FTY720对CD4~+记忆T细胞介导的移植物排斥反应的抑制作用的研究
摘要
目的探讨建立小鼠腹部异位心脏移植模型的手术方法及技术改进。
方法实验分为2组：同系移植组,供、受体均为C57BL/6小鼠；同种异基因移植组,供体为C3H小鼠,受体为C57BL/6小鼠；每组各50对小鼠。采用供心主动脉与受体腹主动脉、供心肺动脉与受体下腔静脉端侧吻合的方法,对小鼠进行腹部心脏移植术,术后记录两组小鼠供心的存活时间,观察供心的组织学改变。结果2组小鼠行腹部心脏移植手术共100对,存活91对,建模成功率为91%。同种异基因移植组供心平均存活时间为(7.7±0.8)d；而在同系移植组中,除2只小鼠在术后第7天因出现暖风机意外死亡之外,其余受体小鼠的供心在移植后第40天(观察终点)均存活,两组之间有显著性差异(P＜0.01)。结论利用小鼠腹部异位心脏移植的手术方法可建立稳定可靠的心脏移植模型,适用于移植免疫学方面的研究。
目的研究同种反应性CD4+记忆T细胞(Tmm)的免疫磁珠分离方法,以及检测其表型及功能。方法利用小鼠皮肤移植模型,通过免疫磁珠技术分离同种反应性CD4+Tm,应用台盼蓝染色法和流式细胞技术检测细胞活性、纯度和鉴定表型,并在体外借助ELISPOT检测CD4+Tm在不同抗原刺激时IFN-γ的分泌频数。结果上述方法分离所得的活细胞百分率为(98.9±0.3)%,其中CD4+CD44+CD62L-CCR7-细胞的比例约为95%,符合CD4+Tm的表型特征,且经检测其IFN-γ的分泌具有良好的供体特异性。结论通过小鼠皮肤移植模型和免疫磁珠分离技术,制备高纯度的CD4+Tm,同时使其细胞活力不受影响,并具有良好的供体特异性,可作为稳定可靠的分离Tm的方法,为深入研究其在移植免疫方面的作用奠定了基础。
目的探讨小剂量FTY720对CD4+记忆T细胞介导的小鼠心脏移植物排斥反应的影响,并探讨其机制。方法通过皮肤移植模型和免疫磁珠技术分离同种反应性CD4+记忆T细胞(Tm),经尾静脉过继性输入,借助小鼠腹部异位心脏移植模型,研究小剂量FTY720对CD4+Tm介导的同种异体移植物的存活时间、移植物组织病理学、Th细胞因子分泌等的影响。用免疫荧光技术检测移植心脏中CD4+T淋巴细胞的浸润情况,以及颗粒酶B和FasL的表达情况。实验分为4组：A.同种异基因移植组,即阳性对照组；B.阴性对照组,利用RAGl-／-小鼠(体内无成熟的T、B淋巴细胞)作为移植受体；C.Tm组,RAG1-/-小鼠在移植前1天经尾静脉过继性输入CD4+Tm;D.FTY720处理组,RAG1-/-小鼠在移植前4天开始FTY720灌胃0.3mg／kg/d,术前1天经尾静脉过继性输入CD4+Tm。结果在同种异基因抗原的刺激下,CFSE标记的CD4+Tm在体内出现明显的增殖。与未输注Tm的阴性对照组相比,Tm组移植物的平均存活时间明显缩短；心肌的中环层有较多CD4+T淋巴细胞浸润：仅冠脉周围有少量颗粒酶B表达；但有大量的FasL阳性细胞浸润,主要分布于心外膜及心内膜下,尤以血管周围较为明显。各组之间的差异有显著性(P<0.01)。FTY720组供心的存活时间比Tm组延长,移植物内未见明显CD4+T淋巴细胞浸润,以及颗粒酶B和FasL的表达,同时显著抑制了IFN-γ、IL-2、IL-4、IL-10细胞因子的分泌(P<0.01)。结论同种反应性CD4+Tm能直接浸润至移植物,缩短其存活时间,在此过程中可能以FasL-Fas为代表的非分泌性杀伤性途径发挥了主要作用；同时使Th1和Th2类细胞因子都明显上调,介导同种异体排斥反应的发生。持续小剂量应用FTY720后,可以明显减少移植物内CD4+T淋巴细胞的浸润,同时抑制Th细胞因子的分泌,减弱其对Tm的趋化作用,从而抑制了排斥反应的发生,使移植物存活时间延长。FTY720的免疫抑制作用可能还与诱导Treg的生成有关。
Objective To build the animal model of murine ventral heterotopic cardiac transplantation and explore the improved technique.
Methods All abdominal heterotopic heart transplantation models were divided into tow groups as follows, allograft group and isograft group. The donor heart aorta and the recipient ventral aorta, as well as the donor pulmonary artery and the recipient inferior caval vein, were anastomosed by using the end-to-side suture technique respectively. In each group, mean survival times (MST) of transplanted hearts and their pathologic histological changes at respective rejection point or observation termination were analyzed.
Results The succeeding rate was 91%(91/100). All heart allografts in isograft group survive more than 40d, except for 2 cases (7d), significantly longer than group A, in which the MST of allograft group is (7.7±0.8)d, P<0.05. At postoperative 7th day, the lymphocyte significantly increased in allograft group, with obvious necrosis changes, and the pathologic histological change was Grade 3R. At postoperative 28th day, transplanted hearts in isograft group were hardly damaged with a Grade OR pathologic histological change, and there was no lymphocytes infiltrated.
Conclusions The method to build the murine ventral heterotopic cardiac transplantation model is stable and reliable, so it can be used for the study of transplantation immunity.
Objective To explore the role of the activity, purity and the alloreactivity of the CD4+ memory T isolated from skin grafts.
Methods With use of the mouse skin transplantation model, the CD4+Tm were isolated by magnetic activated cell sorting (MACS). The activity, purity and the alloreactivity of the CD4+Tm cells were detected.
Results The activity of the CD4+Tm cells was (98.9±0.3)%, and the proportion of CD4+CD44+CD62L-CCR7- lymphocytes was approximately 95%. The IFN-γsecreted by CD4+Tm cells was detected by ELISPOT, and its function was donor specific.
Conclusions Magnetic activated cell sorting isolation kit could used to isolate CD4+Tm lymphocytes from skin allografts effectively. The CD4+Tm was detected with good activity and high purity, as well as the alloreactivity. The isolate CD4+Tm lymphocytes could used to do other research in transplantation immunity.
Objective To explore the role of alloreactive CD4+memory T cells in survival of allografts and the mechanisms of survival prolongation of FTY720 in the CD4+memory T cells mediated allograft rejection.
Methods With use of the mouse skin transplantation model, the CD4+Tm were isolated by magnetic activated cell sorting (MACS) from recipients. And then these cells were transferred into RAG-/-recipients to explore that how CD4+Tm influenced the survival of allografts and the role of FTY720 on CD4+Tm in allografts.
Results The fluorescence intensity of alloreactive CD4+Tm cells labeled with CFSE fell off gradually after transferred into recipents via tail vein injection 1 day before operation. The mean survival time (MST) of allografts in Tm group was shorter than negative group (no transferred Tm) and FTY720 treatment group (a dose of 0.3 mg/kg/d was started on day 4 before surgery and administered throughout the duration of the experiment). There were more CD4+lymphocytes and FasL+lymphocytes infiltrating into the allografts in Tm group compared with negative group and FTY720 treatment group. And the CD4+were mainly in the middle layer especially, the FasL+infiltrated near epicardium, endocardium and around the vessels. The expression level of granzyme B in allografts was much lower in Tm group than positive group. And the secretion of Th1 and Th2 cytokines was down regulated in FTY720 treatment group than Tm group.
Conclusions The alloreactive CD4+Tm from skin allograft could mediate allograft rejection and shorten the survival time of allografts, the main mechanism of which might contain the FasL-Fas non-secreting pathway. And the transplantation rejection could be suppressed by use of low-dose FTY720.
方法实验分为2组：同系移植组,供、受体均为C57BL/6小鼠；同种异基因移植组,供体为C3H小鼠,受体为C57BL/6小鼠；每组各50对小鼠。采用供心主动脉与受体腹主动脉、供心肺动脉与受体下腔静脉端侧吻合的方法,对小鼠进行腹部心脏移植术,术后记录两组小鼠供心的存活时间,观察供心的组织学改变。结果2组小鼠行腹部心脏移植手术共100对,存活91对,建模成功率为91%。同种异基因移植组供心平均存活时间为(7.7±0.8)d；而在同系移植组中,除2只小鼠在术后第7天因出现暖风机意外死亡之外,其余受体小鼠的供心在移植后第40天(观察终点)均存活,两组之间有显著性差异(P＜0.01)。结论利用小鼠腹部异位心脏移植的手术方法可建立稳定可靠的心脏移植模型,适用于移植免疫学方面的研究。
目的研究同种反应性CD4+记忆T细胞(Tmm)的免疫磁珠分离方法,以及检测其表型及功能。方法利用小鼠皮肤移植模型,通过免疫磁珠技术分离同种反应性CD4+Tm,应用台盼蓝染色法和流式细胞技术检测细胞活性、纯度和鉴定表型,并在体外借助ELISPOT检测CD4+Tm在不同抗原刺激时IFN-γ的分泌频数。结果上述方法分离所得的活细胞百分率为(98.9±0.3)%,其中CD4+CD44+CD62L-CCR7-细胞的比例约为95%,符合CD4+Tm的表型特征,且经检测其IFN-γ的分泌具有良好的供体特异性。结论通过小鼠皮肤移植模型和免疫磁珠分离技术,制备高纯度的CD4+Tm,同时使其细胞活力不受影响,并具有良好的供体特异性,可作为稳定可靠的分离Tm的方法,为深入研究其在移植免疫方面的作用奠定了基础。
目的探讨小剂量FTY720对CD4+记忆T细胞介导的小鼠心脏移植物排斥反应的影响,并探讨其机制。方法通过皮肤移植模型和免疫磁珠技术分离同种反应性CD4+记忆T细胞(Tm),经尾静脉过继性输入,借助小鼠腹部异位心脏移植模型,研究小剂量FTY720对CD4+Tm介导的同种异体移植物的存活时间、移植物组织病理学、Th细胞因子分泌等的影响。用免疫荧光技术检测移植心脏中CD4+T淋巴细胞的浸润情况,以及颗粒酶B和FasL的表达情况。实验分为4组：A.同种异基因移植组,即阳性对照组；B.阴性对照组,利用RAGl-／-小鼠(体内无成熟的T、B淋巴细胞)作为移植受体；C.Tm组,RAG1-/-小鼠在移植前1天经尾静脉过继性输入CD4+Tm;D.FTY720处理组,RAG1-/-小鼠在移植前4天开始FTY720灌胃0.3mg／kg/d,术前1天经尾静脉过继性输入CD4+Tm。结果在同种异基因抗原的刺激下,CFSE标记的CD4+Tm在体内出现明显的增殖。与未输注Tm的阴性对照组相比,Tm组移植物的平均存活时间明显缩短；心肌的中环层有较多CD4+T淋巴细胞浸润：仅冠脉周围有少量颗粒酶B表达；但有大量的FasL阳性细胞浸润,主要分布于心外膜及心内膜下,尤以血管周围较为明显。各组之间的差异有显著性(P<0.01)。FTY720组供心的存活时间比Tm组延长,移植物内未见明显CD4+T淋巴细胞浸润,以及颗粒酶B和FasL的表达,同时显著抑制了IFN-γ、IL-2、IL-4、IL-10细胞因子的分泌(P<0.01)。结论同种反应性CD4+Tm能直接浸润至移植物,缩短其存活时间,在此过程中可能以FasL-Fas为代表的非分泌性杀伤性途径发挥了主要作用；同时使Th1和Th2类细胞因子都明显上调,介导同种异体排斥反应的发生。持续小剂量应用FTY720后,可以明显减少移植物内CD4+T淋巴细胞的浸润,同时抑制Th细胞因子的分泌,减弱其对Tm的趋化作用,从而抑制了排斥反应的发生,使移植物存活时间延长。FTY720的免疫抑制作用可能还与诱导Treg的生成有关。
Objective To build the animal model of murine ventral heterotopic cardiac transplantation and explore the improved technique.
Methods All abdominal heterotopic heart transplantation models were divided into tow groups as follows, allograft group and isograft group. The donor heart aorta and the recipient ventral aorta, as well as the donor pulmonary artery and the recipient inferior caval vein, were anastomosed by using the end-to-side suture technique respectively. In each group, mean survival times (MST) of transplanted hearts and their pathologic histological changes at respective rejection point or observation termination were analyzed.
Results The succeeding rate was 91%(91/100). All heart allografts in isograft group survive more than 40d, except for 2 cases (7d), significantly longer than group A, in which the MST of allograft group is (7.7±0.8)d, P<0.05. At postoperative 7th day, the lymphocyte significantly increased in allograft group, with obvious necrosis changes, and the pathologic histological change was Grade 3R. At postoperative 28th day, transplanted hearts in isograft group were hardly damaged with a Grade OR pathologic histological change, and there was no lymphocytes infiltrated.
Conclusions The method to build the murine ventral heterotopic cardiac transplantation model is stable and reliable, so it can be used for the study of transplantation immunity.
Objective To explore the role of the activity, purity and the alloreactivity of the CD4+ memory T isolated from skin grafts.
Methods With use of the mouse skin transplantation model, the CD4+Tm were isolated by magnetic activated cell sorting (MACS). The activity, purity and the alloreactivity of the CD4+Tm cells were detected.
Results The activity of the CD4+Tm cells was (98.9±0.3)%, and the proportion of CD4+CD44+CD62L-CCR7- lymphocytes was approximately 95%. The IFN-γsecreted by CD4+Tm cells was detected by ELISPOT, and its function was donor specific.
Conclusions Magnetic activated cell sorting isolation kit could used to isolate CD4+Tm lymphocytes from skin allografts effectively. The CD4+Tm was detected with good activity and high purity, as well as the alloreactivity. The isolate CD4+Tm lymphocytes could used to do other research in transplantation immunity.
Objective To explore the role of alloreactive CD4+memory T cells in survival of allografts and the mechanisms of survival prolongation of FTY720 in the CD4+memory T cells mediated allograft rejection.
Methods With use of the mouse skin transplantation model, the CD4+Tm were isolated by magnetic activated cell sorting (MACS) from recipients. And then these cells were transferred into RAG-/-recipients to explore that how CD4+Tm influenced the survival of allografts and the role of FTY720 on CD4+Tm in allografts.
Results The fluorescence intensity of alloreactive CD4+Tm cells labeled with CFSE fell off gradually after transferred into recipents via tail vein injection 1 day before operation. The mean survival time (MST) of allografts in Tm group was shorter than negative group (no transferred Tm) and FTY720 treatment group (a dose of 0.3 mg/kg/d was started on day 4 before surgery and administered throughout the duration of the experiment). There were more CD4+lymphocytes and FasL+lymphocytes infiltrating into the allografts in Tm group compared with negative group and FTY720 treatment group. And the CD4+were mainly in the middle layer especially, the FasL+infiltrated near epicardium, endocardium and around the vessels. The expression level of granzyme B in allografts was much lower in Tm group than positive group. And the secretion of Th1 and Th2 cytokines was down regulated in FTY720 treatment group than Tm group.
Conclusions The alloreactive CD4+Tm from skin allograft could mediate allograft rejection and shorten the survival time of allografts, the main mechanism of which might contain the FasL-Fas non-secreting pathway. And the transplantation rejection could be suppressed by use of low-dose FTY720.
引文
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