Graft-versus-host disease(GVHD)is a prevalent and potential complication of hematopoietic stem cell trans-plantation.An animal model,xenogeneic GVHD(X-GVHD),that mimics accurately the clinical presentation of GVHD wou...Graft-versus-host disease(GVHD)is a prevalent and potential complication of hematopoietic stem cell trans-plantation.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 indi-cated 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.Com-pared with control group,IL-21 induced robust immuno-globulin 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 fi rst to fi nd 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 fi ndings show evidence of the involvement of B cells in X-GVHD and may have implications in the treat-ment of the disease.展开更多
基金the National Natural Science Foundation of China(Grant No.81000920).
文摘Graft-versus-host disease(GVHD)is a prevalent and potential complication of hematopoietic stem cell trans-plantation.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 indi-cated 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.Com-pared with control group,IL-21 induced robust immuno-globulin 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 fi rst to fi nd 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 fi ndings show evidence of the involvement of B cells in X-GVHD and may have implications in the treat-ment of the disease.
