Th17细胞在移植物抗宿主病中的作用和基因工程Th17细胞的制备及鉴定
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摘要
本论文分为两个部分。第一部分主要探讨Th17细胞及白细胞介素-17（IL-17）与小鼠异基因造血干细胞移植后移植物抗宿主病（GVHD）之间的关系；第二部分则探索了一种基于基因工程技术制备和分选Th17细胞的新方法。
Th17细胞是近年提出的一个辅助性T细胞新亚群，主要通过分泌IL-17等细胞因子发挥功能，与抗感染免疫和自身免疫病发生密切相关。然而，Th17细胞与GVHD的关系至今仍有很大争论。在第一部分研究中，我们首先通过输注不同的脾细胞量建立了重度和轻-中度GVHD小鼠模型，发现外周血Th17细胞的比率和IL-17水平与GVHD严重程度成负相关关系。我们进一步细化了allo-HSCT后CD4+T细胞亚群失衡与不同靶脏器损伤的相关性，发现Th1细胞与肝脏损伤相关，Th17细胞与肺损伤相关，Th1/Th17细胞比率与小肠损伤相关。为了进一步验证Th17细胞与GVHD相关肺损伤的关系，我们使用了肺特异性高表达IL-17的转基因小鼠作为受鼠建立GVHD模型，不仅证实IL-17是GVHD相关肺损伤的促进因素，而且发现IL-17系通过促进肺组织表达趋化因子增加炎症细胞招募和促进Th1细胞分化加重GVHD相关肺损伤，初步阐明了其作用机制。
Th17细胞由于含量很低且无膜表面特异性标志或标记组合，又由于其发育调控的复杂性导致体外诱导产率不高而难以制备和纯化。在第二部分研究中，我们尝试将过表达Th17细胞发育的主要正调控因子RORγt与TGF-β+IL-6细胞因子体外处理联合起来，使naive CD4+T细胞获得了更高的Th17细胞得率。此外，我们在载体上负载了IL-17启动子驱动的截短型人神经生长因子受体（ΔNGFR）报告基因，通过分选ΔNGFR+细胞纯化了制备的基因工程Th17细胞。表型和功能鉴定表明，过表达RORγt联合TGF-β+IL-6细胞因子体外处理制备的Th17细胞较单纯过表达RORγt制备的Th17细胞更接近天然的Th17细胞，可为Th17细胞功能的研究提供有效的工具。
This research paper contains two independent parts. Part one was focused on therelationship between interleukin-17/Th17cells and Graft-vs-Host disease (GVHD) ina mouse allogenetic hematopoietic stem cell transplantation (allo-HSCT) model; andin part two, a novel method was explored to generate and purify genetic engineeredTh17cells.
Th17cell is a newly identified CD4+T help cell subset, which secretspreinflammatory cytokines such as IL-17, and plays a crucial role in autoimmunediseases and host defence against microbial pathogens. However, the function ofTh17cell in GVHD is still controversial. In researchs belong part one, we establishedsever and mild to moderate mouse GVHD model via different dose of splenocytesinfusion. We found that the ratio of Th17cell and the concentration of IL-17inperipheral blood is negative correlation to the severity of GVHD. We further exploredthe relationship between CD4+T cell subsets imbalance and organ specific GVHD.We found Th1subset was positive correlated to liver GVHD, Th17subset waspositive correlated to lung GVHD, and Th1/Th17ratio is positive correlated to smallintestine GVHD. To elucidate the relationship of Th17cell and GVHD associatedlung injury, we have used lung-specific-overexpression IL-17transgenic mouse asallo-HSCT receipts. Using this model, we have approved that IL-17is contributed toGVHD associated lung injury after allo-HSCT. Besides, we identified the mechanismis IL-17can recruit inflammatory cell by up-regulating the transcription of many chemokins and can promote Th1cell differentiation in lung tissue.
Currently, efficient production and purification of Th17cells remains extremelydifficult. There are several reasons for this difficulty:(1) Th17cells is a rare cellpopulation,(2) no specific cell surface marker or panel of surface markers have beenidentified to enable Th17cell isolation and (3) complexity of Th17development. Inpart two, we introduced a novel method to obtain highly-purified genetic engineeredTh17cells. We have combined over-expression of RORγt to TGF-β and IL-6treatment to get superior Th17production efficiency. Besides, we embedded IL-17promoter-derived truncated human nerve growth factor receptor (ΔNGFR) gene as atag to detect IL-17transcription and to sort Th17cells. We have approved that thesegenetic engineered Th17cells produced by over-expression of RORγt plus TGF-β andIL-6treatment was more similar to natural occurred Th17cells as compare to geneticengineered Th17which produced by over-expression of RORγt alone. This techniquemay provide a useful toll to explore the function of Th17cells.
Th17细胞是近年提出的一个辅助性T细胞新亚群，主要通过分泌IL-17等细胞因子发挥功能，与抗感染免疫和自身免疫病发生密切相关。然而，Th17细胞与GVHD的关系至今仍有很大争论。在第一部分研究中，我们首先通过输注不同的脾细胞量建立了重度和轻-中度GVHD小鼠模型，发现外周血Th17细胞的比率和IL-17水平与GVHD严重程度成负相关关系。我们进一步细化了allo-HSCT后CD4+T细胞亚群失衡与不同靶脏器损伤的相关性，发现Th1细胞与肝脏损伤相关，Th17细胞与肺损伤相关，Th1/Th17细胞比率与小肠损伤相关。为了进一步验证Th17细胞与GVHD相关肺损伤的关系，我们使用了肺特异性高表达IL-17的转基因小鼠作为受鼠建立GVHD模型，不仅证实IL-17是GVHD相关肺损伤的促进因素，而且发现IL-17系通过促进肺组织表达趋化因子增加炎症细胞招募和促进Th1细胞分化加重GVHD相关肺损伤，初步阐明了其作用机制。
Th17细胞由于含量很低且无膜表面特异性标志或标记组合，又由于其发育调控的复杂性导致体外诱导产率不高而难以制备和纯化。在第二部分研究中，我们尝试将过表达Th17细胞发育的主要正调控因子RORγt与TGF-β+IL-6细胞因子体外处理联合起来，使naive CD4+T细胞获得了更高的Th17细胞得率。此外，我们在载体上负载了IL-17启动子驱动的截短型人神经生长因子受体（ΔNGFR）报告基因，通过分选ΔNGFR+细胞纯化了制备的基因工程Th17细胞。表型和功能鉴定表明，过表达RORγt联合TGF-β+IL-6细胞因子体外处理制备的Th17细胞较单纯过表达RORγt制备的Th17细胞更接近天然的Th17细胞，可为Th17细胞功能的研究提供有效的工具。
This research paper contains two independent parts. Part one was focused on therelationship between interleukin-17/Th17cells and Graft-vs-Host disease (GVHD) ina mouse allogenetic hematopoietic stem cell transplantation (allo-HSCT) model; andin part two, a novel method was explored to generate and purify genetic engineeredTh17cells.
Th17cell is a newly identified CD4+T help cell subset, which secretspreinflammatory cytokines such as IL-17, and plays a crucial role in autoimmunediseases and host defence against microbial pathogens. However, the function ofTh17cell in GVHD is still controversial. In researchs belong part one, we establishedsever and mild to moderate mouse GVHD model via different dose of splenocytesinfusion. We found that the ratio of Th17cell and the concentration of IL-17inperipheral blood is negative correlation to the severity of GVHD. We further exploredthe relationship between CD4+T cell subsets imbalance and organ specific GVHD.We found Th1subset was positive correlated to liver GVHD, Th17subset waspositive correlated to lung GVHD, and Th1/Th17ratio is positive correlated to smallintestine GVHD. To elucidate the relationship of Th17cell and GVHD associatedlung injury, we have used lung-specific-overexpression IL-17transgenic mouse asallo-HSCT receipts. Using this model, we have approved that IL-17is contributed toGVHD associated lung injury after allo-HSCT. Besides, we identified the mechanismis IL-17can recruit inflammatory cell by up-regulating the transcription of many chemokins and can promote Th1cell differentiation in lung tissue.
Currently, efficient production and purification of Th17cells remains extremelydifficult. There are several reasons for this difficulty:(1) Th17cells is a rare cellpopulation,(2) no specific cell surface marker or panel of surface markers have beenidentified to enable Th17cell isolation and (3) complexity of Th17development. Inpart two, we introduced a novel method to obtain highly-purified genetic engineeredTh17cells. We have combined over-expression of RORγt to TGF-β and IL-6treatment to get superior Th17production efficiency. Besides, we embedded IL-17promoter-derived truncated human nerve growth factor receptor (ΔNGFR) gene as atag to detect IL-17transcription and to sort Th17cells. We have approved that thesegenetic engineered Th17cells produced by over-expression of RORγt plus TGF-β andIL-6treatment was more similar to natural occurred Th17cells as compare to geneticengineered Th17which produced by over-expression of RORγt alone. This techniquemay provide a useful toll to explore the function of Th17cells.
引文
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