小鼠脐血移植模型的建立及角质细胞生长因子在移植后免疫重建中作用机制研究
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摘要
一、小鼠脐带血造血干细胞移植模型的建立
目的:探讨小鼠脐带血收集方法、建立可长期生存的小鼠异基因脐带血造血干细胞移植模型。
方法:采用C57BL/6雌性小鼠腹腔注射5IU孕马血清促性腺激素,48h后注射5IUβ-人绒毛膜促性腺激素促进排卵并按2:1雌雄比与C57BL/6雌性小鼠合笼,次晨分开。取孕E19.5 d小鼠,无菌条件下取出胎鼠,置于0.4%柠檬酸钠的RPMI-1640完全培养基内,先后剪开胎鼠颈动脉和心脏,充分释放外周血。将32只8-10周龄SPF级BALB/c小鼠随机分为4组,每组8只,BALB/c小鼠接受8.0Gy X射线全身照射。分别输注0.4ml PBS或1×10~6、2×10~6或3×10~6个脐血TNCs。+8天每只鼠输注1×10~9个血小板。
结果:成年C57BL/6小鼠予促排卵处理单次妊娠可获得6-11只胎鼠/胎,平均8只。单个胎鼠采集外周血有核细胞数6.4×10~5-11.4×10~5个,平均有核细胞数9.37×10~5个。PBS对照组小鼠13.5d内全部死于造血衰竭。同基因脐血移植输注1×10~6、2×10~6 TNCs两组小鼠100d生存率分别为87.5%(7/8只)、100.0%(8/8只),三组生存时间差别具有统计学意义(P<0.001)。同基因脐血移植输注1×10~6个脐血TNCs小鼠给予血小板输注支持100d生存率为100.0%(8/8只)。异基因脐血移植输注1×10~6、2×10~6、3×10~6个TNCs三组小鼠100d生存率分别为25%(2/8只)、37.5%(3/8只)、37.5%(3/8只),三组生存时间比较差别无统计学意义(χ~2=0.4990,P=0.7792),移植组与PBS对照组相比生存时间具有统计学意义(χ~2=39.99,P<0.001)(图3A)。第二批脐血移植实验中含血小板输注支持,异基因脐血移植输注1×10~6、2×10~6、3×10~6个TNCs三组小鼠100d生存率分别为87.5%(7/8只)、100.0%(8/8只)、100.0%(8/8只)。长期生存小鼠无明显GVHD表现。
结论:采用抗凝培养基可以明显增加单个胎鼠平均采集脐带血有核细胞数,在小鼠脐血移植后予血小板输注成功建立了能重建造血并长期生存的异基因小鼠脐血移植模型。
二、白血病小鼠脐带血造血干细胞移植模型的建立
目的:建立C57BL/6→BALB/c白血病小鼠异基因脐带血造血干细胞移植模型。
方法:BALB/c小鼠尾静脉接种1×10~6个EL9611细胞。接种4天后分组:无TBI对照、TBI对照、同基因小鼠脐带血造血干细胞移植对照、异基因小鼠脐带血造血干细胞移植组,每组8只。TBI处理后输注2×10~6个脐带血TNCs;移植后+8d予输血小板支持。
结果:无TBI处理对照组小鼠接种后14天内全部死于白血病。单纯TBI处理组小鼠处理后14天内全部死于造血衰竭所致全血细胞减少。同基因对照小鼠20天内全部死于白血病,移植前4天接种EL9611白血病细胞后予TBI预处理可成功制备白血病微小残留病灶模型。异基因UCBT组3/8只小鼠长期生存,5/8只小鼠于UCBT后44天内死于EL9611白血病复发。四组生存时间采用Log-rank检验,χ~2=29.24, P < 0.0001。异基因UCBT组小鼠生存期明显比同基因UCBT组小鼠生存期长(χ~2= 9.545, P= 0.0020)。结论:在成功建立血小板输注支持的小鼠异基因脐带血造血干细胞移植模型的基础上,本部分采用脐血移植前4天尾静脉接种EL9611白血病细胞建立白血病脐血造血干细胞移植模型。异基因UCBT具有明显的移植物抗白血病作用
三、KGF对小鼠脐带血造血干细胞移植后免疫重建和白血病复发的影响
目的:探讨研究KGF输注对移植后免疫重建和白血病复发的影响。
方法:采用定量PCR方法检测脾细胞sjTREC评价胸腺输出功能;RT-PCR方法检测T细胞受体β链谱型;流式细胞仪检测淋系重建;外周血涂片瑞氏染色检测白血病复发。免疫重建实验共设立2组,每组12只小鼠。PBS免疫重建对照组:不接种白血病,小鼠自TBI前-3d起每日皮下注射0.2ml PBS连用7天,TBI处理后输注2×10~6个脐带血TNCs,移植后+8d予输血小板支持;KGF免疫重建实验组:不接种白血病,小鼠自TBI前-3d起每日皮下注射重组人KGF(Peprotech)1mg/kg连用7天,TBI处理后输注2×10~6个脐带血TNCs,移植后+8d予输血小板支持。白血病实验共设立4组,每组10-12只小鼠。对照1组:接种白血病,无TBI处理;对照2组:TBI前-4d时接种白血病,单纯TBI处理;PBS白血病实验对照组:TBI前-4d时接种白血病,小鼠自TBI前-3d起每日皮下注射0.2ml PBS连用7天,TBI处理后输注2×10~6个脐带血TNCs,移植后+8d予输血小板支持;KGF白血病实验组:接种白血病,小鼠自TBI前-3d起每日皮下注射重组人KGF 1mg/kg连用7天,TBI处理后输注2×10~6个脐带血TNCs,移植后+8d予输血小板支持。
结果: +35天PBS免疫重建对照组小鼠脾细胞总数、T、NK和B细胞数分别为(3.51±0.31)×10~7、(9.32±0.48)×10~6、(1.59±0.11)×10~6、(18.74±2.01)×10~6个;KGF免疫重建实验组小鼠脾细胞总数、T、NK和B细胞数分别为(4.06±0.19)×10~7、(13.20±1.14)×10~6、(1.75±0.12)×10~6、(20.36±0.86)×10~6个。KGF免疫重建组脾细胞总细胞数、T细胞、NK细胞较PBS对照组高(P<0.05)。PBS对照组小鼠sjTRECs水平为182.2±10.7拷贝/105脾细胞;KGF实验组小鼠为sjTRECs水平为224.2±9.6拷贝/105脾细胞,KGF免疫重建实验组sjTRECs水平明显高于PBS对照组(P=0.019)。PBS白血病对照组白血病小鼠脐带血移植后28天后陆续出现白血病复发,4/12只生存期超过100天,100天生存率33.3%。KGF白血病实验组白血病小鼠脐带血移植后34天后陆续出现白血病复发,9/12只生存期超过100天,100天生存率75.0%。两组白血病小鼠生存时间比较差别有统计学意义(χ~2= 4.996,P= 0.0254)。
结论:异基因脐带血造血干细胞移植TBI预处理前KGF输注可以促进胸腺上皮功能恢复,增强胸腺输出功能,促进外周T淋系免疫重建,并且增强的T细胞免疫重建可降低异基因脐带血移植后白血病复发。
Part ?: Establishment of a viable murine umbilical cord blood stem cell transplantation (UCBT) model.
Objective: To explore the isolation of murine umbilical cord blood and establishment of a viable murine umbilical cord blood stem cell transplantation (UCBT) model. Methods: Female C57BL/6 mice were treated with 5IU PMSG i.p., female C57BL/6 mice were mated with male C57BL/6 mice at a ratio of 2:1. We humanely killed E19.5d pregnant mice. We collected umbilical cord blood with 0.4% sodium citrate supplemented RPMI-1640 complete medium. Thirty-two BALB/c mice were assigned to four groups with 8 mice per group. Recipient mice were reconstituted with PBS, 1×10~6, 2×10~6 or 3×10~6 umbilical cord blood TNCs。Platelet concentrate support with 1×10~9 platelets was incorporated in parts of experiment.
Results: Average number of peripheral blood TNCs is 9.37×10~5 (range, 6.4×10~5 to 11.4×10~5) per fetus by using anticoagulant-supplemented media. BALB/c mice received TBI and PBS treatment died of hematopoietic failure between + 9.5 and +14 day post TB. The 100-day survival rates of C57BL/6 mice reconstituted with 1×10~6, 2×10~6 UCB TNCs were 87.5% (7/8) and 100% (8/8), respectively.
The 100-day survival rates of BALB/c mice reconstituted with 1×10~6, 2×10~6, 3×10~6 UCB TNCs were 25.0% (2/8), 37.5% (3/8) and 37.5% (3/8), respectively(χ~2=0.4990, P=0.7792. There was not a trend of prolonged survival time with increasing UCB NCs inoculation. The 100-day survival rates of BALB/c mice reconstituted with 1×10~6, 2×10~6, 3×10~6 UCB NCs in the second experiment cohort were 87.5% (7/8), 100.0% (8/8) and 100.0% (8/8), respectively. No GVHD was observed post UCBT.
Conclusion: We had modified a protocol with anticoagulant supplemented medium to collect murine umbilical cord TNCs. We established a viable murine allogeneic umbilical cord blood transplantation model.
PartПEstablishment of leukemia-bearing murine allogeniec umbilical cord blood hematopoietic stem cell transplantation model Objective: To establish C57BL/6→BALB/c leukemia-bearing murine allogeniec umbilical cord blood hematopoietic stem cell transplantation model.
Methods: BALB/c mice were inoculated with 1×10~6 EL9611 cells 4 days prior to TBI conditioning. BALB/c mice were randomly assigned to four groups, no TBI, TBI, syngeneic UCBT control, allogeneic UCBT. Recipient mice were reconstituted with 2×10~6 UCB TNCs with platelet concentrate support on +8day post UCBT.
Results: All mice died of leukemia within 14d with no TBI. All mice died of aplasia within 14d with TBI. All mice of syngeneic UCBT group died of leukemia relapse within 20d. 62.5%(5/8) of mice of allogeneic UCBT group died of leukemia relapse within 20d, 37.5%(3/8) mice survived 100d post UCBT. The survival time of four groups are significant different (χ~2=29.24, P < 0.0001). Allogeneic group had a prolonged survival than syngeneic group (χ~2= 9.545, P= 0.0020).
Conclusion: We established a viable C57BL/6→BALB/c leukemia-bearing murine allogeneic umbilical cord blood hematopoietic stem cell transplantation model with platelet concentrate support.
PartШThe effects of KGF on immune reconstitution and leukemia relapse post allogeneic umbilical cord blood transplantation
Objective: To explore the effects KGF on immune reconstitution and leukemia relapse post allogeneic umbilical cord blood transplantation.
Methods: Real-time quantitative PCR was used to assay TREC in splenocytes. RT-PCR and runoff PCR were used to assay TRBV family spectrum. FCM was used to assay splenic lymphoid immune reconstitution.
In the immune reconstitution model, twenty-four BALB/c mice were randomly assigned to allogeneic UCBT PBS control group and KGF treatment group. KGF group mice received KGF treatment s.c. 3 days prior to TBI for 7 consecutive days. Mice were reconstituted with 2×10~6 UCB TNCs with platelet concentrate support on +8 days. In the leukemia model, forty-four leukemia-loaded BALB/c mice were randomly assigned to allogeneic UCBT PBS control group and KGF treatment group. KGF group mice received KGF treatment s.c. 3 days prior to TBI for 7 consecutive days. All mice were reconstituted with 2×10~6 UCB TNCs with platelet concentrate support on +8 days.
Results: The total splenocytes, T cell, NK cell and B cell per mouse of mice on +35day in PBS treatment group were (3.51±0.31)×10~7, (9.32±0.48)×10~6 and (1.59±0.11)×10~6 and (18.74±2.01)×10~6 , respectively. The splenic T, NK cell counts in KGF treatment group were higher than those of PBS control group. The sjTREC level of PBS control group was 182.2±10.7 per 105 cells, while the sjTREC level of KGF treatment group were 224.2±9.6 per 105 cells, respectively. 75.0 percent of KGF treated mice (9/12) survived +100 d and 25.0 percent (3/12) died of leukemia. 33.3 percent of PBS treated mice (4/12) survived +100 d and 66.7 percent (8/12) died of leukemia. KGF group mice had prolonged survival than PBS control group (χ~2= 4.996, P= 0.0254).
Conclusion: KGF pretreatment prior to TBI could protect thymus tissue, promote T lymphoid immune reconstitution and enhance graft-versus-leukemia effect in leukemia-loaded murine allogeneic UCBT.
目的:探讨小鼠脐带血收集方法、建立可长期生存的小鼠异基因脐带血造血干细胞移植模型。
方法:采用C57BL/6雌性小鼠腹腔注射5IU孕马血清促性腺激素,48h后注射5IUβ-人绒毛膜促性腺激素促进排卵并按2:1雌雄比与C57BL/6雌性小鼠合笼,次晨分开。取孕E19.5 d小鼠,无菌条件下取出胎鼠,置于0.4%柠檬酸钠的RPMI-1640完全培养基内,先后剪开胎鼠颈动脉和心脏,充分释放外周血。将32只8-10周龄SPF级BALB/c小鼠随机分为4组,每组8只,BALB/c小鼠接受8.0Gy X射线全身照射。分别输注0.4ml PBS或1×10~6、2×10~6或3×10~6个脐血TNCs。+8天每只鼠输注1×10~9个血小板。
结果:成年C57BL/6小鼠予促排卵处理单次妊娠可获得6-11只胎鼠/胎,平均8只。单个胎鼠采集外周血有核细胞数6.4×10~5-11.4×10~5个,平均有核细胞数9.37×10~5个。PBS对照组小鼠13.5d内全部死于造血衰竭。同基因脐血移植输注1×10~6、2×10~6 TNCs两组小鼠100d生存率分别为87.5%(7/8只)、100.0%(8/8只),三组生存时间差别具有统计学意义(P<0.001)。同基因脐血移植输注1×10~6个脐血TNCs小鼠给予血小板输注支持100d生存率为100.0%(8/8只)。异基因脐血移植输注1×10~6、2×10~6、3×10~6个TNCs三组小鼠100d生存率分别为25%(2/8只)、37.5%(3/8只)、37.5%(3/8只),三组生存时间比较差别无统计学意义(χ~2=0.4990,P=0.7792),移植组与PBS对照组相比生存时间具有统计学意义(χ~2=39.99,P<0.001)(图3A)。第二批脐血移植实验中含血小板输注支持,异基因脐血移植输注1×10~6、2×10~6、3×10~6个TNCs三组小鼠100d生存率分别为87.5%(7/8只)、100.0%(8/8只)、100.0%(8/8只)。长期生存小鼠无明显GVHD表现。
结论:采用抗凝培养基可以明显增加单个胎鼠平均采集脐带血有核细胞数,在小鼠脐血移植后予血小板输注成功建立了能重建造血并长期生存的异基因小鼠脐血移植模型。
二、白血病小鼠脐带血造血干细胞移植模型的建立
目的:建立C57BL/6→BALB/c白血病小鼠异基因脐带血造血干细胞移植模型。
方法:BALB/c小鼠尾静脉接种1×10~6个EL9611细胞。接种4天后分组:无TBI对照、TBI对照、同基因小鼠脐带血造血干细胞移植对照、异基因小鼠脐带血造血干细胞移植组,每组8只。TBI处理后输注2×10~6个脐带血TNCs;移植后+8d予输血小板支持。
结果:无TBI处理对照组小鼠接种后14天内全部死于白血病。单纯TBI处理组小鼠处理后14天内全部死于造血衰竭所致全血细胞减少。同基因对照小鼠20天内全部死于白血病,移植前4天接种EL9611白血病细胞后予TBI预处理可成功制备白血病微小残留病灶模型。异基因UCBT组3/8只小鼠长期生存,5/8只小鼠于UCBT后44天内死于EL9611白血病复发。四组生存时间采用Log-rank检验,χ~2=29.24, P < 0.0001。异基因UCBT组小鼠生存期明显比同基因UCBT组小鼠生存期长(χ~2= 9.545, P= 0.0020)。结论:在成功建立血小板输注支持的小鼠异基因脐带血造血干细胞移植模型的基础上,本部分采用脐血移植前4天尾静脉接种EL9611白血病细胞建立白血病脐血造血干细胞移植模型。异基因UCBT具有明显的移植物抗白血病作用
三、KGF对小鼠脐带血造血干细胞移植后免疫重建和白血病复发的影响
目的:探讨研究KGF输注对移植后免疫重建和白血病复发的影响。
方法:采用定量PCR方法检测脾细胞sjTREC评价胸腺输出功能;RT-PCR方法检测T细胞受体β链谱型;流式细胞仪检测淋系重建;外周血涂片瑞氏染色检测白血病复发。免疫重建实验共设立2组,每组12只小鼠。PBS免疫重建对照组:不接种白血病,小鼠自TBI前-3d起每日皮下注射0.2ml PBS连用7天,TBI处理后输注2×10~6个脐带血TNCs,移植后+8d予输血小板支持;KGF免疫重建实验组:不接种白血病,小鼠自TBI前-3d起每日皮下注射重组人KGF(Peprotech)1mg/kg连用7天,TBI处理后输注2×10~6个脐带血TNCs,移植后+8d予输血小板支持。白血病实验共设立4组,每组10-12只小鼠。对照1组:接种白血病,无TBI处理;对照2组:TBI前-4d时接种白血病,单纯TBI处理;PBS白血病实验对照组:TBI前-4d时接种白血病,小鼠自TBI前-3d起每日皮下注射0.2ml PBS连用7天,TBI处理后输注2×10~6个脐带血TNCs,移植后+8d予输血小板支持;KGF白血病实验组:接种白血病,小鼠自TBI前-3d起每日皮下注射重组人KGF 1mg/kg连用7天,TBI处理后输注2×10~6个脐带血TNCs,移植后+8d予输血小板支持。
结果: +35天PBS免疫重建对照组小鼠脾细胞总数、T、NK和B细胞数分别为(3.51±0.31)×10~7、(9.32±0.48)×10~6、(1.59±0.11)×10~6、(18.74±2.01)×10~6个;KGF免疫重建实验组小鼠脾细胞总数、T、NK和B细胞数分别为(4.06±0.19)×10~7、(13.20±1.14)×10~6、(1.75±0.12)×10~6、(20.36±0.86)×10~6个。KGF免疫重建组脾细胞总细胞数、T细胞、NK细胞较PBS对照组高(P<0.05)。PBS对照组小鼠sjTRECs水平为182.2±10.7拷贝/105脾细胞;KGF实验组小鼠为sjTRECs水平为224.2±9.6拷贝/105脾细胞,KGF免疫重建实验组sjTRECs水平明显高于PBS对照组(P=0.019)。PBS白血病对照组白血病小鼠脐带血移植后28天后陆续出现白血病复发,4/12只生存期超过100天,100天生存率33.3%。KGF白血病实验组白血病小鼠脐带血移植后34天后陆续出现白血病复发,9/12只生存期超过100天,100天生存率75.0%。两组白血病小鼠生存时间比较差别有统计学意义(χ~2= 4.996,P= 0.0254)。
结论:异基因脐带血造血干细胞移植TBI预处理前KGF输注可以促进胸腺上皮功能恢复,增强胸腺输出功能,促进外周T淋系免疫重建,并且增强的T细胞免疫重建可降低异基因脐带血移植后白血病复发。
Part ?: Establishment of a viable murine umbilical cord blood stem cell transplantation (UCBT) model.
Objective: To explore the isolation of murine umbilical cord blood and establishment of a viable murine umbilical cord blood stem cell transplantation (UCBT) model. Methods: Female C57BL/6 mice were treated with 5IU PMSG i.p., female C57BL/6 mice were mated with male C57BL/6 mice at a ratio of 2:1. We humanely killed E19.5d pregnant mice. We collected umbilical cord blood with 0.4% sodium citrate supplemented RPMI-1640 complete medium. Thirty-two BALB/c mice were assigned to four groups with 8 mice per group. Recipient mice were reconstituted with PBS, 1×10~6, 2×10~6 or 3×10~6 umbilical cord blood TNCs。Platelet concentrate support with 1×10~9 platelets was incorporated in parts of experiment.
Results: Average number of peripheral blood TNCs is 9.37×10~5 (range, 6.4×10~5 to 11.4×10~5) per fetus by using anticoagulant-supplemented media. BALB/c mice received TBI and PBS treatment died of hematopoietic failure between + 9.5 and +14 day post TB. The 100-day survival rates of C57BL/6 mice reconstituted with 1×10~6, 2×10~6 UCB TNCs were 87.5% (7/8) and 100% (8/8), respectively.
The 100-day survival rates of BALB/c mice reconstituted with 1×10~6, 2×10~6, 3×10~6 UCB TNCs were 25.0% (2/8), 37.5% (3/8) and 37.5% (3/8), respectively(χ~2=0.4990, P=0.7792. There was not a trend of prolonged survival time with increasing UCB NCs inoculation. The 100-day survival rates of BALB/c mice reconstituted with 1×10~6, 2×10~6, 3×10~6 UCB NCs in the second experiment cohort were 87.5% (7/8), 100.0% (8/8) and 100.0% (8/8), respectively. No GVHD was observed post UCBT.
Conclusion: We had modified a protocol with anticoagulant supplemented medium to collect murine umbilical cord TNCs. We established a viable murine allogeneic umbilical cord blood transplantation model.
PartПEstablishment of leukemia-bearing murine allogeniec umbilical cord blood hematopoietic stem cell transplantation model Objective: To establish C57BL/6→BALB/c leukemia-bearing murine allogeniec umbilical cord blood hematopoietic stem cell transplantation model.
Methods: BALB/c mice were inoculated with 1×10~6 EL9611 cells 4 days prior to TBI conditioning. BALB/c mice were randomly assigned to four groups, no TBI, TBI, syngeneic UCBT control, allogeneic UCBT. Recipient mice were reconstituted with 2×10~6 UCB TNCs with platelet concentrate support on +8day post UCBT.
Results: All mice died of leukemia within 14d with no TBI. All mice died of aplasia within 14d with TBI. All mice of syngeneic UCBT group died of leukemia relapse within 20d. 62.5%(5/8) of mice of allogeneic UCBT group died of leukemia relapse within 20d, 37.5%(3/8) mice survived 100d post UCBT. The survival time of four groups are significant different (χ~2=29.24, P < 0.0001). Allogeneic group had a prolonged survival than syngeneic group (χ~2= 9.545, P= 0.0020).
Conclusion: We established a viable C57BL/6→BALB/c leukemia-bearing murine allogeneic umbilical cord blood hematopoietic stem cell transplantation model with platelet concentrate support.
PartШThe effects of KGF on immune reconstitution and leukemia relapse post allogeneic umbilical cord blood transplantation
Objective: To explore the effects KGF on immune reconstitution and leukemia relapse post allogeneic umbilical cord blood transplantation.
Methods: Real-time quantitative PCR was used to assay TREC in splenocytes. RT-PCR and runoff PCR were used to assay TRBV family spectrum. FCM was used to assay splenic lymphoid immune reconstitution.
In the immune reconstitution model, twenty-four BALB/c mice were randomly assigned to allogeneic UCBT PBS control group and KGF treatment group. KGF group mice received KGF treatment s.c. 3 days prior to TBI for 7 consecutive days. Mice were reconstituted with 2×10~6 UCB TNCs with platelet concentrate support on +8 days. In the leukemia model, forty-four leukemia-loaded BALB/c mice were randomly assigned to allogeneic UCBT PBS control group and KGF treatment group. KGF group mice received KGF treatment s.c. 3 days prior to TBI for 7 consecutive days. All mice were reconstituted with 2×10~6 UCB TNCs with platelet concentrate support on +8 days.
Results: The total splenocytes, T cell, NK cell and B cell per mouse of mice on +35day in PBS treatment group were (3.51±0.31)×10~7, (9.32±0.48)×10~6 and (1.59±0.11)×10~6 and (18.74±2.01)×10~6 , respectively. The splenic T, NK cell counts in KGF treatment group were higher than those of PBS control group. The sjTREC level of PBS control group was 182.2±10.7 per 105 cells, while the sjTREC level of KGF treatment group were 224.2±9.6 per 105 cells, respectively. 75.0 percent of KGF treated mice (9/12) survived +100 d and 25.0 percent (3/12) died of leukemia. 33.3 percent of PBS treated mice (4/12) survived +100 d and 66.7 percent (8/12) died of leukemia. KGF group mice had prolonged survival than PBS control group (χ~2= 4.996, P= 0.0254).
Conclusion: KGF pretreatment prior to TBI could protect thymus tissue, promote T lymphoid immune reconstitution and enhance graft-versus-leukemia effect in leukemia-loaded murine allogeneic UCBT.
引文
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