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

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⁺ CD38^high 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

References

[1] Blazar, B.R., Murphy, W.J., and Abedi, M. (2012). Advances in graftversus-host disease biology and therapy. Nat Rev Immunol 12, 443-458 .10.1038/nri3212
[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 .10.1182/blood-2009-05-221135
[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 .10.1182/blood-2009-01-200527
[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 .10.1111/j.1600-065X.2008.00631.x
[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 .
[6] Evenou, J.P., Wagner, J., Zenke, G., Brinkmann, V., Wagner, K., Kovarik, J., Welzenbach, K.A., Weitz-Schmidt, G., Guntermann, C., Towbin, H., . (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 .10.1124/jpet.109.153205
[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 .
[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/gammac-mouse model. Bone Marrow Transplant 47, 439-450 .10.1038/bmt.2011.93
[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., . (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 .10.1182/blood-2010-07-294785
[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., . (2012). Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes. Blood 119, 619-628 .10.1182/blood-2011-07-368027
[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 .10.1097/TP.0b013e3181a5cb07
[12] Konforte, D., Simard, N., and Paige, C.J. (2009). IL-21: an executor of B cell fate. J Immunol 182, 1781-1787 .10.4049/jimmunol.0803009
[13] Leonard, W.J., and Spolski, R. (2005). Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol 5, 688-698 .10.1038/nri1688
[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 .10.1681/ASN.2006050422
[15] Meguro, A., Ozaki, K., Hatanaka, K., Oh, I., Sudo, K., Ohmori, T., Matsu, H., Tatara, R., Sato, K., Sakata, Y., . (2011). Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells. Bone Marrow Transplant 46, 1557-1565 .10.1038/bmt.2010.342
[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 .10.1038/bmt.2009.223
[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 .10.1158/1078-0432.CCR-06-0035
[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 .10.1002/art.20018
[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., . (2011). Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood 117, 2275-2283 .10.1182/blood-2010-10-307819
[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 .10.1016/j.semarthrit.2004.07.002
[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 .10.1182/blood-2008-10-161638
[22] Shlomchik, W.D. (2007). Graft-versus-host disease. Nat Rev Immunol 7, 340-352 .10.1038/nri2000
[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 .10.1111/j.1749-6632.2011.06310.x
[24] Shultz, L.D., Ishikawa, F., and Greiner, D.L. (2007). Humanized mice in translational biomedical research. Nat Rev Immunol 7, 118-130 .10.1038/nri2017
[25] Spolski, R., and Leonard, W.J. (2008). Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol 26, 57-79 .10.1146/annurev.immunol.26.021607.090316
[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., . (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 .
[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., . (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 .10.1182/blood-2002-10-3241
[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 .10.1182/blood.V99.5.1544
[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 .10.1146/annurev.immunol.25.022106.141606
[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 .10.1038/nature11501
[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 .10.1182/blood-2005-09-3623