rAAV2转CTLA4lg基因胰岛门静脉移植治疗糖尿病猴研究
摘要
糖尿病是严重威胁人类健康的常见病和多发病,异种胰岛移植是治疗糖尿病极具发展潜力的方法,但免疫排斥反应是影响胰岛移植效果的重要原因之一。异种胰岛移植免疫排斥反应主要由T淋巴细胞介导,T细胞的活化及其效应有赖于MHC2抗原复合体识别及协同刺激信号传递,封闭共刺激通路可诱导受者对供者抗原特异性T细胞无能而产生耐受。细胞毒T淋巴细胞相关抗原4免疫球蛋白(CTLA4Ig)是CTLA4分子的胞外段与IgFc段的融合蛋白,可阻断CD28介导的T细胞协同刺激通路,抑制T细胞的活化,从而降低与移植排斥反应有直接关系的白介素-2(IL-2)、肿瘤坏死因子-α(TNF-α)、干扰素-γ(IFN-γ)等细胞因子的产生,对移植排斥反应有明显的抑制作用。但全身使用CTLA4Ig或体内基因转染可干扰整体免疫功能并导致非特异性免疫抑制,甚至发生严重并发症,而且需要重复给予,价格昂贵。重组腺相关病毒rAAV具有安全性高、免疫原性低、物理性质稳定、感染细胞谱广等优点,对宿主固有的免疫系统影响小,不会引起严重的急性炎症反应,被认为是最有前途的基因治疗载体之一。
本研究中应用rAAV2携带CTLA4Ig基因体外转染新生猪胰岛,CTLA4Ig基因成功转入了新生猪胰岛,并合成了具有正常功能的CTLA4Ig蛋白,而且转染后的新生猪胰岛形态、活性及生理功能完好。
使用本研究的胰岛储运方法可以有效地防止胰岛运输过程中出现的短时间内温度巨变,以该种方法保存胰岛5小时以内,其形态、功能未见明显改变,有效地减少了储运过程中正常胰岛的丢失,在一定时间内起到了安全、有效转运胰岛的作用。而且此法方法简便,耗资少,易于推广,对于胰岛移植的临床应用有着积极的意义。
新生猪胰岛转染CTLA4Ig基因移植并联合使用免疫抑制治疗,能够产生更好的免疫耐受,更好的保护植入胰岛,实现良好的移植效果；新生猪胰岛转染CTLA4Ig基因后移植有可能一定程度减少免疫抑制剂的使用量,降低免疫抑制剂对于植入胰岛的损伤作用,从而间接地保护胰岛,为提高移植疗效起到促进作用。
Diabetes is a serious threat to human health, common and frequently occurring. Islet xenotransplantation is a great development potential treatment of diabetes, but the immune rejection is one of the important reasons affecting the effects of islet transplantation. Xenogeneic islet allograft rejection is mainly mediated by T lymphocytes, T cell activation and its effect depends on complex identification MHC2antigen and co-stimulatory signals pass, closed costimulatory pathway can induce recipients of donor antigen-specific T cellsincompetence and tolerance. The cytotoxic T lymphocyte-associated antigen4immunoglobulin (CTLA4Ig) is a segment of a fusion protein of the extracellular domain of the CTLA4molecule and IgFc, can block CD28-mediated T cell co-stimulatory pathway, inhibition of T cell activation, therebyreduce transplant rejection have a direct relationship, interleukin-2(IL-2), tumor necrosis factor-a (TNF-a), interferon-y (IFN-y), etc., the production of cytokines, transplant rejectioninhibition. But the systemic use of CTLA4Ig in vivo or gene transfection can interfere with the overall immune function and lead to non-specific immune suppression, and even serious complications, and need to be repeated to give. Recombinant adeno-associated virus rAAV has the advantages of high security, low immunogenicity, stable physical properties, a broad spectrum of infected cells, a small impact on the the inherent host immune system, does not cause the severe acute inflammatory response, is considered to be the most promisinggene therapy vector one.
In this study, the use of rAAV as a carrier, CTLA4Ig gene transfection in vitro porcine islet cells, so that long-term stabilizing effect on the expression CTLA4Ig protein to block islet cell transplant rejection CD28/B7costimulatory signaling pathways, causing Th1cell differentiation offset and related cytokines were down-regulated. Then implanted through the portal vein of the liver of the diabetic monkeys, to detect the receptor in vivo the expression of the CTLA4Ig, study receptor changes of diabetes, in order to obtain a new method by the local expression of CTLA4Ig to anti-rejection therapy. The experiment proved rAAV2-CTLA4Ig are genetically modified new hog islet, expression of CTLA4Ig can inhibit the activation of immune cells, without affecting the physiological function of the pancreatic islets, can effectively inhibit the local occurrence of graft rejection, to improve graft survivaland play a function of time, the interference of the systemic immune system of transplant recipients at the same time. IT can be seen that the islet cells in vitro transfection transplant may be a treatment for diabetes security, effective method.
And the experimental group using the own storage and transportation method of transport islets, can greatly increase the survival rate of the porcine islets to effectively reduce the loss of normal pancreatic storing process, and within a certain time played a safe, effective transporter islet for the clinical application of islet transplantation has a positive meaning, may lead to new islet transplantation model, pancreas-islet processing center for the center, and guarantee safe and effective islet storage and transportation within the region to establish islet sharing circle to make islet transplantation more convenient.
本研究中应用rAAV2携带CTLA4Ig基因体外转染新生猪胰岛,CTLA4Ig基因成功转入了新生猪胰岛,并合成了具有正常功能的CTLA4Ig蛋白,而且转染后的新生猪胰岛形态、活性及生理功能完好。
使用本研究的胰岛储运方法可以有效地防止胰岛运输过程中出现的短时间内温度巨变,以该种方法保存胰岛5小时以内,其形态、功能未见明显改变,有效地减少了储运过程中正常胰岛的丢失,在一定时间内起到了安全、有效转运胰岛的作用。而且此法方法简便,耗资少,易于推广,对于胰岛移植的临床应用有着积极的意义。
新生猪胰岛转染CTLA4Ig基因移植并联合使用免疫抑制治疗,能够产生更好的免疫耐受,更好的保护植入胰岛,实现良好的移植效果；新生猪胰岛转染CTLA4Ig基因后移植有可能一定程度减少免疫抑制剂的使用量,降低免疫抑制剂对于植入胰岛的损伤作用,从而间接地保护胰岛,为提高移植疗效起到促进作用。
Diabetes is a serious threat to human health, common and frequently occurring. Islet xenotransplantation is a great development potential treatment of diabetes, but the immune rejection is one of the important reasons affecting the effects of islet transplantation. Xenogeneic islet allograft rejection is mainly mediated by T lymphocytes, T cell activation and its effect depends on complex identification MHC2antigen and co-stimulatory signals pass, closed costimulatory pathway can induce recipients of donor antigen-specific T cellsincompetence and tolerance. The cytotoxic T lymphocyte-associated antigen4immunoglobulin (CTLA4Ig) is a segment of a fusion protein of the extracellular domain of the CTLA4molecule and IgFc, can block CD28-mediated T cell co-stimulatory pathway, inhibition of T cell activation, therebyreduce transplant rejection have a direct relationship, interleukin-2(IL-2), tumor necrosis factor-a (TNF-a), interferon-y (IFN-y), etc., the production of cytokines, transplant rejectioninhibition. But the systemic use of CTLA4Ig in vivo or gene transfection can interfere with the overall immune function and lead to non-specific immune suppression, and even serious complications, and need to be repeated to give. Recombinant adeno-associated virus rAAV has the advantages of high security, low immunogenicity, stable physical properties, a broad spectrum of infected cells, a small impact on the the inherent host immune system, does not cause the severe acute inflammatory response, is considered to be the most promisinggene therapy vector one.
In this study, the use of rAAV as a carrier, CTLA4Ig gene transfection in vitro porcine islet cells, so that long-term stabilizing effect on the expression CTLA4Ig protein to block islet cell transplant rejection CD28/B7costimulatory signaling pathways, causing Th1cell differentiation offset and related cytokines were down-regulated. Then implanted through the portal vein of the liver of the diabetic monkeys, to detect the receptor in vivo the expression of the CTLA4Ig, study receptor changes of diabetes, in order to obtain a new method by the local expression of CTLA4Ig to anti-rejection therapy. The experiment proved rAAV2-CTLA4Ig are genetically modified new hog islet, expression of CTLA4Ig can inhibit the activation of immune cells, without affecting the physiological function of the pancreatic islets, can effectively inhibit the local occurrence of graft rejection, to improve graft survivaland play a function of time, the interference of the systemic immune system of transplant recipients at the same time. IT can be seen that the islet cells in vitro transfection transplant may be a treatment for diabetes security, effective method.
And the experimental group using the own storage and transportation method of transport islets, can greatly increase the survival rate of the porcine islets to effectively reduce the loss of normal pancreatic storing process, and within a certain time played a safe, effective transporter islet for the clinical application of islet transplantation has a positive meaning, may lead to new islet transplantation model, pancreas-islet processing center for the center, and guarantee safe and effective islet storage and transportation within the region to establish islet sharing circle to make islet transplantation more convenient.
引文
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