异基因造血干细胞移植后急性移植物抗宿主病过程中T细胞趋化和迁移相关指标的表达研究

发布时间：2018-07-03 19:36

  本文选题：异基因造血干细胞移植 + 急性移植物抗宿主病　； 参考：《中国人民解放军军医进修学院》2008年博士论文

【摘要】： 研究目的急性移植物抗宿主病(aGVHD)是异基因造血干细胞移植(allo-HSCT)后的主要并发症,效应细胞迁移到靶组织是发生aGVHD的必需环节。多种趋化因子受体、整合素β7、选择素L、粘附分子CD11a/CD54与1磷酸鞘氨醇受体1(S1P1)可能在其中发挥作用。本研究的目的在于探索T细胞迁移在aGVHD中的作用机制,为临床寻找具有早期预警、动态监测及指导治疗aGVHD的指标提供实验依据,为寻找治疗aGVHD的新方法提供实验基础。 研究方法本研究以allo-HSCT后受者造血重建后100天内不同时期的血细胞为研究对象,通过流式细胞术监测外周血淋巴细胞CCR7、CD45RA、CCR4、CCR9、CXCR3、CCR5及整合素β7、CD25、选择素L、粘附分子CD11a/CD54的抗原表达情况,计算各指标百分比及绝对值。以磁分选方法纯化CD4~+T淋巴细胞,以实时定量PCR的方法检测CD4纯化细胞中S1P_1及整合素β7的mRNA表达水平。收集临床资料,根据临床诊断分为aGVHD及无aGVHD组,根据aGVHD发生部位分为单纯皮肤组、单纯肠道组、单纯肝脏组、混合部位组,根据腹泻原因分为肠道GVHD组、炎性腹泻受者组及炎性腹泻志愿者组,进行统计学分析。 研究结果①aGVHD组较无aGVHD组Tna(?)ve、T_(CM)百分比及绝对值升高,T_(EM)、T_(TD)百分比及绝对值下降,CCR7表达百分比及绝对值上调,CD8~+细胞中CD8~+CCR7~+表达量明显上升。两组间T细胞、NK细胞、B细胞、CD45RA及CD4~+CCR7~+/CD4~+百分比及绝对值无显著性差异。 ②aGVHD组较无aGVHD组间CCR4及其在CD4~+与CD8~+细胞中的表达百分比及绝对值、CCR9百分比、CCR5百分比及绝对值、CCR5在CD4~+细胞及CD8~+细胞中的表达百分比均显著上升。aGVHD组与无aGVHD组间CXCR3百分比及绝对值均无统计学差异。 ③aGVHD组较无aGVHD组间整合素β7及其在CD4~+与CD8~+细胞中的表达百分比及绝对值均显著上升,且具有部位特异性,肝脏、肠道部位GVHD者较单纯皮肤GVHD明显升高。肠道GVHD组与炎性腹泻受者组组间整合素β7表达百分比及绝对值及其在CD4~+与CD8~+细胞中的表达百分比均具有显著性差异,肠道GVHD组＞炎性腹泻志愿者组＞炎性腹泻受者组。 ④aGVHD组较无aGVHD组间CD25及CD4~+CD25~+调节性T细胞百分比及绝对值均显著上升。肠道GVHD组与炎性腹泻受者组组间CD25百分比及绝对值、CD4~+ CD25~+调节性T细胞百分比、CD54百分比及其在CD8+细胞中的表达百分比绝对值显著升高。两组间CD11a及CD62L表达百分比及绝对值无统计学差异。 ⑤aGVHD组较无aGVHD组间S1P_1及整合素β7的mRNA表达显著性上调。 结论allo-HSCT后aGVHD发生过程中T细胞中表达的CCR7、CCR4、CCR9、CCR5、整合素β7、CD25、CD54及S1P_1均明显上调。以上信号途径可能成为预防和治疗aGVHD的新靶点。
[Abstract]:Objective Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several chemokine receptors, integrin 尾 7, selectin L, adhesion molecule CD11a / CD54 and sphingosine 1 phosphate receptor 1 (S1P1) may play a role. The purpose of this study was to explore the mechanism of T cell migration in aGVHD, to provide experimental basis for early warning, dynamic monitoring and guiding treatment of aGVHD, and to provide experimental basis for finding a new treatment method for aGVHD. Methods in this study, the blood cells of recipients at different stages after hematopoietic reconstitution after allo-HSCT were studied. The expression of CD45RAR4, CCR9CXCR3CCR5, CD25, selectin Land CD11a / CD54 in peripheral blood lymphocytes were detected by flow cytometry (FCM), and the expression of CD11a / CD54 in peripheral blood lymphocytes was detected by flow cytometry (FCM), and the expression of CXCR3CCR5, selectin and adhesion molecule CD11a / CD54 in peripheral blood lymphocytes were detected by flow cytometry. Calculate the percentage and absolute value of each index. CD4T lymphocytes were purified by magnetic separation and the mRNA expressions of S1Pst1 and integrin 尾 7 in CD4 purified cells were detected by real-time quantitative PCR. Clinical data were collected and divided into aGVHD group and non-aGVHD group according to clinical diagnosis. According to the location of aGVHD, it was divided into simple skin group, simple intestinal group, simple liver group, mixed site group, and intestinal GVHD group according to the causes of diarrhea. The patients with inflammatory diarrhea and the volunteers with inflammatory diarrhea were analyzed statistically. Results 1 the percentage and absolute value of Tna (?) TCM in aGVHD group were higher than those in aGVHD group. There was no significant difference in the percentage and absolute value of CD45RA and CD4 ~ CCR7- / CD4-. 2the percentage of CCR4 and its expression in CD4- and CD8- cells in the aGVHD group was higher than that in the non-aGVHD group and the absolute CCR9 percentage was CCR5. The percentage and absolute value of CCR5 in CD4 ~ cells and CD8 ~ cells increased significantly. There was no significant difference in the percentage and absolute value of CXCR3 between aGVHD group and non-aGVHD group. The percentage and absolute value of its expression in CD4 ~ and CD8 ~ cells increased significantly. GVHD in liver and intestine was significantly higher than that in skin. There were significant differences in the percentage and absolute value of integrin 尾 7 expression between the GVHD group and the inflammatory diarrhea recipient group, as well as the percentage of integrin 尾 7 expression in CD4 ~ and CD8 ~ cells. The percentage and absolute value of CD25 and CD4 ~ CD25 ~ regulatory T cells in GVHD group were significantly higher than those in non-aGVHD group. The percentage of CD25 and the absolute value of CD4 ~ CD25 ~ regulatory T cell in GVHD group and the recipient group of inflammatory diarrhea were significantly increased. The percentage of CD54 and its expression in CD8 cells were significantly increased. There was no significant difference in the percentage and absolute value of CD11a and CD62L expression between the two groups, and the mRNA expression of S1P1 and integrin 尾 7 was significantly up-regulated in 5aGVHD group than in the non-aGVHD group. Conclusion CCR7 + CCR4 + CCR9 + CCR5, integrin 尾 7 + CD25 + CD54 and S1P- 1 are up-regulated during aGVHD after allo-HSCT. These signaling pathways may be a new target for the prevention and treatment of aGVHD.
【学位授予单位】：中国人民解放军军医进修学院
【学位级别】：博士
【学位授予年份】：2008
【分类号】：R392

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