sTNFR Ⅰ基因修饰的未成熟树突细胞对异基因骨髓移植小
鼠移植物抗宿主病和移植物抗白血病作用的研究
王淑华;李德鹏;张艳君;张璞;曾令宇;潘秀英;徐开林;黄一虹
【期刊名称】《中华血液学杂志》 【年(卷),期】2012(033)002
【摘要】Objective To investigate the effect of immature dendritic cells (inDC) genetically modified to express sTNFR Ⅰ on acute graft-versus-host disease (aGVHD) and the graft-versus-leukemia (GVL)effect offer allogeneic bone marrow transplantation (allo-BMT) in leukemic mice and its mechanism.Methods An EL4 leukemia allo-BMT model was established with the BALB/c ( H-2d ) donor mice (DM) and C57BL/6 (H-2b) recipient mice (RM).The RM received DM bone marrow (BM) cells at a 1:1 ratio with spleen cells intravenously via tail vein at 4 h after TBI.Fifty DM were separated randomly into five groups:①Group A:total body irradiation (TBI) group,②Group B:lymphoma cell leukemia group,③Group C:allo-BMT group,④Group D:pXZ9-DC group,⑤Group E:sTNFR Ⅰ -DC group.Acute GVHD scores,incidence of leukemic cell infiltration,histopathological analysis,survival rate,and survival rate of the
recipients
were
estimated
after
allo-BMT.Enzyme-linked
immunosorbent assay (ELISA) method was used to detect cytokines (INF-y and IL-4 ) production.Flow cytometry (FCM) analysis was used to detect allogeneic chimerism.Results ①The mice in group A and group B
all died of the BM failure and lymphoma cell leukemia,respectively.The mice in group C developed typical clinical signs of aGVHD after BMT with an average survival time(AST) of (11.50 ± 3.50) d.The signs of aGVHD were less evident in the group D and E,and their AST (21.70 ±5.80 and 25.80 ± 5.20 days,respectively) were all longer than that in group C ( P ＜0.05 ).AST of group E was the longest (P ＜ 0.05 ).The mice in group B all died of leukemia within 18 days after engraftment of ELA cells.There was was no significant difference in groups C,D and E in the incidence of leukemia (P ＞0.05).② Serum IFN-ylevel reached peak value.At + 12 d,then decreased gradually in group C,D,and E,and then reached the nadir at + 18 d post-BMT,with the lowest in group E (P ＜0.05 ),and the level was significantly lower in group D than in group C ( P ＜ 0.05 ).After BMT,serum IL-4 level slightly decreased in group C,but gradually elevated in group D and E and reached their peak at + 12 d,and even more significantly increased in group E (P ＜ 0.05).There was no statistical significance in the pair wise comparison among three group( P ＜ 0.05 ).③The average proportion of H-2d positive cells in RM was 95％ - 100％ on day 30 post-BMT,with complete donor-type implantation.Conclusion
Immature
DC
can
induce
immuno
tolerance.Immature DC genetically modified to express sTNFR Ⅰ has been shown to prevent acute GVHD in lethally irradiated mice reconstituted with allogeneic bone marrow grafts while maintaining the
GVL response.%目的 探讨可溶性肿瘤坏死因子受体Ⅰ (sTNFR Ⅰ)基因修饰的未成熟树突细胞(DC)对白血病小鼠异基因骨髓移植(allo-BMT)后移植物抗宿主病(GVHD)和移植物抗白血病(GVL)效应的影响及其机制.方法 以BALB/c(H-2d)小鼠为供鼠,C57 BL/6( H-2b)小鼠为受鼠,建立小鼠T细胞白血病BMT模型.受鼠全身照射(TBI)后4h内,将供鼠骨髓细胞和脾细胞按1:1混合,经尾静脉输注于受鼠体内,同时输注T细胞白血病/淋巴瘤细胞株EL4细胞.实验分组:①A组:单纯照射组;②B组:白血病发病组;③C组:allo-BMT组(移植物未做任何处理);④D组:pXZ9-DC组(未经修饰的未成熟DC组);⑤E组:sTNFR Ⅰ -DC组(sTNFR Ⅰ修饰的未成熟DC组).观察移植小鼠GVHD典型症状、病理分级、白血病细胞浸润情况、存活时间、生存率等,采用ELISA法测定IFN-y和IL-4浓度,采用流式细胞术( FCM)检测异基因嵌合率.结果①A组小鼠均于10 d内死于骨髓衰竭.B组小鼠均死于淋巴瘤/白血病.C组小鼠出现明显急性GVHD表现,而D组和E组小鼠只有部分出现GVHD表现,且GVHD评分及病理表现均较C组明显减低或减轻(P值均＜0.05),其中E组小鼠GVHD评分较C和D组均降低(P值均＜ 0.05),病理学改变最轻.C、D和E组小鼠存活时间分别为(11.50±3.50)、(21.70 ±5.80)和(25.80±5.20)d,D、E组小鼠存活时间均较C组明显延长(P值均＜0.05),其中E组小鼠平均存活时间最长.B组小鼠18 d内均死于白血病,C、D和E组小鼠白血病的发病率分别为10％、20％、10％,各组发病率比较差异无统计学意义(P＞0.05).②移植后C、D和E组小鼠血清IFN-y浓度在+12 d时达高峰,后逐渐下降,+18 d时IFN-(y)的浓度E组较C和D组降低(P＜0.05),D组较C组低(P＜0.05).C组小鼠血清IL-4降低,而D和E组浓度渐升高,+12 d达高峰,三组间两两比较差异均有统计学意义(P值均＜0.05).③+30
d,C、D和E组存活受鼠骨髓异基因嵌合率为95％ ～ 100％,证实为完全供鼠型植入.结论 未成熟DC可诱导allo-BMT免疫耐受,输注sTNFR Ⅰ基因修饰的未成熟DC可延长移植小鼠的存活时间,在一定程度上减轻GVHD的同时又保留GVL效应.
【总页数】6页(88-93)
【关键词】树突细胞;肿瘤坏死因子受体,可溶性;移植物抗白血病效应;移植物抗宿主病
【作者】王淑华;李德鹏;张艳君;张璞;曾令宇;潘秀英;徐开林;黄一虹
【作者单位】济宁医学院附属医院血液科,272029;221002 徐州医学院附属医院血液科;徐州市市级机关医院;221002 徐州医学院附属医院血液科;221002 徐州医学院附属医院血液科;221002 徐州医学院附属医院血液科;221002 徐州医学院附属医院血液科;221002 徐州医学院附属医院血液科 【正文语种】中文 【中图分类】 【文献来源】
https://www.zhangqiaokeyan.com/academic-journal-cn_chinese-journal-hematology_thesis/0201232755954.html 【相关文献】
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sTNFR Ⅰ基因修饰的未成熟树突细胞对异基因骨髓移植小鼠移植物抗宿
