CTLA4Ig基因修饰的树突状细胞诱导哮喘免疫耐受的实验研究
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摘要
第一部分腺病毒转导CTLA4Ig基因修饰树突状细胞
目的：构建CTLA4Ig基因修饰的树突状细胞,观察基因转导对树突状细胞表型的影响。
方法：小鼠骨髓来源的细胞悬液,在GM-CSF和IL-4作用下,体外培养7天。光学显微镜下观察细胞生长状况和形态学变化。流式细胞仪鉴定细胞表型,确定是否为树突状细胞及其成熟度。确定为树突状细胞后,与重组腺病毒AdCTLA4Ig、AdGFP以及OVA共孵育48小时,荧光显微镜观察细胞内目的基因表达,流式细胞仪测定转染效率。
结果：1、小鼠骨髓来源的细胞培养第7天可见树突状细胞特征性的树枝状形态和细胞集落形成。2、流式检测发现64.01%的细胞为CDllc阳性的未成熟的DC；33.49%的细胞为CD1lc+CD80+细胞；14.65%的细胞为CD11c+CD86+细胞；21.53%的细胞为CD11c+MHCⅡ+细胞。3、与重组腺病毒和OVA共孵育48小时后,荧光显微镜下可观察到树突状细胞内发出绿色荧光。流式细胞仪分析检测显示AdCTLA4Ig转染率为41.29%。4、与重组腺病毒和OVA共孵育48小时后,流式细胞仪检测显示42.65%的细胞为CDl1c+CD80+细胞；22.30%的细胞为CD11c+CD86+细胞；32.46%的细胞为CD11c+MHCⅡ+细胞。
结论：成功构建了CTLA4Ig基因修饰的树突状细胞。
第二部分CTLA4Ig基因修饰的树突状细胞的体外功能研究
目的：研究CTLA4Ig基因修饰的树突状细胞在体外的功能,了解CTLA4Ig转染对树突状细胞表达细胞因子IL-10、IL-12的影响以及对刺激T细胞活化增殖功能的影响。
方法：分离和培养小鼠骨髓来源的DC。将体外培养7天的树突状细胞分成4组,一组为DC组,一组为DC+OVA组,另外两组分别加入1μ1病毒滴度为1.5×108VP/ml的AdGFP或AdCTLA4Ig和OVA。这4组细胞分别共培养48小时后,分离细胞和上清。上清用ELISA方法检测IL-10和IL-12。细胞用于和BALB/c小鼠外周血来源的T淋巴细胞进行混合淋巴细胞反应。
结果：1、CTLA4Ig基因转染树突状细胞后,促进树突状细胞分泌IL-10(P<0.05)。
2、CTLA4Ig基因转染树突状细胞后,降低树突状细胞分泌IL-12的能力(P<0.05)。
3、CTLA4Ig基因转染树突状细胞后,树突状细胞促T淋巴细胞增殖的能力下降(P<0.05)。
结论：CTLA4Ig基因转染树突状细胞高表达IL-10,低表达IL-12,促T细胞增殖的能力降低。
第三部分新生小鼠回输CTLA4Ig基因修饰的树突状细胞抑制成年期气道过敏性炎症
目的：研究将CTLA4Ig基因修饰的树突状细胞回输给新生小鼠,观察其对成年期OVA致敏／激发的小鼠气道炎症的影响,并探讨其发病机制。
方法：以OVA腹腔注射致敏小鼠并雾化吸入激发的方法制作哮喘模型。将CTLA4Ig基因修饰的树突状细胞回输给新生的BALB/c小鼠,在成年期OVA致敏／激发小鼠,观察CTLA4Ig基因修饰的树突状细胞对小鼠气道炎症的影响。同样方法设立对照组AdGFP干预组,另设立空白对照组、哮喘模型组。通过观察各组小鼠OVA激发时的表现、肺泡灌洗液(BALF)中嗜酸粒细胞比例和肺部病理切片改变了解小鼠气道炎症情况。ELISA方法测定血清及BALF的IgE、IL-4、IL-10及INF-y水平。
结果：1、OVA腹腔注射致敏小鼠并雾化吸入激发的方法能成功制作哮喘模型。2、新生小鼠给予CTLA4Ig基因修饰的树突状细胞明显减轻成年期哮喘发作的症状、减少肺泡灌洗液中嗜酸性细胞的生成和病理切片中的炎症表现。3、CTLA4Ig基因修饰的树突状细胞可以减轻成年期小鼠哮喘发作时的血清和肺泡灌洗液中IgE水平。4、CTLA4Ig基因修饰的树突状细胞可减轻成年期小鼠哮喘发作时的血清和肺泡灌洗液中IL-4水平。5、CTLA4Ig基因修饰的树突状细胞可提高成年期小鼠血清中IL-10水平。6、CTLA4Ig基因修饰的树突状细胞对成年期小鼠哮喘发作时血清和肺泡灌洗液中INF-y水平无明显影响。
结论：新生小鼠给予CTLA4Ig基因修饰的树突状细胞可在成年期时抑制OVA致敏/激发小鼠的气道炎症,使OVA致敏/激发小鼠血清IL-10水平增高,降低Th2细胞因子的分泌,对Thl细胞因子的分泌无明显影响。本研究为哮喘的预防和免疫治疗提供了新的思路。
Part I CTLA4Ig Gene Were Transducted into Dendritic Cells by Adenovirus
Objective:To construct CTLA4Ig gene modified dendritic cells.
Methods:The mouse bone marrow cells were isolated and cultured in complete medium with GM-CSF and IL-4for7days. Cell growth and morphological changes were observed under optical micro scope. The phenotype and the maturation of dendritic cells were analyzed by flow cytometry, examining the expression of CD11c, MHC Ⅱ, CD80and CD86. The cells were incubated with recombinant adenovirus (AdCTLA4Ig, AdGFP)and OVA for48hour, then target gene expression were observed under the fluorescence microscopy, transfection efficiency were determined by flow cytometry.
Results:1. Mouse bone marrow-derived cells showed characteristic dendritic morphology of dendritic cells and formed cell colony on the day7.2. The cell phenotype determined by flow cytometry showed that64.01%of cells were positive for CD11c,33.49%of the cells were positive for CD11c+CD80+cells,14.65%of the cells were positive for CD11c+CD86+cells,21.53%of the cells were positive for CD11c+MHCⅡ+cells.3. Incubated with recombinant adenovirus and OVA for48hours, green fluorescence in cells was observed under a fluorescence microscope. Flow cytometry analysis showed AdCTLA4Ig transfection rate was41.29%.4. Incubated with recombinant adenovirus and OVA for48hours,42.65%of the cells were CD11c+CD80+cells,22.30%of the cells were CD11c+CD86+cells,32.46%of the cells were CD11c+MHC Ⅱ+cells.
Conclusion:Constructing CTLA4Ig gene modified dendritic cells successfully.
Part Ⅱ The Functional Studies of CTLA4Ig Gene-modified Dendritic Cells in vitro
Objective:To study the function of CTLA4Ig gene-modified dendritic cells in vitro.
Methods:The mouse bone marrow-derived DCs were isolated and cultivated. The cultured dendritic cells for7days were divided into four groups:DC group, DC+OVA group, the other two groups were added1μl(1.5×108VP/ml) AdGFP or AdCTLA4Ig and OVA. All groups were cultured for48hours, then supernatant and cells were separated. The levels of IL-10and IL-12in supernatant were measured by ELISA. Cells were used to perform mixed lymphocyte reaction with peripheral blood T-lymphocytes of BALB/c mice.
Results:1. CTLA4Ig gene transfected in dendritic cells promoted IL-10secretion (P<0.05).2. CTLA4Ig gene transfected in dendritic cells, reduced IL-12secretion (P<0.05).3. CTLA4Ig gene transfected in dendritic cells decreased the dendritic cells'ability to promote T lymphocyte proliferation (P<0.05).
Conclusion:CTLA4Ig gene modified dendritic cells can promote the expression of IL-10, reduce the expression of IL-12and supress T cell proliferation.
Part III CTLA4Ig Gene-modified Dendritic Cells Transfused To Mice In Neonatal Period Suppress Adult Airway Allergic Inflammation
Objective:To study the impact of CTLA4Ig gene-modified dendritic cells transfused to mice in neonatal period on the airway inflammation of adult OVA-sensitized/challenged mice, and to explore its pathogenesis.
Methods:Use OVA-sensitized/challenged mice by intraperitoneal injection and inhalation methods to establish asthma model. The CTLA4Ig gene-modified dendritic cells were given to the newborn BALB/c mice, OVA-sensitized/challenged the mice in the adulthood. Establish the AdGFP intervention group with the same method. In addition, establish the control group and asthma model group. The manifestation of OVA challenged mice in each group, BALF eosinophils and lung pathological changes were observed to study the impact of CTLA4Ig gene-modified dendritic cells on airway inflammation. The level of IgE, IL-4, IL-10and INF-γ were detected by ELISA methods.
Results:1. Asthma model were established successfully by OVA-sensitized/challenged mice.2. CTLA4Ig gene-modified dendritic cells given in neonatal period significantly improved the symptoms of asthma in adulthood, reduced eosinophils in BALF and improved the airway inflammation in biopsy.3. CTLA4Ig gene-modified dendritic cells reduced IgE levels in serum and BALF during the onset of adulthood asthma.4. CTLA4Ig gene-modified dendritic cells reduced IL-4level in serum and BALF during the onset of adulthood asthma.5. CTLA4Ig gene-modified dendritic cells increased IL-10level in serum during the onset of adulthood asthma.6. CTLA4Ig gene-modified dendritic cells had no impact on level of INF-y in serum and BALF during the onset of adulthood asthma.
Conclusion:CTLA4Ig gene-modified dendritic cells given in neonatal period suppress the airway inflammation of OVA-sensitized/challenged mice in adulthood, elevate the serum levels of IL-10, reduce the secretion of Th2cytokines, has no impact on the secretion of Thl cytokines. In conclusion, this study provides a new idea to prevent and contol asthma.
目的：构建CTLA4Ig基因修饰的树突状细胞,观察基因转导对树突状细胞表型的影响。
方法：小鼠骨髓来源的细胞悬液,在GM-CSF和IL-4作用下,体外培养7天。光学显微镜下观察细胞生长状况和形态学变化。流式细胞仪鉴定细胞表型,确定是否为树突状细胞及其成熟度。确定为树突状细胞后,与重组腺病毒AdCTLA4Ig、AdGFP以及OVA共孵育48小时,荧光显微镜观察细胞内目的基因表达,流式细胞仪测定转染效率。
结果：1、小鼠骨髓来源的细胞培养第7天可见树突状细胞特征性的树枝状形态和细胞集落形成。2、流式检测发现64.01%的细胞为CDllc阳性的未成熟的DC；33.49%的细胞为CD1lc+CD80+细胞；14.65%的细胞为CD11c+CD86+细胞；21.53%的细胞为CD11c+MHCⅡ+细胞。3、与重组腺病毒和OVA共孵育48小时后,荧光显微镜下可观察到树突状细胞内发出绿色荧光。流式细胞仪分析检测显示AdCTLA4Ig转染率为41.29%。4、与重组腺病毒和OVA共孵育48小时后,流式细胞仪检测显示42.65%的细胞为CDl1c+CD80+细胞；22.30%的细胞为CD11c+CD86+细胞；32.46%的细胞为CD11c+MHCⅡ+细胞。
结论：成功构建了CTLA4Ig基因修饰的树突状细胞。
第二部分CTLA4Ig基因修饰的树突状细胞的体外功能研究
目的：研究CTLA4Ig基因修饰的树突状细胞在体外的功能,了解CTLA4Ig转染对树突状细胞表达细胞因子IL-10、IL-12的影响以及对刺激T细胞活化增殖功能的影响。
方法：分离和培养小鼠骨髓来源的DC。将体外培养7天的树突状细胞分成4组,一组为DC组,一组为DC+OVA组,另外两组分别加入1μ1病毒滴度为1.5×108VP/ml的AdGFP或AdCTLA4Ig和OVA。这4组细胞分别共培养48小时后,分离细胞和上清。上清用ELISA方法检测IL-10和IL-12。细胞用于和BALB/c小鼠外周血来源的T淋巴细胞进行混合淋巴细胞反应。
结果：1、CTLA4Ig基因转染树突状细胞后,促进树突状细胞分泌IL-10(P<0.05)。
2、CTLA4Ig基因转染树突状细胞后,降低树突状细胞分泌IL-12的能力(P<0.05)。
3、CTLA4Ig基因转染树突状细胞后,树突状细胞促T淋巴细胞增殖的能力下降(P<0.05)。
结论：CTLA4Ig基因转染树突状细胞高表达IL-10,低表达IL-12,促T细胞增殖的能力降低。
第三部分新生小鼠回输CTLA4Ig基因修饰的树突状细胞抑制成年期气道过敏性炎症
目的：研究将CTLA4Ig基因修饰的树突状细胞回输给新生小鼠,观察其对成年期OVA致敏／激发的小鼠气道炎症的影响,并探讨其发病机制。
方法：以OVA腹腔注射致敏小鼠并雾化吸入激发的方法制作哮喘模型。将CTLA4Ig基因修饰的树突状细胞回输给新生的BALB/c小鼠,在成年期OVA致敏／激发小鼠,观察CTLA4Ig基因修饰的树突状细胞对小鼠气道炎症的影响。同样方法设立对照组AdGFP干预组,另设立空白对照组、哮喘模型组。通过观察各组小鼠OVA激发时的表现、肺泡灌洗液(BALF)中嗜酸粒细胞比例和肺部病理切片改变了解小鼠气道炎症情况。ELISA方法测定血清及BALF的IgE、IL-4、IL-10及INF-y水平。
结果：1、OVA腹腔注射致敏小鼠并雾化吸入激发的方法能成功制作哮喘模型。2、新生小鼠给予CTLA4Ig基因修饰的树突状细胞明显减轻成年期哮喘发作的症状、减少肺泡灌洗液中嗜酸性细胞的生成和病理切片中的炎症表现。3、CTLA4Ig基因修饰的树突状细胞可以减轻成年期小鼠哮喘发作时的血清和肺泡灌洗液中IgE水平。4、CTLA4Ig基因修饰的树突状细胞可减轻成年期小鼠哮喘发作时的血清和肺泡灌洗液中IL-4水平。5、CTLA4Ig基因修饰的树突状细胞可提高成年期小鼠血清中IL-10水平。6、CTLA4Ig基因修饰的树突状细胞对成年期小鼠哮喘发作时血清和肺泡灌洗液中INF-y水平无明显影响。
结论：新生小鼠给予CTLA4Ig基因修饰的树突状细胞可在成年期时抑制OVA致敏/激发小鼠的气道炎症,使OVA致敏/激发小鼠血清IL-10水平增高,降低Th2细胞因子的分泌,对Thl细胞因子的分泌无明显影响。本研究为哮喘的预防和免疫治疗提供了新的思路。
Part I CTLA4Ig Gene Were Transducted into Dendritic Cells by Adenovirus
Objective:To construct CTLA4Ig gene modified dendritic cells.
Methods:The mouse bone marrow cells were isolated and cultured in complete medium with GM-CSF and IL-4for7days. Cell growth and morphological changes were observed under optical micro scope. The phenotype and the maturation of dendritic cells were analyzed by flow cytometry, examining the expression of CD11c, MHC Ⅱ, CD80and CD86. The cells were incubated with recombinant adenovirus (AdCTLA4Ig, AdGFP)and OVA for48hour, then target gene expression were observed under the fluorescence microscopy, transfection efficiency were determined by flow cytometry.
Results:1. Mouse bone marrow-derived cells showed characteristic dendritic morphology of dendritic cells and formed cell colony on the day7.2. The cell phenotype determined by flow cytometry showed that64.01%of cells were positive for CD11c,33.49%of the cells were positive for CD11c+CD80+cells,14.65%of the cells were positive for CD11c+CD86+cells,21.53%of the cells were positive for CD11c+MHCⅡ+cells.3. Incubated with recombinant adenovirus and OVA for48hours, green fluorescence in cells was observed under a fluorescence microscope. Flow cytometry analysis showed AdCTLA4Ig transfection rate was41.29%.4. Incubated with recombinant adenovirus and OVA for48hours,42.65%of the cells were CD11c+CD80+cells,22.30%of the cells were CD11c+CD86+cells,32.46%of the cells were CD11c+MHC Ⅱ+cells.
Conclusion:Constructing CTLA4Ig gene modified dendritic cells successfully.
Part Ⅱ The Functional Studies of CTLA4Ig Gene-modified Dendritic Cells in vitro
Objective:To study the function of CTLA4Ig gene-modified dendritic cells in vitro.
Methods:The mouse bone marrow-derived DCs were isolated and cultivated. The cultured dendritic cells for7days were divided into four groups:DC group, DC+OVA group, the other two groups were added1μl(1.5×108VP/ml) AdGFP or AdCTLA4Ig and OVA. All groups were cultured for48hours, then supernatant and cells were separated. The levels of IL-10and IL-12in supernatant were measured by ELISA. Cells were used to perform mixed lymphocyte reaction with peripheral blood T-lymphocytes of BALB/c mice.
Results:1. CTLA4Ig gene transfected in dendritic cells promoted IL-10secretion (P<0.05).2. CTLA4Ig gene transfected in dendritic cells, reduced IL-12secretion (P<0.05).3. CTLA4Ig gene transfected in dendritic cells decreased the dendritic cells'ability to promote T lymphocyte proliferation (P<0.05).
Conclusion:CTLA4Ig gene modified dendritic cells can promote the expression of IL-10, reduce the expression of IL-12and supress T cell proliferation.
Part III CTLA4Ig Gene-modified Dendritic Cells Transfused To Mice In Neonatal Period Suppress Adult Airway Allergic Inflammation
Objective:To study the impact of CTLA4Ig gene-modified dendritic cells transfused to mice in neonatal period on the airway inflammation of adult OVA-sensitized/challenged mice, and to explore its pathogenesis.
Methods:Use OVA-sensitized/challenged mice by intraperitoneal injection and inhalation methods to establish asthma model. The CTLA4Ig gene-modified dendritic cells were given to the newborn BALB/c mice, OVA-sensitized/challenged the mice in the adulthood. Establish the AdGFP intervention group with the same method. In addition, establish the control group and asthma model group. The manifestation of OVA challenged mice in each group, BALF eosinophils and lung pathological changes were observed to study the impact of CTLA4Ig gene-modified dendritic cells on airway inflammation. The level of IgE, IL-4, IL-10and INF-γ were detected by ELISA methods.
Results:1. Asthma model were established successfully by OVA-sensitized/challenged mice.2. CTLA4Ig gene-modified dendritic cells given in neonatal period significantly improved the symptoms of asthma in adulthood, reduced eosinophils in BALF and improved the airway inflammation in biopsy.3. CTLA4Ig gene-modified dendritic cells reduced IgE levels in serum and BALF during the onset of adulthood asthma.4. CTLA4Ig gene-modified dendritic cells reduced IL-4level in serum and BALF during the onset of adulthood asthma.5. CTLA4Ig gene-modified dendritic cells increased IL-10level in serum during the onset of adulthood asthma.6. CTLA4Ig gene-modified dendritic cells had no impact on level of INF-y in serum and BALF during the onset of adulthood asthma.
Conclusion:CTLA4Ig gene-modified dendritic cells given in neonatal period suppress the airway inflammation of OVA-sensitized/challenged mice in adulthood, elevate the serum levels of IL-10, reduce the secretion of Th2cytokines, has no impact on the secretion of Thl cytokines. In conclusion, this study provides a new idea to prevent and contol asthma.
引文
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