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Aberrant germinal center formation, follicular T-helper cells, and germinal center B-cells were involved in chronic graft-versus-host disease

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Abstract

Chronic graft-versus-host disease (cGVHD) is an important complication after allogeneic hematopoietic stem cell transplantation (HSCT). To define the roles of T-cells and B-cells in cGVHD, a murine minor histocompatibility complex–mismatched HSCT model was used. Depletion of donor splenocyte CD4+ T-cells and B220+ B-cells alleviated cGVHD. Allogeneic recipients had significantly increased splenic germinal centers (GCs), with significant increases in follicular T-helper (Tfh) cells and GC B-cells. There were increased expressions in Tfh cells of inducible T-cell co-stimulator (ICOS), interleukin (IL)-4 and IL-17, and in GC B-cells of B-cell activating factor receptor and ICOS ligand. Depletion of donor splenocyte CD4+ T-cells abrogated aberrant GC formation and suppressed Tfh cells and GC B-cells. Interestingly, depletion of donor splenocyte B200+ B-cells also suppressed Tfh cells in addition to GC B-cells. These results suggested that in cGVHD, both Tfh and GC B-cells were involved, and their developments were mutually dependent. The mammalian target of rapamycin (mTOR) inhibitor everolimus was effective in suppressing cGVHD, Tfh cells, and GC B-cells, either as a prophylaxis or when cGVHD had established. These results implied that therapeutic targeting of both T-cells and B-cells in cGVHD might be effective. Signaling via mTOR may be another useful target in cGVHD.

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References

  1. Blazar BR, Murphy WJ, Abedi M (2012) Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 12(6):443–458

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Blazar B, White ES, Couriel D (2012) Understanding chronic GVHD from different angles. Biol Blood Marrow Transplant 18(1 Suppl):S184–S188

    Article  PubMed Central  PubMed  Google Scholar 

  3. Patriarca F, Skert C, Sperotto A, Zaja F, Falleti E, Mestroni R et al (2006) The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery. Exp Hematol 34(3):389–396

    Article  CAS  PubMed  Google Scholar 

  4. Kharfan-Dabaja MA, Bazarbachi A (2010) Emerging role of CD20 blockade in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 16(10):1347–1354

    Article  PubMed  Google Scholar 

  5. Sarantopoulos S, Stevenson KE, Kim HT, Washel WS, Bhuiya NS, Cutler CS et al (2011) Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood 117(7):2275–2283

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Arai S, Sahaf B, Narasimhan B, Chen GL, Jones CD, Lowsky R et al (2012) Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence. Blood 119(25):6145–6154

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Vinuesa CG, Chang PP (2013) Innate B cell helpers reveal novel types of antibody responses. Nat Immunol 14(2):119–126

    Article  CAS  PubMed  Google Scholar 

  8. Zotos D, Tarlinton DM (2012) Determining germinal centre B cell fate. Trends Immunol 33(6):281–288

    Article  CAS  PubMed  Google Scholar 

  9. Tangye SG, Ma CS, Brink R, Deenick EK (2013) The good, the bad and the ugly - TFH cells in human health and disease. Nat Rev Immunol 13(6):412–426

    Article  CAS  PubMed  Google Scholar 

  10. Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG et al (2010) Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum 62(1):234–244

    Article  CAS  PubMed  Google Scholar 

  11. Li XY, Wu ZB, Ding J, Zheng ZH, Li XY, Chen LN, Zhu P (2012) Role of the frequency of blood CD4(+) CXCR5(+) CCR6(+) T cells in autoimmunity in patients with Sjögren’s syndrome. Biochem Biophys Res Commun 422(2):238–244

    Article  CAS  PubMed  Google Scholar 

  12. Liu R, Wu Q, Su D, Che N, Chen H, Geng L et al (2012) A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res Ther 14(6):R255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Zhu C, Ma J, Liu Y, Tong J, Tian J, Chen J et al (2012) Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab 97(3):943–950

    Article  CAS  PubMed  Google Scholar 

  14. Tackenberg B, Kruth J, Bartholomaeus JE, Schlegel K, Oertel WH, Willcox N et al (2007) Clonal expansions of CD4+ B helper T cells in autoimmune myasthenia gravis. Eur J Immunol 37(3):849–863

    Article  CAS  PubMed  Google Scholar 

  15. Ma CS, Deenick EK, Batten M, Tangye SG (2012) The origins, function, and regulation of T follicular helper cells. J Exp Med 209(7):1241–1253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. King C, Sprent J (2012) Emerging cellular networks for regulation of T follicular helper cells. Trends Immunol 33(2):59–65

    Article  CAS  PubMed  Google Scholar 

  17. Crotty S (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29:621–663

    Article  CAS  PubMed  Google Scholar 

  18. Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman S et al (2006) Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood 107(7):2993–3001

    Article  CAS  PubMed  Google Scholar 

  19. Kaplan DH, Anderson BE, McNiff JM, Jain D, Shlomchik MJ, Shlomchik WD (2004) Target antigens determine graft-versus-host disease phenotype. J Immunol 173(9):5467–5475

    Article  CAS  PubMed  Google Scholar 

  20. Pang A, Au WY, Kwong YL (2004) Caveolin-1 gene is coordinately regulated with the multidrug resistance 1 gene in normal and leukemic bone marrow. Leuk Res 28(9):973–977

    Article  CAS  PubMed  Google Scholar 

  21. Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, von Bergwelt-Baildon MS (2009) The role of B cells in the pathogenesis of graft-versus-host disease. Blood 114(24):4919–4927

    Article  PubMed  Google Scholar 

  22. Akiba H, Takeda K, Kojima Y, Usui Y, Harada N, Yamazaki T et al (2005) The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J Immunol 175(4):2340–2348

    Article  CAS  PubMed  Google Scholar 

  23. Sweet RA, Lee SK, Vinuesa CG (2012) Developing connections amongst key cytokines and dysregulated germinal centers in autoimmunity. Curr Opin Immunol 24(6):658–664

    Article  CAS  PubMed  Google Scholar 

  24. Rodriguez R, Nakamura R, Palmer JM, Parker P, Shayani S, Nademanee A et al (2010) A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. Blood 115(5):1098–1105

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Schmitt N, Ueno H (2013) Human T follicular helper cells: development and subsets. Adv Exp Med Biol 785:87–94

    Article  CAS  PubMed  Google Scholar 

  26. Socié G (2011) Chronic GVHD: B cells come of age. Blood 117(7):2086–2087

    Article  PubMed  Google Scholar 

  27. Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M et al (2009) Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 113(16):3865–3874

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kuzmina Z, Krenn K, Petkov V, Körmöczi U, Weigl R, Rottal A et al (2013) CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome. Blood 121(10):1886–1895

    Article  CAS  PubMed  Google Scholar 

  29. Greinix HT, Pohlreich D, Kouba M, Körmöczi U, Lohmann I, Feldmann K et al (2008) Elevated numbers of immature/transitional CD21− B lymphocytes and deficiency of memory CD27+ B cells identify patients with active chronic graft-versus-host disease. Biol Blood Marrow Transplant 14(2):208–219

    Article  PubMed  Google Scholar 

  30. Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA et al (2012) Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood 119(6):1570–1580

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA, et al (2014) Increased T follicular helper cells and germinal center B cells are required for chronic GVHD (cGVHD) and bronchiolitis obliterans. Blood 123(25):3988–98

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Acknowledgments

We thank Dr. Yuk Chun (Division of Pathology, Queen Mary Hospital, Hong Kong) for his kind help in preparing the histological slides and Miss Wen-Ying Piao, Ka-Wai Leong, and Mr. Kin-Ho Lo, Lok-Man Yue, Chun-Hung Chow, and Ho-Chun Han (Department of Medicine, the University of Hong Kong) for their technique support. We also thank Dr. Xue-qiong Fu (Department of Gastroentorology and Hematology, Longgang District Central Hospital, Shenzhen) for her kind help in the experiment. This research was supported by a grant from the National Natural Science Foundation of China (No.81160074).

Conflict of interest

The authors have no financial conflicts of interest.

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Authors and Affiliations

  1. Department of Medicine, University of Hong Kong, Hong Kong, China

    Liang Shao, Albert K. W. Lie, Cheuk-Hong Wong & Yok-Lam Kwong

  2. Division of Hematology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China

    Liang Shao & You Zhang

  3. Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, China

    Yok-Lam Kwong

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  1. Liang Shao
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  2. Albert K. W. Lie
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Correspondence to Yok-Lam Kwong.

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Shao, L., Lie, A.K.W., Zhang, Y. et al. Aberrant germinal center formation, follicular T-helper cells, and germinal center B-cells were involved in chronic graft-versus-host disease. Ann Hematol 94, 1493–1504 (2015). https://doi.org/10.1007/s00277-015-2394-z

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  • DOI: https://doi.org/10.1007/s00277-015-2394-z

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