Skip to main content
PMC home page
Protein & Cell logoLink to Protein & Cell
. 2013 Nov 10;4(11):863–871. doi: 10.1007/s13238-013-3088-8

IL-21 accelerates xenogeneic graft-versus-host disease correlated with increased B-cell proliferation

Xiaoran Wu 1,2, Yi Tan 1,2, Qiao Xing 1,✉, Shengdian Wang 1,✉
PMCID: PMC4875455  PMID: 24214876

Abstract

Graft-versus-host disease (GVHD) is a prevalent and potential complication of hematopoietic stem cell transplantation. An animal model, xenogeneic GVHD (X-GVHD), that mimics accurately the clinical presentation of GVHD would provide a tool for investigating the mechanism involved in disease pathogenesis. Murine models indicated that inhibiting IL-21 signaling was a good therapy to reduce GVHD by impairing T cell functions. We sought to investigate the effect of exogenous human IL-21 on the process of X-GVHD. In this study, human IL-21 was expressed by hydrodynamic gene delivery in BALB/c-Rag2−/− IL-2RΓc−/− (BRG) immunodeficient mice which were intravenously transplanted human peripheral blood mononuclear cells (hPBMCs). We found that human IL-21 exacerbated X-GVHD and resulted in rapid fatality. As early as 6 days after hPBMCs transplanted to BRG mice, a marked expansion of human CD19+ B cells, but not T cells, was observed in spleen of IL-21-treated mice. Compared with control group, IL-21 induced robust immunoglobulin secretion, which was accompanied by increased accumulation of CD19+ CD38high plasma cells in spleen. In addition, we demonstrated that B-cell depletion was able to ameliorate X-GVHD. These results are the first to find in vivo expansion and differentiation of human B cells in response to IL-21, and reveal a correlation between the expansion of B cells and the exacerbation of xenogeneic GVHD. Our findings show evidence of the involvement of B cells in X-GVHD and may have implications in the treatment of the disease.

Keywords: IL-21, B cell, xenogeneic GVHD, immunodeficient mice, immunoglobulin

Contributor Information

Qiao Xing, Email: qiaoxing@moon.ibp.ac.cn.

Shengdian Wang, Email: sdwang@moon.ibp.ac.cn.

Reference

  1. Blazar BR, Murphy WJ, Abedi M. Advances in graftversushost disease biology and therapy. Nat Rev Immunol. 2012;12:443–458. doi: 10.1038/nri3212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bucher C, Koch L, Vogtenhuber C, Goren E, Munger M, Panoskaltsis-Mortari A, Sivakumar P, Blazar BR. IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation. Blood. 2009;114:5375–5384. doi: 10.1182/blood-2009-05-221135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Christopeit M, Schutte V, Theurich S, Weber T, Grothe W, Behre G. Rituximab reduces the incidence of acute graftversus-host disease. Blood. 2009;113:3130–3131. doi: 10.1182/blood-2009-01-200527. [DOI] [PubMed] [Google Scholar]
  4. Ettinger R, Kuchen S, Lipsky PE. The role of IL-21 in regulating B-cell function in health and disease. Immunol Rev. 2008;223:60–86. doi: 10.1111/j.1600-065X.2008.00631.x. [DOI] [PubMed] [Google Scholar]
  5. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, Leonard WJ, Lipsky PE. IL-21 induces differentiation of human naive and memory B cells into antibodysecreting plasma cells. J Immunol. 2005;175:7867–7879. doi: 10.4049/jimmunol.175.12.7867. [DOI] [PubMed] [Google Scholar]
  6. Evenou JP, Wagner J, Zenke G, Brinkmann V, Wagner K, Kovarik J, Welzenbach KA, Weitz-Schmidt G, Guntermann C, Towbin H, et al. The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. J Pharmacol Exp Ther. 2009;330:792–801. doi: 10.1124/jpet.109.153205. [DOI] [PubMed] [Google Scholar]
  7. Good KL, Bryant VL, Tangye SG. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J Immunol. 2006;177:5236–5247. doi: 10.4049/jimmunol.177.8.5236. [DOI] [PubMed] [Google Scholar]
  8. Gregoire-Gauthier J, Durrieu L, Duval A, Fontaine F, Dieng MM, Bourgey M, Patey-Mariaud de Serre N, Louis I, Haddad E. Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/gammacmouse model. Bone Marrow Transplant. 2012;47:439–450. doi: 10.1038/bmt.2011.93. [DOI] [PubMed] [Google Scholar]
  9. Hanash AM, Kappel LW, Yim NL, Nejat RA, Goldberg GL, Smith OM, Rao UK, Dykstra L, Na IK, Holland AM, et al. Abrogation of donor T-cell IL-21 signaling leads to tissuespecific modulation of immunity and separation of GVHD from GVL. Blood. 2011;118:446–455. doi: 10.1182/blood-2010-07-294785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hippen KL, Bucher C, Schirm DK, Bearl AM, Brender T, Mink KA, Waggie KS, Peffault de Latour R, Janin A, Curtsinger JM, et al. Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes. Blood. 2012;119:619–628. doi: 10.1182/blood-2011-07-368027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ito R, Katano I, Kawai K, Hirata H, Ogura T, Kamisako T, Eto T, Ito M. Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. Transplantation. 2009;87:1654–1658. doi: 10.1097/TP.0b013e3181a5cb07. [DOI] [PubMed] [Google Scholar]
  12. Konforte D, Simard N, Paige CJ. IL-21: an executor of B cell fate. J Immunol. 2009;182:1781–1787. doi: 10.4049/jimmunol.0803009. [DOI] [PubMed] [Google Scholar]
  13. Leonard WJ, Spolski R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol. 2005;5:688–698. doi: 10.1038/nri1688. [DOI] [PubMed] [Google Scholar]
  14. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J Am Soc Nephrol. 2006;17:2844–2853. doi: 10.1681/ASN.2006050422. [DOI] [PubMed] [Google Scholar]
  15. Meguro A, Ozaki K, Hatanaka K, Oh I, Sudo K, Ohmori T, Matsu H, Tatara R, Sato K, Sakata Y, et al. Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells. Bone Marrow Transplant. 2011;46:1557–1565. doi: 10.1038/bmt.2010.342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Meguro A, Ozaki K, Oh I, Hatanaka K, Matsu H, Tatara R, Sato K, Leonard WJ, Ozawa K. IL-21 is critical for GVHD in a mouse model. Bone Marrow Transplant. 2010;45:723–729. doi: 10.1038/bmt.2009.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mutis T, van Rijn RS, Simonetti ER, Aarts-Riemens T, Emmelot ME, van Bloois L, Martens A, Verdonck LF, Ebeling SB. Human regulatory T cells control xenogeneic graft-versushost disease induced by autologous T cells in RAG2−/−gammac−/− immunodeficient mice. Clin Cancer Res. 2006;12:5520–5525. doi: 10.1158/1078-0432.CCR-06-0035. [DOI] [PubMed] [Google Scholar]
  18. Nielen MM, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, Habibuw MR, Vandenbroucke JP, Dijkmans BA. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50:380–386. doi: 10.1002/art.20018. [DOI] [PubMed] [Google Scholar]
  19. Sarantopoulos S, Stevenson KE, Kim HT, Washel WS, Bhuiya NS, Cutler CS, Alyea EP, Ho VT, Soiffer RJ, Antin JH, et al. Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood. 2011;117:2275–2283. doi: 10.1182/blood-2010-10-307819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sherer Y, Gorstein A, Fritzler MJ, Shoenfeld Y. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum. 2004;34:501–537. doi: 10.1016/j.semarthrit.2004.07.002. [DOI] [PubMed] [Google Scholar]
  21. Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, von Bergwelt-Baildon MS. The role of B cells in the pathogenesis of graft-versus-host disease. Blood. 2009;114:4919–4927. doi: 10.1182/blood-2008-10-161638. [DOI] [PubMed] [Google Scholar]
  22. Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7:340–352. doi: 10.1038/nri2000. [DOI] [PubMed] [Google Scholar]
  23. Shultz LD, Brehm MA, Bavari S, Greiner DL. Humanized mice as a preclinical tool for infectious disease and biomedical research. Ann N Y Acad Sci. 2011;1245:50–54. doi: 10.1111/j.1749-6632.2011.06310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7:118–130. doi: 10.1038/nri2017. [DOI] [PubMed] [Google Scholar]
  25. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 2008;26:57–79. doi: 10.1146/annurev.immunol.26.021607.090316. [DOI] [PubMed] [Google Scholar]
  26. van Oosterhout YV, van Emst L, Schattenberg AV, Tax WJ, Ruiter DJ, Spits H, Nagengast FM, Masereeuw R, Evers S, de Witte T, et al. A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease. Blood. 2000;95:3693–3701. [PubMed] [Google Scholar]
  27. van Rijn RS, Simonetti ER, Hagenbeek A, Hogenes MC, de Weger RA, Canninga-van Dijk MR, Weijer K, Spits H, Storm G, van Bloois L, et al. A new xenograft model for graftversus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2−/− gammac−/− double-mutant mice. Blood. 2003;102:2522–2531. doi: 10.1182/blood-2002-10-3241. [DOI] [PubMed] [Google Scholar]
  28. Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck G, Eibel H, Schlesier M, Peter HH. Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood. 2002;99:1544–1551. doi: 10.1182/blood.V99.5.1544. [DOI] [PubMed] [Google Scholar]
  29. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol. 2007;25:139–170. doi: 10.1146/annurev.immunol.25.022106.141606. [DOI] [PubMed] [Google Scholar]
  30. Yoshizaki A, Miyagaki T, DiLillo DJ, Matsushita T, Horikawa M, Kountikov EI, Spolski R, Poe JC, Leonard WJ, Tedder TF. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature. 2012;491:264–268. doi: 10.1038/nature11501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman S, Strober S, Zeng D. Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood. 2006;107:2993–3001. doi: 10.1182/blood-2005-09-3623. [DOI] [PubMed] [Google Scholar]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES