本文選題：異基因造血干細(xì)胞移植 + 急性移植物抗宿主病��； 參考：《中國人民解放軍軍醫(yī)進(jìn)修學(xué)院》2008年博士論文

【摘要】： 研究目的急性移植物抗宿主病(aGVHD)是異基因造血干細(xì)胞移植(allo-HSCT)后的主要并發(fā)癥,效應(yīng)細(xì)胞遷移到靶組織是發(fā)生aGVHD的必需環(huán)節(jié)。多種趨化因子受體、整合素β7、選擇素L、粘附分子CD11a/CD54與1磷酸鞘氨醇受體1(S1P1)可能在其中發(fā)揮作用。本研究的目的在于探索T細(xì)胞遷移在aGVHD中的作用機(jī)制,為臨床尋找具有早期預(yù)警、動態(tài)監(jiān)測及指導(dǎo)治療aGVHD的指標(biāo)提供實(shí)驗(yàn)依據(jù),為尋找治療aGVHD的新方法提供實(shí)驗(yàn)基礎(chǔ)。 研究方法本研究以allo-HSCT后受者造血重建后100天內(nèi)不同時(shí)期的血細(xì)胞為研究對象,通過流式細(xì)胞術(shù)監(jiān)測外周血淋巴細(xì)胞CCR7、CD45RA、CCR4、CCR9、CXCR3、CCR5及整合素β7、CD25、選擇素L、粘附分子CD11a/CD54的抗原表達(dá)情況,計(jì)算各指標(biāo)百分比及絕對值。以磁分選方法純化CD4~+T淋巴細(xì)胞,以實(shí)時(shí)定量PCR的方法檢測CD4純化細(xì)胞中S1P_1及整合素β7的mRNA表達(dá)水平。收集臨床資料,根據(jù)臨床診斷分為aGVHD及無aGVHD組,根據(jù)aGVHD發(fā)生部位分為單純皮膚組、單純腸道組、單純肝臟組、混合部位組,根據(jù)腹瀉原因分為腸道GVHD組、炎性腹瀉受者組及炎性腹瀉志愿者組,進(jìn)行統(tǒng)計(jì)學(xué)分析。 研究結(jié)果①aGVHD組較無aGVHD組Tna(?)ve、T_(CM)百分比及絕對值升高,T_(EM)、T_(TD)百分比及絕對值下降,CCR7表達(dá)百分比及絕對值上調(diào),CD8~+細(xì)胞中CD8~+CCR7~+表達(dá)量明顯上升。兩組間T細(xì)胞、NK細(xì)胞、B細(xì)胞、CD45RA及CD4~+CCR7~+/CD4~+百分比及絕對值無顯著性差異。 ②aGVHD組較無aGVHD組間CCR4及其在CD4~+與CD8~+細(xì)胞中的表達(dá)百分比及絕對值、CCR9百分比、CCR5百分比及絕對值、CCR5在CD4~+細(xì)胞及CD8~+細(xì)胞中的表達(dá)百分比均顯著上升。aGVHD組與無aGVHD組間CXCR3百分比及絕對值均無統(tǒng)計(jì)學(xué)差異。 ③aGVHD組較無aGVHD組間整合素β7及其在CD4~+與CD8~+細(xì)胞中的表達(dá)百分比及絕對值均顯著上升,且具有部位特異性,肝臟、腸道部位GVHD者較單純皮膚GVHD明顯升高。腸道GVHD組與炎性腹瀉受者組組間整合素β7表達(dá)百分比及絕對值及其在CD4~+與CD8~+細(xì)胞中的表達(dá)百分比均具有顯著性差異,腸道GVHD組＞炎性腹瀉志愿者組＞炎性腹瀉受者組。 ④aGVHD組較無aGVHD組間CD25及CD4~+CD25~+調(diào)節(jié)性T細(xì)胞百分比及絕對值均顯著上升。腸道GVHD組與炎性腹瀉受者組組間CD25百分比及絕對值、CD4~+ CD25~+調(diào)節(jié)性T細(xì)胞百分比、CD54百分比及其在CD8+細(xì)胞中的表達(dá)百分比絕對值顯著升高。兩組間CD11a及CD62L表達(dá)百分比及絕對值無統(tǒng)計(jì)學(xué)差異。 ⑤aGVHD組較無aGVHD組間S1P_1及整合素β7的mRNA表達(dá)顯著性上調(diào)。 結(jié)論allo-HSCT后aGVHD發(fā)生過程中T細(xì)胞中表達(dá)的CCR7、CCR4、CCR9、CCR5、整合素β7、CD25、CD54及S1P_1均明顯上調(diào)。以上信號途徑可能成為預(yù)防和治療aGVHD的新靶點(diǎn)。
[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.
【學(xué)位授予單位】：中國人民解放軍軍醫(yī)進(jìn)修學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2008
【分類號】：R392

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