Skip to main content
SpringerLink
Log in

Induction of immune tolerance to platelet antigen by short-term thrombopoietin treatment in a mouse model of immune thrombocytopenia

  • Rapid Communication
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Immune thrombocytopenia (ITP) is an autoimmune disorder caused by IgG anti-platelet autoantibodies. Thrombopoietin (TPO) receptor agonists are highly effective in inducing the recovery of platelet counts in ITP patients. Although these agents are thought to promote platelet production without affecting the autoimmune pathogenesis of the disease, a small subset of ITP patients exhibits sustained platelet recovery after treatment termination. To investigate mechanisms involved in this sustained recovery, we evaluated the effects of short-term TPO treatment using a mouse ITP model generated by Foxp3+ T regulatory cell (Treg) depletion. After treatment, platelet recovery was sustained, along with complete suppression of both anti-platelet autoantibody production and T-cell responses to platelet autoantigens. TPO treatment also promoted the peripheral induction of Foxp3+ Tregs in conjunction with elevated circulating TGF-β levels. In summary, thrombopoietic agents are capable of inducing immune tolerance to platelet autoantigens, thereby suppressing the autoimmune pathogenesis of ITP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Semple JW, Provan D. The immunopathogenesis of immune thrombocytopenia: T cells still take center-stage. Curr Opin Hematol. 2012;19:357–62.

    Article  PubMed  CAS  Google Scholar 

  2. Kuwana M, Kaburaki J, Ikeda Y. Autoreactive cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura: role in production of anti-platelet autoantibody. J Clin Invest. 1998;02:1393–402.

    Article  Google Scholar 

  3. Nishimoto T, Kuwana M. CD4+CD25+Foxp3+ regulatory T cells in pathophysiology of immune thrombocytopenia. Semin Hematol. 2013;50:S43–9.

    Article  PubMed  CAS  Google Scholar 

  4. Nishimoto T, Satoh T, Takeuchi T, Ikeda Y, Kuwana M. Critical role of CD4(+)CD25(+) regulatory T cells in preventing murine autoantibody-mediated thrombocytopenia. Exp Hematol. 2012;40:279–89.

    Article  PubMed  CAS  Google Scholar 

  5. Nishimoto T, Satoh T, Simpson EK, Ni H, Kuwana M. Predominant autoantibody response to GPIb/IX in a regulatory T-cell-deficient mouse model for immune thrombocytopenia. J Thromb Haemost. 2013;11:369–72.

    Article  PubMed  CAS  Google Scholar 

  6. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98:10–23.

    Article  PubMed  CAS  Google Scholar 

  7. Khellaf M, Michel M, Quittet P, et al. Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program. Blood. 2011;118:4338–45.

    Article  PubMed  CAS  Google Scholar 

  8. Bussel JB, Buchanan GR, Nugent DJ, et al. A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia. Blood. 2011;118:28–36.

    Article  PubMed  CAS  Google Scholar 

  9. Ghadaki B, Nazi I, Kelton JG, Arnold DM. Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists. Transfusion. 2013;53:2807–12.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Gómez-Almague D, Herrera-Rojas MA, Jaime-Pérez JC, et al. Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. Blood. 2014;123:3906–8.

    Article  Google Scholar 

  11. Hattori N, Kuwana M, Kaburaki J, Mimori T, Ikeda Y, Kawakami Y. T cells that are autoreactive to β2-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals. Arthritis Rheum. 2000;43:65–75.

    Article  PubMed  CAS  Google Scholar 

  12. Miyazaki H. Physiologic role of TPO in thrombopoiesis. Stem Cells. 1996;14:133–8.

    Article  PubMed  Google Scholar 

  13. Shibuya K, Kuwaki T, Tahara E, et al. Marked improvement of thrombocytopenia in a murine model of idiopathic thrombocytopenic purpura by pegylated recombinant human megakaryocyte growth and development factor. Exp Hematol. 2002;30:1185–92.

    Article  PubMed  CAS  Google Scholar 

  14. Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116:4639–45.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Reipert BM, van Helden PM, Schwarz HP, Hausl C. Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors. Br J Haematol. 2007;136:12–25.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a research grant on intractable diseases from the Japanese Ministry of Health, Labor, and Welfare.

Conflict of interests

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Tetsuya Nishimoto, Miku Numajiri, Hisataka Nakazaki, Yuka Okazaki & Masataka Kuwana

  2. Department of Allergy and Rheumatology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan

    Yuka Okazaki & Masataka Kuwana

Authors
  1. Tetsuya Nishimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miku Numajiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hisataka Nakazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuka Okazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masataka Kuwana
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masataka Kuwana.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nishimoto, T., Numajiri, M., Nakazaki, H. et al. Induction of immune tolerance to platelet antigen by short-term thrombopoietin treatment in a mouse model of immune thrombocytopenia. Int J Hematol 100, 341–344 (2014). https://doi.org/10.1007/s12185-014-1661-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-014-1661-4

Keywords

Search

Navigation