1，25-二羟维生素D_3抑制大鼠角膜移植术后免疫排斥反应的实验研究
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摘要
目的:研究1,25-二羟维生素D3对大鼠穿透性角膜移植术后免疫排斥反应的免疫抑制作用及其机制。
方法:以30只SD大鼠为受体,15只Wistar大鼠为供体,建立同种异体穿透性角膜移植模型,受体SD大鼠随机分成实验组、实验对照组,每组15只;另15只SD大鼠行自体穿透性角膜移植,构成对照组。术后0～13 d,实验组腹腔注射1,25-二羟维生素D3 1.0μg·kg~(-1)·d~(-1),对照组和实验对照组腹腔注射灭菌花生油2 ml/d。术后每天显微镜观察角膜植片存活情况并评分;于术后14 d、21 d、30 d三个时间点,每组随机处死5只大鼠,进行角膜植片病理学检查,ELISA检测外周血IL-1β、IL-2、IL-8、IL-10,流式细胞分析技术检测外周血中T细胞亚群变化、CD4+/CD8+比值。
结果:
1.对照组角膜植片平均存活时间为(21.7±6.8) d,实验对照组为(11.2±2.5) d,实验组为(19.3±5.2) d。实验组角膜植片平均存活时间较实验对照组明显延长,差异有统计学意义(P < 0.01)。
2.实验组排斥反应指数(RI)在手术后14 d、21 d、30 d均低于实验对照组,差异有统计学意义(P < 0.01)。
3.病理学检查显示实验组淋巴细胞浸润和新生血管均较实验对照组少。
4.实验组外周血中IL-1β、IL-2、IL-8含量与实验对照组相比明显下降, IL-10含量明显增高,差异有统计学意义(P < 0.01)。
5.术后同一时间点实验组CD4+均较实验对照组下降(P < 0.01),而CD8+明显增多(P < 0.01),实验组CD4+/CD8+比值较实验对照组均明显降低(P < 0.01),差异有统计学意义。
结论:
1. 1,25-二羟维生素D3能显著延长同种异体大鼠角膜移植术后角膜植片的存活时间。
2. 1,25-二羟维生素D3能有效抑制同种异体大鼠角膜移植术后免疫排斥反应。
3. 1,25-二羟维生素D3可以明显抑制同种异体大鼠角膜移植术后Th1细胞分泌的IL-1β、IL-2、IL-8;并且显著提高Th2细胞分泌的IL-10。
4. 1,25-二羟维生素D3可使同种异体大鼠角膜移植术后外周血CD4+下降,CD8~+上升,CD4~+/CD8~+比值下降,即通过调节T细胞亚群数量及其比值,抑制T细胞介导的角膜移植排斥反应。
Objective: To investigate the effects of 1, 25-dihydroxyvitamin D3 in prevention of corneal transplantaion rejection and its possible mechanism.
Methods: 45 SD rats as recipients were randomly divided into three groups: the autograft control group, the allograft control group and the allograft group. Routine penetrating keratoplasty (PKP) was performed. In the the allograft control group and the allograft group, 30 SD rats were used as recipients, and 15 Wistar rats were used as donors. And in the autograft group, 15 SD rats got their own autografts.After PKP, the control groups were given placebo only, and the allograft group was treated with 1, 25-dihydroxyvitamin D3 (1.0μg·kg~(-1)·d~(-1)). The drugs were delivered for 14 days beginning at the day of transplantation. All grafts were examined by operating microscopy everyday after transplantation. 5 SD rats in every group were killed respectively at the 14th day, 21st day, and 30th day postoperatively. Neovascularization and inflammation were evaluated with HE staining. ELISA assay was used to detect the contents of IL~(-1)β, IL-2, IL-8, and IL-10 in the peripheral blood. Flow cytometry was used to identify the kinetic variation of the peripheral T cell population and CD4+/CD8+ ratio.
Results:
1. The mean survival time (MST) of the autograft control group was (21.7±6.8) days; the MST of the allograft control group was merely (11.2±2.5) days; and the allograft group led to a statistically significant prolongation of the MST to (19.3±5.2) days (P < 0.01).
2. The rejection index of the allograft group was less than the allograft control group in the 14th day, 21st day, and 30th day postoperatively (P < 0.01).
3. The allograft group has less neovascularization and inflammation than the allograft control group.
4. The level of expression of IL~(-1)β, IL-2, and IL-8 in the allograft group was markedly lower than these in the allograft control group, and IL-10 were higher in the allograft control group (P < 0.01).
5. In comparing with the allograft control group, the peripheral CD4+cell and CD4+/CD8+ in the allograft group were decreased significantly, and CD8+ cell was increased(P < 0.01).
Conclusion:
1. 1, 25-dihydroxyvitamin D3 could prolong the survival time of corneal allografts.
2. 1, 25-dihydroxyvitamin D3 could inhibit the immune rejection of corneal transplantation.
3. 1, 25-dihydroxyvitamin D3 could significantly inhibit the expressions of IL-1β, IL-2, IL-8 which were secreted by Th1 cells, and increased the expressions of IL-10 which were secreted by Th2 cells.
4. 1, 25-dihydroxyvitamin D3 could obviously decrease the peripheral CD4~+cell and CD4~+/CD8~+, and increase the peripheral CD8+cell. It is indicated that 1, 25-dihydroxyvitamin D3 could inhibit the lymphocyte activation.
方法:以30只SD大鼠为受体,15只Wistar大鼠为供体,建立同种异体穿透性角膜移植模型,受体SD大鼠随机分成实验组、实验对照组,每组15只;另15只SD大鼠行自体穿透性角膜移植,构成对照组。术后0～13 d,实验组腹腔注射1,25-二羟维生素D3 1.0μg·kg~(-1)·d~(-1),对照组和实验对照组腹腔注射灭菌花生油2 ml/d。术后每天显微镜观察角膜植片存活情况并评分;于术后14 d、21 d、30 d三个时间点,每组随机处死5只大鼠,进行角膜植片病理学检查,ELISA检测外周血IL-1β、IL-2、IL-8、IL-10,流式细胞分析技术检测外周血中T细胞亚群变化、CD4+/CD8+比值。
结果:
1.对照组角膜植片平均存活时间为(21.7±6.8) d,实验对照组为(11.2±2.5) d,实验组为(19.3±5.2) d。实验组角膜植片平均存活时间较实验对照组明显延长,差异有统计学意义(P < 0.01)。
2.实验组排斥反应指数(RI)在手术后14 d、21 d、30 d均低于实验对照组,差异有统计学意义(P < 0.01)。
3.病理学检查显示实验组淋巴细胞浸润和新生血管均较实验对照组少。
4.实验组外周血中IL-1β、IL-2、IL-8含量与实验对照组相比明显下降, IL-10含量明显增高,差异有统计学意义(P < 0.01)。
5.术后同一时间点实验组CD4+均较实验对照组下降(P < 0.01),而CD8+明显增多(P < 0.01),实验组CD4+/CD8+比值较实验对照组均明显降低(P < 0.01),差异有统计学意义。
结论:
1. 1,25-二羟维生素D3能显著延长同种异体大鼠角膜移植术后角膜植片的存活时间。
2. 1,25-二羟维生素D3能有效抑制同种异体大鼠角膜移植术后免疫排斥反应。
3. 1,25-二羟维生素D3可以明显抑制同种异体大鼠角膜移植术后Th1细胞分泌的IL-1β、IL-2、IL-8;并且显著提高Th2细胞分泌的IL-10。
4. 1,25-二羟维生素D3可使同种异体大鼠角膜移植术后外周血CD4+下降,CD8~+上升,CD4~+/CD8~+比值下降,即通过调节T细胞亚群数量及其比值,抑制T细胞介导的角膜移植排斥反应。
Objective: To investigate the effects of 1, 25-dihydroxyvitamin D3 in prevention of corneal transplantaion rejection and its possible mechanism.
Methods: 45 SD rats as recipients were randomly divided into three groups: the autograft control group, the allograft control group and the allograft group. Routine penetrating keratoplasty (PKP) was performed. In the the allograft control group and the allograft group, 30 SD rats were used as recipients, and 15 Wistar rats were used as donors. And in the autograft group, 15 SD rats got their own autografts.After PKP, the control groups were given placebo only, and the allograft group was treated with 1, 25-dihydroxyvitamin D3 (1.0μg·kg~(-1)·d~(-1)). The drugs were delivered for 14 days beginning at the day of transplantation. All grafts were examined by operating microscopy everyday after transplantation. 5 SD rats in every group were killed respectively at the 14th day, 21st day, and 30th day postoperatively. Neovascularization and inflammation were evaluated with HE staining. ELISA assay was used to detect the contents of IL~(-1)β, IL-2, IL-8, and IL-10 in the peripheral blood. Flow cytometry was used to identify the kinetic variation of the peripheral T cell population and CD4+/CD8+ ratio.
Results:
1. The mean survival time (MST) of the autograft control group was (21.7±6.8) days; the MST of the allograft control group was merely (11.2±2.5) days; and the allograft group led to a statistically significant prolongation of the MST to (19.3±5.2) days (P < 0.01).
2. The rejection index of the allograft group was less than the allograft control group in the 14th day, 21st day, and 30th day postoperatively (P < 0.01).
3. The allograft group has less neovascularization and inflammation than the allograft control group.
4. The level of expression of IL~(-1)β, IL-2, and IL-8 in the allograft group was markedly lower than these in the allograft control group, and IL-10 were higher in the allograft control group (P < 0.01).
5. In comparing with the allograft control group, the peripheral CD4+cell and CD4+/CD8+ in the allograft group were decreased significantly, and CD8+ cell was increased(P < 0.01).
Conclusion:
1. 1, 25-dihydroxyvitamin D3 could prolong the survival time of corneal allografts.
2. 1, 25-dihydroxyvitamin D3 could inhibit the immune rejection of corneal transplantation.
3. 1, 25-dihydroxyvitamin D3 could significantly inhibit the expressions of IL-1β, IL-2, IL-8 which were secreted by Th1 cells, and increased the expressions of IL-10 which were secreted by Th2 cells.
4. 1, 25-dihydroxyvitamin D3 could obviously decrease the peripheral CD4~+cell and CD4~+/CD8~+, and increase the peripheral CD8+cell. It is indicated that 1, 25-dihydroxyvitamin D3 could inhibit the lymphocyte activation.
引文
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