白血病抗原致敏树突状细胞联合双自杀基因增强Allo-BMT疗效的实验研究
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摘要
第一部分 白血病抗原致敏树突状细胞应用于荷白血病小鼠免疫治疗的实验研究
目的：探讨白血病抗原冲击致敏的树突状细胞(DC)应用于荷白血病小鼠异基因骨髓移植(Allo-BMT)后免疫治疗的可行性及有效性，并初步探讨其免疫机理。
方法：常规方法制备小鼠骨髓细胞，予mGM-CSF+mIL-4培养诱导DC生成，并于第3天予反复冻融法制备的冻融抗原冲击致敏，第7天获负载白血病抗原的成熟DC。电镜观察细胞形态，流式细胞仪鉴定细胞表型。雌性615小鼠接种L7212细胞3天后以雄性BALB／c鼠为供鼠行异基因骨髓移植(骨髓细胞2×10~7个／只)。移植后第14天分3组：①NS(A组)②普通T细胞(B组)③DC+T细胞(C组)进行免疫试验。观察小鼠骨髓移植及免疫治疗后一般状况、血象变化、GVHD发生等情况。免疫治疗14天通过流式细胞仪检测进行T细胞亚群分析、ELISA法检测血清细胞因子水平、MTT法进行脾细胞毒活力检测，并行C带染色法以进行染色体嵌合率分析，观察移植物植入情况。移植后50天，对所有无病生存的小鼠(除外免疫功能检测中处死的小鼠)用L7212细胞二次攻击，以观察其体内抗白血病免疫能力。
结果：小鼠骨髓细胞在细胞因子mGM-CSF、mIL-4联合作用下培养6天后光镜下及电镜下观察到大量悬浮状态树突状形态细胞生成。该细胞DC相关分化
Part I Experimental study on immunotherapy with leukemia-related-antigen-pulsed dendritic cells in leukemic mice model
Objective
To explore the feasibility and efficiency of immunotherapy with leukemia-related-antigen-pulsed dendritic cells(DCs) in leukemic mice model after allogeneic bone morrow transplantation (Allo-BMT) and investigate its' reasons.
Methods
Mature DCs were proliferated from bone marrow mononuclearcells (MNC) by adding mouse granulocyte-macrophage colony stimulating factor (mGM-CSF) and interleukin-4 (mIL-4).3 days later, they were pulsed with frozen thawing L7212 leukemia-related antigen. In 6~(th) day .observed the morphous of mature DC by electron microscope and phenotype by FCM. 2 ×10~7 bone marrow cells from a male BALB/c mice were transplanted into the myeloablative irradiated female 615 mice which received a single subcutaneous injection of 1×10~6 L7212 leukemia cells 3 days before。 They were divided into control group (A)、T cells group (B) , DC+T cells group (C) to receive immunotherapy in 14~(th) day after Allo-BMT .We observed
目的：探讨白血病抗原冲击致敏的树突状细胞(DC)应用于荷白血病小鼠异基因骨髓移植(Allo-BMT)后免疫治疗的可行性及有效性，并初步探讨其免疫机理。
方法：常规方法制备小鼠骨髓细胞，予mGM-CSF+mIL-4培养诱导DC生成，并于第3天予反复冻融法制备的冻融抗原冲击致敏，第7天获负载白血病抗原的成熟DC。电镜观察细胞形态，流式细胞仪鉴定细胞表型。雌性615小鼠接种L7212细胞3天后以雄性BALB／c鼠为供鼠行异基因骨髓移植(骨髓细胞2×10~7个／只)。移植后第14天分3组：①NS(A组)②普通T细胞(B组)③DC+T细胞(C组)进行免疫试验。观察小鼠骨髓移植及免疫治疗后一般状况、血象变化、GVHD发生等情况。免疫治疗14天通过流式细胞仪检测进行T细胞亚群分析、ELISA法检测血清细胞因子水平、MTT法进行脾细胞毒活力检测，并行C带染色法以进行染色体嵌合率分析，观察移植物植入情况。移植后50天，对所有无病生存的小鼠(除外免疫功能检测中处死的小鼠)用L7212细胞二次攻击，以观察其体内抗白血病免疫能力。
结果：小鼠骨髓细胞在细胞因子mGM-CSF、mIL-4联合作用下培养6天后光镜下及电镜下观察到大量悬浮状态树突状形态细胞生成。该细胞DC相关分化
Part I Experimental study on immunotherapy with leukemia-related-antigen-pulsed dendritic cells in leukemic mice model
Objective
To explore the feasibility and efficiency of immunotherapy with leukemia-related-antigen-pulsed dendritic cells(DCs) in leukemic mice model after allogeneic bone morrow transplantation (Allo-BMT) and investigate its' reasons.
Methods
Mature DCs were proliferated from bone marrow mononuclearcells (MNC) by adding mouse granulocyte-macrophage colony stimulating factor (mGM-CSF) and interleukin-4 (mIL-4).3 days later, they were pulsed with frozen thawing L7212 leukemia-related antigen. In 6~(th) day .observed the morphous of mature DC by electron microscope and phenotype by FCM. 2 ×10~7 bone marrow cells from a male BALB/c mice were transplanted into the myeloablative irradiated female 615 mice which received a single subcutaneous injection of 1×10~6 L7212 leukemia cells 3 days before。 They were divided into control group (A)、T cells group (B) , DC+T cells group (C) to receive immunotherapy in 14~(th) day after Allo-BMT .We observed
引文
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10. Zhang K, Prichard JW, Brown RE.Blastic Natural Killer (NK) Cell Leukemia (Agranular CD4+CD56+ Leukemia). Ann Clin Lab Sci. 2006,36(2):212-215.
11. Koehl U, Esser R, Zimmermann S, Tonn T, Ex vivo expansion of highly purified NK cells for immunotherapy after haploidentical stem cell transplantation in children. Klin Padiatr. 2005,217(6):345-350.
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23.Lee,-W-C,Jeng,-L-B.Dendritic cell progenitors prolong allograft svirvival through T-helper 2 deviation of the Th1/Th2 paradigm. Blood,1995,85:3302-3312
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27.Mutis T, Ghoreschi K, Schrama E,et al.Efficient induction of minor histocompatibility antigen HA-1-specific cytotoxic T-cells using dendritic cells retrovirally transduced with HA-1-coding cDNA.Biol Blood Marrow Transplant. 2002,8(8):412-419.
28. Sato K, Yamashita N, et al.Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity,2003,18(3):367-79
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2. Zeis,-M;Frenzke,-H, et al.Idiotype protein-pulsed dendritic cells produce strong anti-myeloma effects after syngeneic stem cell transplantation..Bone Marrow Transplant. 2002,29(3)213-21
3. Sato K, Yamashita N, Yamashita N,et al.Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity. 2003 Mar; 18(3):367-379.
4. Barnes DW, Loutit JF. Treatment of murine leukaemia with x-rays and homologous bone marrow. Br J Haematol,1957,3:241-252.
5. Mathe G, Amiel JL,Schwarzenberg L,et al. Adoptive immunotherapy of acute leukemia:experimental and clinical results.Cancer Res, 1965, 25:1525-1531.
6. Kolb HJ,Mittermuller J,Clemm C,et al. Donor leukocyte transfusions for treatement of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood, 1990,76:2462-2465.
7. Austyn JM. Death, destruction, danger and dendritic cells. Nat Med, 1999,5(11):1232-3.Appelbaum FR, Rowe JM, Radich J, et al. Acute myeloid leukemia.Hematology,2001, Jan,62-86
8. Klammer M, Roddie PH.Current progress in the development of a cell-based vaccine for the immunotherapy of acute myeloid leukemia. Expert Rev Vaccines. 2006,5(2):211-222.
9. Curti A, Pandolfi S, Aluigi M, et al.Interleukin-12 production by leukemia-derived dendritic cells counteracts the inhibitory effect of leukemic microenvironment on T cells.7. Exp Hematol. 2005,33(12): 1521-1530.
10. Zhang K, Prichard JW, Brown RE.Blastic Natural Killer (NK) Cell Leukemia (Agranular CD4+CD56+ Leukemia). Ann Clin Lab Sci. 2006,36(2):212-215.
11. Koehl U, Esser R, Zimmermann S, Tonn T, Ex vivo expansion of highly purified NK cells for immunotherapy after haploidentical stem cell transplantation in children. Klin Padiatr. 2005,217(6):345-350.
12.Nikolic B, Cooke DT, Zhao G, et al. Both gamma delta T cells and NK cells inhibit the engraftment of enogeneic rat bone marrow cells and the induction of enograft tolerance in mice. J Immunol, 2001,166: 1398-1404.
13. Delluc S, Tourneur L, Fradelizi D, et al.DC-based vaccine loaded with acid-eluted peptides in acute myeloid leukemia: the importance of choosing the best elution method. Cancer Immunol Immunother. 2006, 5,[Epub ahead of print]
14. Roddie H, Klammer M, Thomas C,et al.Phase I/II study of vaccination with dendritic-like leukaemia cells for the immunotherapy of acute myeloid leukaemia. Br J Haematol. 2006 ,133(2): 152-7.
15.Klammer M, Roddie PH.Current progress in the development of a cell-based vaccine for the immunotherapy of acute myeloid leukemia. Expert Rev Vaccines. 2006 ,5(2):211-22.
16.Smit WM,Rihnbeek M, van Bergen CA et al .Generation of dendritic cells expressing bcr-abl from CD34-positive chronic myeloid leukemia precursor cells.Hum Immunol, 1997,53(2):216-223
17.Nieda M,Tomiyama M,Egava K.Ex vivo enhancement of antigen-presenting function of dendritic cells and its application for DC-based immunotherapy.Hum Cell,2003 ,16(4):199-204.
18. Salio M,Dulphy N,Renneson J,et al.Efflcient priming of antigen-specific cytotoxic T lymphocytes by human cord blood dendritic cells. International Immunology, 2003,10(3):1265-1270.
19. Robin M, Schlageter MH, Chomienne C, et al.Targeted immunotherapy in acute myeloblastic leukemia: from animals to humans. 1: Cancer Immunol Immunother. 2005,54(10):933-43.
20. Jin H,Gong D,Adeegbe D,et al.Quantitative assessment concerning the contribution of IL-2R{beta} for superantigen-mediated T cell responses in vivo.Int Immunol. 2006,18(4):565-72.
21.Movassagh M, Laderach D, Galy A.Proteins of the Ikaros family control dendritic cell maturation required to induce optimal Th1 T cell differentiation.Int Immunol. 2004,16(6):867-875.
22. Starzl TE.Chimerism and tolerance in transplantation.Proc Natl Acad Sci U S A. 2004,101 Suppl 2:14607-14.
23.Lee,-W-C,Jeng,-L-B.Dendritic cell progenitors prolong allograft svirvival through T-helper 2 deviation of the Th1/Th2 paradigm. Blood,1995,85:3302-3312
24.Collins RH Jr,Shpiberg O,Drobyski WR, et al.Donor leukocyte infusion in 140 patients with relapsed malignancy after malignancy after allogeneic bone marrow transplantation. J Clin Oncol, 1997,15/;433-444.
25. Slanin S,Nagler A,et al. Nonmyeloablative stem cell transplantation and cell therapy as an alterative to conventional bone marrow transplantation with lethal cytoreductive for the treatment of malignant and nonmalignant hematologic disease. Blood,1998,91:756-763
26. Rezvani K, Grube M, Brenchley JMFunctional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation.Blood. 2003 Oct 15;102(8):2892-900. Epub 2003 Jun 26.
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