Protein & Cell

, Volume 4, Issue 11, pp 863–871 | Cite as

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

Research Article Protein & Cell


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.


IL-21 B cell xenogeneic GVHD immunodeficient mice immunoglobulin 


  1. Blazar, B.R., Murphy, W.J., and Abedi, M. (2012). Advances in graftversushost disease biology and therapy. Nat Rev Immunol 12, 443–458.CrossRefGoogle Scholar
  2. Bucher, C., Koch, L., Vogtenhuber, C., Goren, E., Munger, M., Panoskaltsis-Mortari, A., Sivakumar, P., and Blazar, B.R. (2009). IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation. Blood 114, 5375–5384.CrossRefGoogle Scholar
  3. Christopeit, M., Schutte, V., Theurich, S., Weber, T., Grothe, W., and Behre, G. (2009). Rituximab reduces the incidence of acute graftversus-host disease. Blood 113, 3130–3131.CrossRefGoogle Scholar
  4. Ettinger, R., Kuchen, S., and Lipsky, P.E. (2008). The role of IL-21 in regulating B-cell function in health and disease. Immunol Rev 223, 60–86.CrossRefGoogle Scholar
  5. Ettinger, R., Sims, G.P., Fairhurst, A.M., Robbins, R., da Silva, Y.S., Spolski, R., Leonard, W.J., and Lipsky, P.E. (2005). IL-21 induces differentiation of human naive and memory B cells into antibodysecreting plasma cells. J Immunol 175, 7867–7879.CrossRefGoogle Scholar
  6. Evenou, J.P., Wagner, J., Zenke, G., Brinkmann, V., Wagner, K., Kovarik, J., Welzenbach, K.A., Weitz-Schmidt, G., Guntermann, C., Towbin, H., et al. (2009). 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 330, 792–801.CrossRefGoogle Scholar
  7. Good, K.L., Bryant, V.L., and Tangye, S.G. (2006). Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J Immunol 177, 5236–5247.CrossRefGoogle Scholar
  8. Gregoire-Gauthier, J., Durrieu, L., Duval, A., Fontaine, F., Dieng, M.M., Bourgey, M., Patey-Mariaud de Serre, N., Louis, I., and Haddad, E. (2012). Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/gammacmouse model. Bone Marrow Transplant 47, 439–450.CrossRefGoogle Scholar
  9. Hanash, A.M., Kappel, L.W., Yim, N.L., Nejat, R.A., Goldberg, G.L., Smith, O.M., Rao, U.K., Dykstra, L., Na, I.K., Holland, A.M., et al. (2011). Abrogation of donor T-cell IL-21 signaling leads to tissuespecific modulation of immunity and separation of GVHD from GVL. Blood 118, 446–455.CrossRefGoogle Scholar
  10. Hippen, K.L., Bucher, C., Schirm, D.K., Bearl, A.M., Brender, T., Mink, K.A., Waggie, K.S., Peffault de Latour, R., Janin, A., Curtsinger, J.M., et al. (2012). Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes. Blood 119, 619–628.CrossRefGoogle Scholar
  11. Ito, R., Katano, I., Kawai, K., Hirata, H., Ogura, T., Kamisako, T., Eto, T., and Ito, M. (2009). Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. Transplantation 87, 1654–1658.CrossRefGoogle Scholar
  12. Konforte, D., Simard, N., and Paige, C.J. (2009). IL-21: an executor of B cell fate. J Immunol 182, 1781–1787.CrossRefGoogle Scholar
  13. Leonard, W.J., and Spolski, R. (2005). Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol 5, 688–698.CrossRefGoogle Scholar
  14. Lopez, M., Clarkson, M.R., Albin, M., Sayegh, M.H., and Najafian, N. (2006). A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J Am Soc Nephrol 17, 2844–2853.CrossRefGoogle Scholar
  15. Meguro, A., Ozaki, K., Hatanaka, K., Oh, I., Sudo, K., Ohmori, T., Matsu, H., Tatara, R., Sato, K., Sakata, Y., et al. (2011). Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells. Bone Marrow Transplant 46, 1557–1565.CrossRefGoogle Scholar
  16. Meguro, A., Ozaki, K., Oh, I., Hatanaka, K., Matsu, H., Tatara, R., Sato, K., Leonard, W.J., and Ozawa, K. (2010). IL-21 is critical for GVHD in a mouse model. Bone Marrow Transplant 45, 723–729.CrossRefGoogle Scholar
  17. Mutis, T., van Rijn, R.S., Simonetti, E.R., Aarts-Riemens, T., Emmelot, M.E., van Bloois, L., Martens, A., Verdonck, L.F., and Ebeling, S.B. (2006). Human regulatory T cells control xenogeneic graft-versushost disease induced by autologous T cells in RAG2−/−gammac−/− immunodeficient mice. Clin Cancer Res 12, 5520–5525.CrossRefGoogle Scholar
  18. Nielen, M.M., van Schaardenburg, D., Reesink, H.W., van de Stadt, R.J., van der Horst-Bruinsma, I.E., de Koning, M.H., Habibuw, M.R., Vandenbroucke, J.P., and Dijkmans, B.A. (2004). Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 50, 380–386.CrossRefGoogle Scholar
  19. Sarantopoulos, S., Stevenson, K.E., Kim, H.T., Washel, W.S., Bhuiya, N.S., Cutler, C.S., Alyea, E.P., Ho, V.T., Soiffer, R.J., Antin, J.H., et al. (2011). Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood 117, 2275–2283.CrossRefGoogle Scholar
  20. Sherer, Y., Gorstein, A., Fritzler, M.J., and Shoenfeld, Y. (2004). Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin Arthritis Rheum 34, 501–537.CrossRefGoogle Scholar
  21. Shimabukuro-Vornhagen, A., Hallek, M.J., Storb, R.F., and von Bergwelt-Baildon, M.S. (2009). The role of B cells in the pathogenesis of graft-versus-host disease. Blood 114, 4919–4927.CrossRefGoogle Scholar
  22. Shlomchik, W.D. (2007). Graft-versus-host disease. Nat Rev Immunol 7, 340–352.CrossRefGoogle Scholar
  23. Shultz, L.D., Brehm, M.A., Bavari, S., and Greiner, D.L. (2011). Humanized mice as a preclinical tool for infectious disease and biomedical research. Ann N Y Acad Sci 1245, 50–54.CrossRefGoogle Scholar
  24. Shultz, L.D., Ishikawa, F., and Greiner, D.L. (2007). Humanized mice in translational biomedical research. Nat Rev Immunol 7, 118–130.CrossRefGoogle Scholar
  25. Spolski, R., and Leonard, W.J. (2008). Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol 26, 57–79.CrossRefGoogle Scholar
  26. van Oosterhout, Y.V., van Emst, L., Schattenberg, A.V., Tax, W.J., Ruiter, D.J., Spits, H., Nagengast, F.M., Masereeuw, R., Evers, S., de Witte, T., et al. (2000). A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease. Blood 95, 3693–3701.Google Scholar
  27. van Rijn, R.S., Simonetti, E.R., Hagenbeek, A., Hogenes, M.C., de Weger, R.A., Canninga-van Dijk, M.R., Weijer, K., Spits, H., Storm, G., van Bloois, L., et al. (2003). A new xenograft model for graftversus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2−/− gammac−/− double-mutant mice. Blood 102, 2522–2531.CrossRefGoogle Scholar
  28. Warnatz, K., Denz, A., Drager, R., Braun, M., Groth, C., Wolff-Vorbeck, G., Eibel, H., Schlesier, M., and Peter, H.H. (2002). 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 99, 1544–1551.CrossRefGoogle Scholar
  29. Welniak, L.A., Blazar, B.R., and Murphy, W.J. (2007). Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 25, 139–170.CrossRefGoogle Scholar
  30. Yoshizaki, A., Miyagaki, T., DiLillo, D.J., Matsushita, T., Horikawa, M., Kountikov, E.I., Spolski, R., Poe, J.C., Leonard, W.J., and Tedder, T.F. (2012). Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264–268.CrossRefGoogle Scholar
  31. Zhang, C., Todorov, I., Zhang, Z., Liu, Y., Kandeel, F., Forman, S., Strober, S., and Zeng, D. (2006). Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood 107, 2993–3001.CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Key Laboratory of Infection and Immunity, Institute of BiophysicsChinese Academy of SciencesBeijingChina
  2. 2.University of Chinese Academy of SciencesChinese Academy of SciencesBeijingChina

Personalised recommendations