IL-17在肾移植急性排斥反应中表达的变化及意义
摘要
急性排斥反应(AR)是目前肾移植术后的主要并发症,也是导致移植肾失功的重要的危险因素之一。研究认为急性排斥反应时前炎症细胞因子和趋化因子,参与局部炎症反应,并且在肾小管上皮细胞内出现炎性浸润表达。IL-17细胞是一类新发现的CD4+效应T细胞,是一种前炎性的细胞因子。因此,研究急性排斥反应时IL-17在移植肾中的改变及其临床意义引起了许多研究人员的广泛关注,并逐渐成为新的研究热点。
本课题首先建立了大鼠肾移植急性排斥模型,采用原位低温灌注供肾切取,利用显微外科技术动脉端端吻合、静脉Cuff套管吻合、输尿管端端吻合的方法。选择封闭群SD大鼠为供者,Wistar大鼠为受者建立了大鼠肾移植急性排斥反应模型。
在此模型的基础上,通过RT-PCR半定量、免疫组化等方法研究大鼠急性排斥反应时移植肾白细胞介素17(IL-17)表达的变化及其临床意义。研究结果表明:大鼠同种异体基因移植组排斥时移植肾IL-17表达升高,而在同系基因对照组及同种异体基因移植免疫抑制组不排斥IL-17表达不变。说明肾移植术后急性排斥反应时大鼠移植肾IL-17的表达升高,并且应用免疫抑制剂抑制排斥反应可以减弱或者完全消除这种改变。同时对肾移植患者,通过PCR、免疫组化、定量酶联免疫法进行检测,结果也表明:急性排斥反应的患者其血IL-17表达升高。
IL-17的表达在肾移植急性排斥反应时升高,作为一种前炎性因子。这种改变能够在血液中检测出,因此为肾移植术后急性排斥反应的诊断及治疗提供了一种新思路,具有广阔的临床应用前景。
Th17 cells are a class of independent Th1, Th2 in CD4+ T cell subsets, IL-17 is the main effect factor in Th17 cells. It has a strong recruitment of neutrophils and promote the release of multiple inflammatory cytokines play a part in the body a variety of inflammatory and autoimmune diseases and development. It is through the promotion of mature T cell activation and proliferation, the recruitment of APC to directly or indirectly increase the local inflammatory response in the graft play a role, And the ability to stimulate monocytes and inflammatory cytokines in renal tubular epithelial cells and promotes dendritic cell infiltration of progenitor cell maturation.
Effective immune suppressors, and matching method significantly increased the continuous improvement of renal transplant patients/graft survival, but acute rejection after renal transplantation remains the most serious complication. The key of AR treatment is accurate diagnosis, but current diagnostic criteria is the most effective transplant kidney biopsy. Means for such invasive procedures, some patients fear it because of complications caused by refuse the inspection. So look for early, sensitive and specific monitoring indicators for the early diagnosis of acute rejection has important significance and clinical value. Cytokines are a class of immune function by immune cells, endothelial cells secrete a low molecular weight peptides, research shows that when the immune dysfunction can result in significant changes in cytokines. IL-17 by the helper CD4+T cells and memory T cells, with many inflammatory responses and immune diseases and the development of cytokines. Research has shown that it may be related to transplantation immunity.
Therefore, it becomes a heating research that to learn the changes of IL-17 and its significance in the graft of AR.
The establishing of renal transplantation acute rejection rat model
Select the SD male rats and the distant line of inbred male Wistar rats. All rats are not limited to drinking water, preoperative fasting 12h. At room temperature under 25℃, operation, and the relative humidity of 40% of clean non-sterile environment for breeding. Intraperitoneal injection of 10% chloral hydrate anesthesia, the donor left kidney was cut in situ cold perfusion, the left kidney recipients had to be removed, the left renal fossa using microsurgical technique anastomosis artery, Cuff sleeve anastomosis vein, reason and ureteral anastomosis for acute rejection in rat renal transplantation model. The results showed that open renal blood flow immediately after the kidney transplant from pale to bright red, renal artery Pollex good Renal vein filling; restore the blood supply, the ureter in 3 ~ 5min urine began to flow; donor nephrectomy plus time for a kidney transplant is about (115±25) minutes, the warm ischemia time <10s cold ischemia time <50min ; to normal Wistar male rats as normal control group kidneys; SD male rats as donors, Wister male rats were established by the allogeneic group; inbred Wister male rats were used as donors and a homologous gene control group; SD male rats as donors, Wistar male rats as recipients were administered cyclosporine A to prevent rejection of the establishment of allogeneic immune intervention group. And surgery After 3 days, 5 days, 7 days rats were killed. The results showed that compared with the control group, allogeneic group 3,5,7 days after operation, increased rejection, acute rejection of semi-quantitative score was significantly higher (P <0.05); Department of genes with no rejection in the control group , compared with the control group, no significant difference (P>0.05); immunosuppressive drugs in the intervention group, application of drug control of rejection, compared with the control group, no significant difference (P>0.05). Allogeneic group with the same genome and immune system inhibitors in the intervention group compared to significant pathological changes, acute rejection semi-quantitative score was significantly higher (P <0.05).
The surgical method to establish a stable animal model system gene with minor pathological changes in rats, can serve as a model of acute rejection in the control group; allogeneic rejection in rats after the operation, pathological changes can clearly be used to study the acute rejection reaction; immunosuppressive drugs after the intervention was no rejection in rats.
The significance and changes of IL-17 in rat model in the graft of acute rejection rat renal transplantation model
Kidney transplantation in the rat model of acute rejection based on the application of RT-PCR, respectively, and immunohistochemistry were used to the normal group, allogeneic, with genomic and immunosuppressant intervention group IL-transplant renal 17 gene expression and protein expression changes were detected.
RT-PCR results showed that group compared with the control group compared with the allogeneic rejection in rats occurred after the first day of renal transplantation 3,5,7 IL-17 mRNA expression was significantly increased (P <0.05) ; group compared with the control group compared with the control group and the immune system gene inhibitor intervention group was no renal allograft rejection, their renal IL-17 mRNA expression was not statistically significant (P>0.05); with allogeneic rat renal transplantation after 3,7 days of IL-17 mRNA expression 5 days after kidney transplantation IL-17 mRNA expression was significantly lower than (p <0.05).
Immunohistochemistry results showed that group compared with the control group compared with the allogeneic rejection in rats occurred days after the first 3,5,7 renal IL-17 mRNA expression was significantly increased (P <0.05) ; group compared with the control group compared with the control group and the immune system gene inhibitor intervention group was no renal allograft rejection, their renal IL-17 mRNA expression was not statistically significant (P>0.05); with allogeneic rat renal transplantation after 3,7 days of IL-17 mRNA expression 5 days after kidney transplantation IL-17 mRNA expression was significantly lower than (p<0.05).
These results show that compared with the normal group compared with the control group, rats with allogeneic rejection occurred expression of their IL-17 levels were significantly higher (p <0.05); compared with the control group did not homologous gene group acute rejection of their transplanted kidney changes in the expression of IL-17 was no statistical difference (P>0.05), which may indicate that although as a pro-inflammatory cytokines, but ischemia-reperfusion injury and to nerve damage and other surgical factors and increased expression of IL-17 has nothing to do. Through the use of immunosuppressive agents CsA, we found that this group no significant morphology in tissue rejection, Upregulation of IL-17 also did not appear with the control group without the intervention group compared with immunosuppressive agents, acute rejection of their transplanted kidney changes in the expression of IL-17 was no statistical difference (P>0.05). Therefore, this study suggests that IL-17 expression in the transplanted kidney increased with acute rejection after renal transplantation related.
The significance and changes of IL-17 in patients after renal transplantation
Review after renal transplantation and transplant patients with renal biopsy, according to the pathological changes were divided into four groups: Normal group, acute rejection group, immune poisoning group inhibitor, stable group. Application of PCR detection of renal transplant patients with IL-17 mRNA expression changes; application of immunohistochemistry in renal transplant patients with renal transplantation IL-17 protein expression changes. ELLESAin human renal allograft blood IL-17 expression changes.
Quantitative PCR, and ELISA results showed that compared with the normal group, patients with acute rejection IL-17 expression was significantly increased (p<0.05), while the expression of IL-17 was creased remarkably also with the comparison to drug groups (p<0.05). Immunohistochemistry results showed that compared with the normal group, patients with acute rejection IL-17 expression was significantly increased (p<0.05), while the expression of IL-17 was creased remarkably also with the comparison to drug groups (p<0.05).
To sum up, IL-17 as a pro-inflammatory cytokines, AR expression was increased when IL-17, and this change can be applied to non-invasive way to check out, so that as a new monitoring marker of acute rejection
本课题首先建立了大鼠肾移植急性排斥模型,采用原位低温灌注供肾切取,利用显微外科技术动脉端端吻合、静脉Cuff套管吻合、输尿管端端吻合的方法。选择封闭群SD大鼠为供者,Wistar大鼠为受者建立了大鼠肾移植急性排斥反应模型。
在此模型的基础上,通过RT-PCR半定量、免疫组化等方法研究大鼠急性排斥反应时移植肾白细胞介素17(IL-17)表达的变化及其临床意义。研究结果表明:大鼠同种异体基因移植组排斥时移植肾IL-17表达升高,而在同系基因对照组及同种异体基因移植免疫抑制组不排斥IL-17表达不变。说明肾移植术后急性排斥反应时大鼠移植肾IL-17的表达升高,并且应用免疫抑制剂抑制排斥反应可以减弱或者完全消除这种改变。同时对肾移植患者,通过PCR、免疫组化、定量酶联免疫法进行检测,结果也表明:急性排斥反应的患者其血IL-17表达升高。
IL-17的表达在肾移植急性排斥反应时升高,作为一种前炎性因子。这种改变能够在血液中检测出,因此为肾移植术后急性排斥反应的诊断及治疗提供了一种新思路,具有广阔的临床应用前景。
Th17 cells are a class of independent Th1, Th2 in CD4+ T cell subsets, IL-17 is the main effect factor in Th17 cells. It has a strong recruitment of neutrophils and promote the release of multiple inflammatory cytokines play a part in the body a variety of inflammatory and autoimmune diseases and development. It is through the promotion of mature T cell activation and proliferation, the recruitment of APC to directly or indirectly increase the local inflammatory response in the graft play a role, And the ability to stimulate monocytes and inflammatory cytokines in renal tubular epithelial cells and promotes dendritic cell infiltration of progenitor cell maturation.
Effective immune suppressors, and matching method significantly increased the continuous improvement of renal transplant patients/graft survival, but acute rejection after renal transplantation remains the most serious complication. The key of AR treatment is accurate diagnosis, but current diagnostic criteria is the most effective transplant kidney biopsy. Means for such invasive procedures, some patients fear it because of complications caused by refuse the inspection. So look for early, sensitive and specific monitoring indicators for the early diagnosis of acute rejection has important significance and clinical value. Cytokines are a class of immune function by immune cells, endothelial cells secrete a low molecular weight peptides, research shows that when the immune dysfunction can result in significant changes in cytokines. IL-17 by the helper CD4+T cells and memory T cells, with many inflammatory responses and immune diseases and the development of cytokines. Research has shown that it may be related to transplantation immunity.
Therefore, it becomes a heating research that to learn the changes of IL-17 and its significance in the graft of AR.
The establishing of renal transplantation acute rejection rat model
Select the SD male rats and the distant line of inbred male Wistar rats. All rats are not limited to drinking water, preoperative fasting 12h. At room temperature under 25℃, operation, and the relative humidity of 40% of clean non-sterile environment for breeding. Intraperitoneal injection of 10% chloral hydrate anesthesia, the donor left kidney was cut in situ cold perfusion, the left kidney recipients had to be removed, the left renal fossa using microsurgical technique anastomosis artery, Cuff sleeve anastomosis vein, reason and ureteral anastomosis for acute rejection in rat renal transplantation model. The results showed that open renal blood flow immediately after the kidney transplant from pale to bright red, renal artery Pollex good Renal vein filling; restore the blood supply, the ureter in 3 ~ 5min urine began to flow; donor nephrectomy plus time for a kidney transplant is about (115±25) minutes, the warm ischemia time <10s cold ischemia time <50min ; to normal Wistar male rats as normal control group kidneys; SD male rats as donors, Wister male rats were established by the allogeneic group; inbred Wister male rats were used as donors and a homologous gene control group; SD male rats as donors, Wistar male rats as recipients were administered cyclosporine A to prevent rejection of the establishment of allogeneic immune intervention group. And surgery After 3 days, 5 days, 7 days rats were killed. The results showed that compared with the control group, allogeneic group 3,5,7 days after operation, increased rejection, acute rejection of semi-quantitative score was significantly higher (P <0.05); Department of genes with no rejection in the control group , compared with the control group, no significant difference (P>0.05); immunosuppressive drugs in the intervention group, application of drug control of rejection, compared with the control group, no significant difference (P>0.05). Allogeneic group with the same genome and immune system inhibitors in the intervention group compared to significant pathological changes, acute rejection semi-quantitative score was significantly higher (P <0.05).
The surgical method to establish a stable animal model system gene with minor pathological changes in rats, can serve as a model of acute rejection in the control group; allogeneic rejection in rats after the operation, pathological changes can clearly be used to study the acute rejection reaction; immunosuppressive drugs after the intervention was no rejection in rats.
The significance and changes of IL-17 in rat model in the graft of acute rejection rat renal transplantation model
Kidney transplantation in the rat model of acute rejection based on the application of RT-PCR, respectively, and immunohistochemistry were used to the normal group, allogeneic, with genomic and immunosuppressant intervention group IL-transplant renal 17 gene expression and protein expression changes were detected.
RT-PCR results showed that group compared with the control group compared with the allogeneic rejection in rats occurred after the first day of renal transplantation 3,5,7 IL-17 mRNA expression was significantly increased (P <0.05) ; group compared with the control group compared with the control group and the immune system gene inhibitor intervention group was no renal allograft rejection, their renal IL-17 mRNA expression was not statistically significant (P>0.05); with allogeneic rat renal transplantation after 3,7 days of IL-17 mRNA expression 5 days after kidney transplantation IL-17 mRNA expression was significantly lower than (p <0.05).
Immunohistochemistry results showed that group compared with the control group compared with the allogeneic rejection in rats occurred days after the first 3,5,7 renal IL-17 mRNA expression was significantly increased (P <0.05) ; group compared with the control group compared with the control group and the immune system gene inhibitor intervention group was no renal allograft rejection, their renal IL-17 mRNA expression was not statistically significant (P>0.05); with allogeneic rat renal transplantation after 3,7 days of IL-17 mRNA expression 5 days after kidney transplantation IL-17 mRNA expression was significantly lower than (p<0.05).
These results show that compared with the normal group compared with the control group, rats with allogeneic rejection occurred expression of their IL-17 levels were significantly higher (p <0.05); compared with the control group did not homologous gene group acute rejection of their transplanted kidney changes in the expression of IL-17 was no statistical difference (P>0.05), which may indicate that although as a pro-inflammatory cytokines, but ischemia-reperfusion injury and to nerve damage and other surgical factors and increased expression of IL-17 has nothing to do. Through the use of immunosuppressive agents CsA, we found that this group no significant morphology in tissue rejection, Upregulation of IL-17 also did not appear with the control group without the intervention group compared with immunosuppressive agents, acute rejection of their transplanted kidney changes in the expression of IL-17 was no statistical difference (P>0.05). Therefore, this study suggests that IL-17 expression in the transplanted kidney increased with acute rejection after renal transplantation related.
The significance and changes of IL-17 in patients after renal transplantation
Review after renal transplantation and transplant patients with renal biopsy, according to the pathological changes were divided into four groups: Normal group, acute rejection group, immune poisoning group inhibitor, stable group. Application of PCR detection of renal transplant patients with IL-17 mRNA expression changes; application of immunohistochemistry in renal transplant patients with renal transplantation IL-17 protein expression changes. ELLESAin human renal allograft blood IL-17 expression changes.
Quantitative PCR, and ELISA results showed that compared with the normal group, patients with acute rejection IL-17 expression was significantly increased (p<0.05), while the expression of IL-17 was creased remarkably also with the comparison to drug groups (p<0.05). Immunohistochemistry results showed that compared with the normal group, patients with acute rejection IL-17 expression was significantly increased (p<0.05), while the expression of IL-17 was creased remarkably also with the comparison to drug groups (p<0.05).
To sum up, IL-17 as a pro-inflammatory cytokines, AR expression was increased when IL-17, and this change can be applied to non-invasive way to check out, so that as a new monitoring marker of acute rejection
引文
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