

Keywords

Indoleamine 2,3-dioxygenase CTLA-4-Ig Dendritic cells Immune thrombocytopenia 

Supplementary material

277_2012_1451_MOESM1_ESM.doc (40 kb)
Supplementary Table 1Clinical characteristics of ITP patients. (DOC 40 kb)

References

  1. 1.
    McMillan R (2007) The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol 44(4 suppl 5):S3–S11PubMedCrossRefGoogle Scholar
  2. 2.
    Shimizu T, Nomiyama S, Hirata F, Hayaishi O (1978) Indoleamine 2,3-dioxygenase: purification and some properties. J Biol Chem 253(13):4700–4706PubMedGoogle Scholar
  3. 3.
    Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, Fioretti MC, Puccetti P (2002) T cell apoptosis by tryptophan catabolism. Cell Death Differ 9(10):1069–1077PubMedCrossRefGoogle Scholar
  4. 4.
    Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB (2002) Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 196(4):459–468PubMedCrossRefGoogle Scholar
  5. 5.
    Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22(5):633–642PubMedCrossRefGoogle Scholar
  6. 6.
    Zhu L, Ji F, Wang Y, Liu Q, Zhang JZ, Matsushima K, Cao Q, Zhang Y (2006) Synovial autoreactive T cells in rheumatoid arthritis resist IDO-mediated inhibition. J Immunol 177(11):8226–8233PubMedGoogle Scholar
  7. 7.
    Munn DH, Mellor AL, Rossi M, Young JW (2005) Dendritic cells have the option to express IDO-mediated suppression or not. Blood 105(6):2618PubMedCrossRefGoogle Scholar
  8. 8.
    Hayashi T, Beck L, Rossetto C, Gong X, Takikawa O, Takabayashi K, Broide DH, Carson DA, Raz E (2004) Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest 114(2):270–279PubMedGoogle Scholar
  9. 9.
    Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, Straus D, Samelson LE, Thompson CB, Bluestone JA (1998) Molecular basis of T cell inactivation by CTLA-4. Science 282(5397):2263–2266PubMedCrossRefGoogle Scholar
  10. 10.
    Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC et al (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3(11):1097–1101PubMedCrossRefGoogle Scholar
  11. 11.
    Munn DH, Sharma MD, Mellor AL (2004) Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J Immunol 172:4100–4110PubMedGoogle Scholar
  12. 12.
    Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N et al (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113(11):2386–2393PubMedCrossRefGoogle Scholar
  13. 13.
    Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, Marshall B, Chandler P, Antonia SJ, Burgess R et al (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297(5588):1867–1870PubMedCrossRefGoogle Scholar
  14. 14.
    Jonuleit H, Kühn U, Müller G, Steinbrink K, Paragnik L, Schmitt E, Knop J, Enk AH (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum free conditions. Eur J Immunol 27(12):3135–3142PubMedCrossRefGoogle Scholar
  15. 15.
    Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30(9):e36PubMedCrossRefGoogle Scholar
  16. 16.
    Ware RE, Howard TA (1993) Phenotypic and clonal analysis of T lymphocytes in childhood immune thrombocytopenic purpura. Blood 82(7):2137–2142PubMedGoogle Scholar
  17. 17.
    Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, Azuma M, Blazar BR, Mellor AL, Munn DH (2007) Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117(9):2570–2582PubMedCrossRefGoogle Scholar
  18. 18.
    Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N et al (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113(11):232386–232393CrossRefGoogle Scholar
  19. 19.
    Wang CY, Shi Y, Min YN, Zhu XJ, Guo CS, Peng J, Dong XY, Qin P, Sun JZ, Hou M (2011) Decreased IDO activity and increased TTS expression break immune tolerance in patients with immune thrombocytopenia. J Clin Immunol 31(4):643–649PubMedCrossRefGoogle Scholar
  20. 20.
    King NJ, Thomas SR (2007) Molecules in focus: indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol 39(12):2167–2172PubMedCrossRefGoogle Scholar
  21. 21.
    Semple JW, Milev Y, Cosgrave D et al (1996) Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood 87(10):4245–4254PubMedGoogle Scholar
  22. 22.
    Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA (2000) Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol 164(7):3596–399PubMedGoogle Scholar
  23. 23.
    Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4(10):762–774PubMedCrossRefGoogle Scholar
  24. 24.
    Sukati H, Watson HG, Urbaniak SJ, Barker RN (2007) Mapping helper T-cell epitopes on platelet membrane glycoprotein IIIa in chronic autoimmune thrombocytopenic purpura. Blood 109(10):4528–4538PubMedCrossRefGoogle Scholar
  25. 25.
    Thomas SR, Terentis AC, Cai H, Takikawa O, Levina A, Lay PA, Freewan M, Stocker R (2007) Post-translational regulation of human indoleamine 2,3-dioxygenase activity by nitric oxide. J Biol Chem 282:23778–23787PubMedCrossRefGoogle Scholar
  26. 26.
    Mellor AL, Baban B, Chandler P et al (2003) Cutting edge: induced indoleamine 2,3-dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 171(4):1652–1655PubMedGoogle Scholar
  27. 27.
    Liu B, Zhao H, Poon MC, Han Z, Gu D, Xu M, Jia H, Yang R, Han ZC (2007) Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol 78(2):139–143PubMedGoogle Scholar
  28. 28.
    Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Shu-qian Xu
    • 1
  • Chun-yan Wang
    • 1
    • 2
  • Xiao-juan Zhu
    • 1
    • 3
  • Xiao-yuan Dong
    • 1
  • Yan Shi
    • 1
  • Jun Peng
    • 1
    • 4
  • Ping Qin
    • 1
  • Jian-zhi Sun
    • 1
  • Chengshan Guo
    • 5
  • Heyu Ni
    • 6
  • Ming Hou
    • 1
    • 4
  1. 1.Hematology Oncology Centre, Qilu HospitalShandong UniversityJinanChina
  2. 2.Department of General MedicineSecond Hospital of Shandong UniversityJinanChina
  3. 3.Department of General MedicineProvincial Hospital affiliated to Shandong UniversityJinanChina
  4. 4.Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of Education and Chinese Ministry of HealthJinanChina
  5. 5.Department of HematologySecond Hospital of Shandong UniversityJinanChina
  6. 6.Canadian Blood Services and Toronto Platelet Immunobiology Group and Department of Laboratory Medicine and Pathobiology, Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael’s HospitalUniversity of TorontoTorontoCanada

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