细胞因子在造血干细胞移植中诱导免疫耐受的基础和应用研究

Immune tolerance induced by cytokines in allogeneic hematopoietic stem cell transplantation

Allo-HSCT is a potentially curative therapy for many hematological malignancies,the basis of which is graft-versus-leukemia(GVL) effect.However,acute graft-versus-host disease(GVHD) is responsible for 15% to 40% of mortality and is the major cause of morbidity after transplantation.Therefore,separation of GVHD and GVL partially or completely could improve the transplant outcomes.This study focuses on the effects of G-CSF on T cells in peripheral blood stem cell grafts and bone marrow grafts and its mechanisms after in vivo G-CSF application.The separation of GVHD and GVL effect and the mechanisms of which after in vivo G-CSF and interleukin-11(IL-11) treatment of healthy donors were investigated.The main contributions of this research are listed as follows:(1) Immune tolerance of T cells was induced simultaneously in peripheral blood stem cell grafts and bone marrow grafts after in vivo G-CSF application;(2) T cell hyporesponsiveness and polarization of T cells from Th1 to Th2 were maintained after mixture of G-CSF-mobilized peripheral blood grafts(G-PB) and G-CSF-primed bone marrow grafts(G-BM) according to different proportions in vitro;(3) Treating donor with G-CSF and IL-11 decreased GVHD and retained GVL effect;(4) The incidence of acute GVHD was decreased after Allo-HSCT using G-PB and G-BM as allografts;(5) In combination with other techniques,the HLA barriers were overcomed using G-PB and G-BM as allografts;(6) The incidences of acute GVHD were significantly decreased and the GVL effects were retained or enhanced in relapsed patients after treatment by G-CSF-mobilized peripheral blood graft infusion compared with those received steady-state peripheral blood lymphocyte infusion,indicating that GVHD and GVL could be partially separated in clinical settings.Based on our results,we would conclude that the issues on the deficiency of donors are resolved,and novel strategies offered for the prophylaxis and treatment of patients with hematological malignancies who relapse after Allo-HSCT.Further studies on the mechanism of the separation of GVL and GVHD are warranted.

SUMMARY Allo-HSCT is a potentially curative therapy for many hematological malignancies, the basis of which is graft-versus-leukemia （GVL） effect. However, acute graft-versus-host disease （GVHD） is responsible for 15% to 40% of mortality and is the major cause of morbidity after transplantation. Therefore, separation of GVHD and GVL partially or completely could improve the transplant outcomes. This study focuses on the effects of G-CSF on T cells in peripheral blood stem cell grafts and bone marrow grafts and its mechanisms after in vivo G-CSF application. The separation of GVHD and GVL effect and the mechanisms of which after in vivo G-CSF and interleukin-11 （ IL-11 ） treatment of healthy donors were investigated. The main contributions of this research are listed as follows ： （ 1 ） Immune tolerance of T cells was induced simultaneously in peripheral blood stem cell grafts and bone marrow grafts after in vivo G-CSF application; （2） T cell hyporesponsiveness and polarization of T cells from Thl to Th2 were maintained after mixture of G-CSF-mobilized peripheral blood grafts （G-PB） and G-CSF-primed bone marrow grafts （G-BM） according to different proportions in vitro; （3） Treating donor with G-CSF and IL-11 decreased GVHD and retained GVL effect; （4） The incidence of acute GVHD was decreased after Allo- HSCT using G-PB and G-BM as allografts; （5） In combination with other techniques, the HLA barriers were overcomed using G-PB and G-BM as allografts; （6） The incidences of acute GVHD were significantly decreased and the GVL effects were retained or enhanced in relapsed patients after treatment by G- CSF-mobilized peripheral blood graft infusion compared with those received steady-state peripheral blood lymphocyte infusion, indicating that GVHD and GVL could be partially separated in clinical settings. Based on our results, we would conclude that the issues on the deficiency of donors are resolved, and novel strategies offered for the prophylaxis and treatment of patients with hematological malignancies who relapse after Allo-HSCT. Further studies on the mechanism of the separation of GVL and GVHD are warranted.