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Medical Oncology

, 32:197 | Cite as

Antithymocyte globulin combined with cyclosporine A down-regulates T helper 1 cells by modulating T cell immune response cDNA 7 in aplastic anemia

  • Feng Zhu
  • Jianlin Qiao
  • Xiao-min Zhong
  • Qing-yun Wu
  • Wei Chen
  • Yao Yao
  • Ming-shan Niu
  • Chun-ling Fu
  • Ling-yu Zeng
  • Zhen-yu Li
  • Kai-lin XuEmail author
Original Paper

Abstract

Antithymocyte globulin (ATG) combined with cyclosporine A (CsA) has been widely used as a standard regimen in the treatment of aplastic anemia (AA), especially in severe aplastic anemia (SAA). Abnormally activated T cells might be the immune pathogenesis of AA. T cell immune response cDNA 7 (TIRC7) has been demonstrated its essential role in T cell activation; however, little is known about the role of TIRC7 in AA. In this study, we documented that TIRC7 levels in CsA group were higher than that in ATG + CsA (AC) group only in the follow-up phase (P < 0.05; P < 0.05); nevertheless, TIRC7 levels in SAA group were elevated than non severe aplastic anemia group not only in the treatment phase (P < 0.05; P < 0.05) but also in the follow-up phase (P < 0.05; P < 0.01). The trend of changes of T helper (Th) 1, Th17 and Th22 levels before and after treatment was similar to the changes of TIRC7 levels in either AC group or CsA group. Thus, TIRC7 might be involved in the pathogenesis of AA and AC might down-regulate Th1 cells by modulating the expression of TIRC7 in AA.

Keywords

Antithymocyte globulin Aplastic anemia Cyclosporine A T cell immune response cDNA 7 T helper 1 (IFN-γ) 

Notes

Acknowledgments

We would like to thank all patients for their collaboration. We also thank Xiu-ying Pan, Xu-peng He, Hai-ying Sun, De-peng Li, Yi-hong Huang, Zhi-ling Yan, Wei Sang and Jiang Cao for their clinical assistance to patients included in this study. This work was supported by grants from the National Nature Science Foundation of China (Grant Nos. 81270637, 81300441).

Conflict of interest

The authors have no conflicts of interest to declare.

References

  1. 1.
    Brodsky RA, Jones RJ. Aplastic anaemia. Lancet. 2005;365(9471):1647–56.PubMedCrossRefGoogle Scholar
  2. 2.
    Li JP, Zheng CL, Han ZC. Abnormal immunity and stem/progenitor cells in acquired aplastic anemia. Crit Rev Oncol Hematol. 2010;75(2):79–93. doi: 10.1016/j.critrevonc.2009.12.001.PubMedCrossRefGoogle Scholar
  3. 3.
    Young NS, Scheinber P, Calado RT. Aplastic anemia. Curr Opin Hematol. 2008;15(3):162–8. doi: 10.1097/MOH.0b013e3282fa7470.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Marsh JC, Chang J, Testa NG, Hows JM, Dexter TM. The hematopoietic defect in aplastic anemia assessed by long-term marrow culture. Blood. 1990;76(9):1748–57.PubMedGoogle Scholar
  5. 5.
    Chatterjee S, Dutta RK, Basak P, Das P, Das M, Pereira JA, et al. Alteration in marrow stromal microenvironment and apoptosis mechanisms involved in aplastic anemia: an animal model to study the possible disease pathology. Stem Cells Int. 2010;2010:932354. doi: 10.4061/2010/932354.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Kordasti S, Marsh J, Al-Khan S, Jiang J, Smith A, Mohamedali A, et al. Functional characterization of CD4+T cells in aplastic anemia. Blood. 2012;119(9):2033–43. doi: 10.1182/blood-2011-08-368308.PubMedCrossRefGoogle Scholar
  7. 7.
    Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108(8):2509–19.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Utku N, Heinemann T, Tullius SG, Bulwin GC, Beinke S, Blumberg RS, et al. Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein. Immunity. 1998;9(4):509–18.PubMedCrossRefGoogle Scholar
  9. 9.
    Heinemann T, Bulwin GC, Randall J, Schnieders B, Sandhoff K, Volk HD, et al. Genomic organization of the gene coding for TIRC7, a novel membrane protein essential for T cell activation. Genomics. 1999;57(3):398–406.PubMedCrossRefGoogle Scholar
  10. 10.
    Bulwin GC, Heinemann T, Bugge V, Winter M, Lohan A, Schlawinsky M, et al. TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression. J Immunol. 2006;177(10):6833–41.PubMedCrossRefGoogle Scholar
  11. 11.
    Kumamoto Y, Tomschegg A, Bennai-Sanfourche F, Boerner A, Kaser A, Schmidt-Knosalla I, et al. Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice. Am J Transplant. 2004;4(4):505–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Malard F, Bossard C, Brissot E, Chevallier P, Guillaume T, Delaunay J, et al. Increased Th17/Treg ratio in chronic liver GVHD. Bone Marrow Transplant. 2014;49(4):539–44. doi: 10.1038/bmt.2013.215.PubMedCrossRefGoogle Scholar
  13. 13.
    Hsu HY, Kuan YC, Lin TY, Tsao SM, Hsu J, Ma LJ, et al. Reishi protein LZ-8 induces FOXP3(+) Treg expansion via a CD45-Dependent signaling pathway and alleviates acute intestinal inflammation in mice. Evid Based Complement Altern Med. 2013;2013:513542. doi: 10.1155/2013/513542.Google Scholar
  14. 14.
    Park JS, Kwok SK, Lim MA, Kim EK, Ryu JG, Kim SM, et al. STA-21, a promising STAT3 inhibitor that reciprocally regulates Th17 and Treg, inhibits osteoclastogenesis and alleviates autoimmune inflammation. Arthritis Rheum. 2014;66(4):918–29. doi: 10.1002/art.38305.CrossRefGoogle Scholar
  15. 15.
    Wakkach A, Augier S, Breittmayer JP, Blin-Wakkach C, Carle GF. Characterization of IL-10-secreting T cells derived from regulatory CD4 + CD25 + cells by the TIRC7 surface marker. J Immunol. 2008;180(9):6054–63.PubMedCrossRefGoogle Scholar
  16. 16.
    Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser P, et al. Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice. Clin Exp Immunol. 2006;144(1):142–51.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Zhu F, Qiao JL, Wu QY, Cao J, Zeng LY, Li ZY, et al. Elevated levels of T-cell immune response cDNA 7 in patients with immune thrombocytopenia. Hematology. 2014;19(8):477–82. doi: 10.1179/1607845414Y.0000000156.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhu F, Qiao J, Chen W, Pan B, Wu QY, Cao J, et al. Increased expression of T cell immune response cDNA 7 in patients with acute graft-versus-host disease. Ann Hematol. 2015;94(6):1025–32. doi: 10.1007/s00277-015-2300-8.PubMedCrossRefGoogle Scholar
  19. 19.
    Young NS. Autoimmunity and its treatment in aplastic anemia. Ann Intern Med. 1997;126(2):166–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Tichelli A, Schrezenmeier H, Socié G, Marsh J, Bacigalupo A, Dührsen U, et al. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA working party of the European Group for blood and marrow transplantation. Blood. 2011;117(17):4434–41. doi: 10.1182/blood-2010-08-304071.PubMedCrossRefGoogle Scholar
  21. 21.
    Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, et al. British Committee for standards in haematology. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009;147(1):43–70. doi: 10.1111/j.1365-2141.2009.07842.x.PubMedCrossRefGoogle Scholar
  22. 22.
    DeZern AE, Brodsky RA. Clinical management of aplastic anemia. Expert Rev Hematol. 2011;4(2):221–30. doi: 10.1586/ehm.11.11.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Marsh J, Schrezenmeier H, Marin P, Ilhan O, Ljungman P, McCann S, et al. Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European blood and marrow transplant (EBMT) severe aplastic anaemia working party. Blood. 1999;93(7):2191–5.PubMedGoogle Scholar
  24. 24.
    Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. Jama. 2003;289(9):1130–5.PubMedCrossRefGoogle Scholar
  25. 25.
    de Latour RP, Visconte V, Takaku T, Wu C, Erie AJ, Sarcon AK, et al. Th17 immune responses contribute to the pathophysiology of aplastic anemia. Blood. 2010;116(20):4175–84. doi: 10.1182/blood-2010-01-266098.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Li X, Xu F, He Q, Wu L, Zhang Z, Chang C. Comparison of immunological abnormalities of lymphocytes in bone marrow in myelodysplastic syndrome (MDS) and aplastic anemia (AA). Intern Med. 2010;49(14):1349–55.PubMedCrossRefGoogle Scholar
  27. 27.
    Giannakoulas NC, Karakantza M, Theodorou GL, Pagoni M, Galanopoulos A, Kakagianni T, et al. Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients. Br J Haematol. 2004;124(1):97–105.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Feng Zhu
    • 1
  • Jianlin Qiao
    • 1
    • 2
  • Xiao-min Zhong
    • 3
  • Qing-yun Wu
    • 1
    • 2
  • Wei Chen
    • 1
  • Yao Yao
    • 1
    • 2
  • Ming-shan Niu
    • 1
    • 2
  • Chun-ling Fu
    • 1
    • 2
  • Ling-yu Zeng
    • 1
    • 2
  • Zhen-yu Li
    • 1
  • Kai-lin Xu
    • 1
    Email author
  1. 1.Department of HematologyThe Affiliated Hospital of Xuzhou Medical CollegeXuzhouChina
  2. 2.Lab of Transplant ImmunologyXuzhou Medical CollegeXuzhouChina
  3. 3.Department of OncologyAffiliated Huai’an First People’s Hospital of Nanjing Medical UniversityHuai’anChina

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