天花粉蛋白和IL-12p40基因在小鼠同种胰岛移植排斥反应中的作用及机制研究
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摘要
糖尿病是常见慢性疾病之一,会带来一系列并发症,严重威胁患者的健康和生命。胰岛素的问世虽然大大降低了糖尿病患者的死亡率,但其存在低血糖等不良反应,对于糖尿病的并发症也无法有效控制。胰岛移植是有希望替代胰岛素的一种新的治疗措施,接受胰岛移植的患者在一段时期内,在一定程度上可以摆脱对胰岛素的依赖。但是,植入的胰岛不能长期发挥作用,针对移植物的排斥反应是削弱胰岛移植长期效果的重要原因。本项研究即着眼于同种胰岛移植的免疫排斥反应问题,旨在探索排斥反应的相关机制,并用适当干预措施作用于受体获得免疫抑制,以期缓解针对胰岛移植物的排斥作用。
首先,我们建立了链脲佐菌素诱导的糖尿病小鼠进行肾被膜下胰岛移植的动物模型。在小鼠胰岛的获取上我们吸取了前人的经验并加以改进。然后我们进行了BALB/c小鼠对C57BL/6小鼠的同种胰岛移植,腹腔注射天花粉蛋白来干预受体小鼠的免疫反应,探讨天花粉蛋白对胰岛移植排斥反应的作用和可能的机制,并了解其对胰岛功能的影响。以IL-12p40基因敲除小鼠为移植受体,与野生型的受体相比较,来了解IL-12p40基因及其涉及的免疫环节在小鼠同种胰岛移植排斥中的作用和地位。
第一部分小鼠胰岛移植模型的建立
目的:
建立简便高效的小鼠胰岛获取方法和稳定的糖尿病小鼠胰岛移植动物模型。
方法:
(1)用改良的胆囊穿刺胶原酶P灌注法消化小鼠胰腺,了解操作难度和消化效果。分两组(n=6)比较Ficoll梯密度离心法和滤网过滤法纯化胰岛的效果。(2)用链脲佐菌素诱导小鼠糖尿病,行肾被膜下胰岛移植,观察糖尿病模型的稳定度及胰岛移植后小鼠血糖的纠正情况。
结果:
(1)改良的胆囊穿刺胶原酶P灌注方法简单、有效,胰腺消化充分,胰岛形态良好;胰岛纯化方法上,滤网过滤法获得的胰岛数量和纯度都比Ficoll梯密度离心法要高(P＜0.05),而操作时间则显著减少(P＜0.01)。胰岛素释放试验显示滤网过滤纯化的胰岛释放胰岛素的能力高于Ficoll梯密度离心法(P＜0.05)。(2)链脲佐菌素注射后48小时内小鼠血糖即升高至16.7mmol/L以上形成糖尿病,而胰岛移植(n=10)后第1天血糖即得到纠正,在发生排斥反应以前血糖都能维持正常水平。
结论:
胆囊穿刺胶原酶P灌注加滤过纯化的方法简便、高效,是获取小鼠胰岛的有效措施;链脲佐菌素诱导的糖尿病小鼠行肾被膜下胰岛移植是可靠的胰岛移植模型。
第二部分天花粉蛋白在小鼠同种胰岛移植中的应用
目的:
探讨天花粉蛋白(TCS)对小鼠同种胰岛移植排斥反应的抑制作用;探索这种抑制作用的可能机制;初步了解天花粉蛋白对胰岛功能的影响。
方法:
(1)行BALB/c小鼠至C57BL/6小鼠的同种异基因胰岛移植,随机分为天花粉蛋白腹腔注射组(n=6)和对照组(n=6),移植后每天测血糖,了解胰岛移植物存活时间。(2)设TCS组、胰岛移植组、胰岛移植+TCS组和空白对照组(每组n=5),检测各组T细胞增殖水平和分泌IFN-γ水平,及外周淋巴组织内T细胞的组成比例,探索天花粉蛋白的抑制作用机理。(3)体内实验,检测天花粉蛋白使用前、后胰岛移植物分泌C肽的水平;体外实验,胰岛培养时加入天花粉蛋白,做胰岛素释放试验并与对照组比较,了解其对胰岛功能的影响。
结果:
(1)天花粉蛋白腹腔注射组胰岛移植物存活时间为12.2±1.7天,对照组为9.7±1.4天,移植物存活时间有所延长(P＜0.05)。(2)天花粉蛋白注射后T细胞对供体特异性抗原刺激的增殖反应明显减弱(P＜0.05);分泌IFN-γ水平下降;外周淋巴组织内调节型T细胞比例上升。(3)体内实验,天花粉蛋白使用前、后C肽水平无明显改变;体外实验,胰岛培养时加入天花粉蛋白,胰岛分泌胰岛素的水平下降(P＜0.05)。
结论:
天花粉蛋白可以减缓小鼠同种胰岛移植的排斥反应;其机制可能与天花粉蛋白抑制小鼠的抗原特异性T细胞增殖及上调调节型T细胞有关。天花粉蛋白直接作用于胰岛,对胰岛的功能有抑制作用。
第三部分IL-12p40在胰岛移植排斥反应中作用的研究
目的:
了解IL-12p40基因在小鼠同种胰岛移植排斥反应中的作用,探索IL-12p40基因缺陷所导致的Th1向Th2的免疫偏离能否产生对同种胰岛移植的免疫耐受。
方法:
用IL-12p40基因敲除小鼠为受体行同种胰岛移植(n=7),与野生型受体(n=6)比较,观察胰岛移植物存活时间,移植区域CD4~+和CD8~+T细胞的浸润情况,以及细胞因子IL-4和IFN-γ的表达水平。
结果:
IL-12p40基因敲除受体胰岛移植物的存活时间为10.0±2.9天,对照组为9.7±2.1天,差异无统计学意义(P＞0.05);两组小鼠移植区域CD4~+和CD8~+T细胞的浸润情况,以及细胞因子IL-4和IFN-γ的表达水平都没有明显差异。
结论:
IL-12p40基因缺陷所导致的受体Th1向Th2的免疫偏离不能明显减弱小鼠同种胰岛移植的排斥反应,因此也无法诱导免疫耐受。
我们的实验从药物干预和基因敲除两方面来探讨小鼠同种胰岛移植排斥反应的发生机制及防治措施。初步探索了中药成分天花粉蛋白在对抗免疫排斥中的作用和机制,也明确了IL-12p40基因缺陷无法导致对同种胰岛移植物的免疫耐受。研究结果有助于加深对胰岛移植排斥反应及免疫耐受的认识,对在移植领域进一步研究应用天花粉蛋白或其他中药成分起到了积极作用。
Diabetes mellitus is one of the common chronic diseases with a lot of complications threatening health and life of patients.Although the application of insulin had saved lives of many diabetes patients,hypoglycemia is one of its adverse effects and complications of diabetes mellitus can not be controlled thoroughly.Islet transplantation is a new hopeful therapeutic measure in instead of insulin injection. Patients who accepted islet transplantation could get rid of insulin in some extent.But islet allograft could not be functional constantly,rejection toward allograft is the main reason.This study was interested in mechanisms of allograft rejection in islet transplantation.In order to prolong allograft survival of islet transplantation,we applied immunosuppressive drugs to recipient to prevent the rejection.
We established the model of streptozotocin induced diabetes mouse on the first step and then allogenic islets were transplanted beneath the capsule of the left kidney.We modified the method of pancreas digestion and islet purification based on previous studies.Then we studied the allo-transplantantion of islet from BALB/c mice to C57BL/6 mice.Trichosanthin was injected intraperitoneally to affect the immune response of recipient mice.Influence to function of islet and immunosuppressive effect was assessed and its mechanisms were investigated.In purpose of comprehend the role of IL-12p40 in allograft rejection of islet transplantation,we compared the immune rejections in recipients of IL-12p40 knock-out mice and wild type C57BL/6 mice.
PartⅠEstablishment of islet transplantation model in mouse
Objective:
To obtain a convenient and high performance method of harvesting mouse islet,and establish a stable model of islet transplantation in diabetes mouse.
Methods:
(1) Mouse pancreas was digested by collagenase P which was perfused by means of a gallbladder puncture.We observed the result of digestion and difficulty of operation. We compared the results of Ficoll density gradient centrifugation and filtration in islet purification(n=6 in each group).(2) We also performed islet transplantation in streptozotocin induced diabetes mice to observe the stability of diabetes model and correction of hyperglycemia after transplantation.
Results:
(1) The method of collagenase P perfusion by gallbladder puncture in pancreas digestion is easy and high performance.Filtration is better than Ficoll density gradient centrifugation in islet purification for quantity and purity of islets were elevated (P＜0.05),operating time was saved significantly(P＜0.01).Insulin release test showed that islets achieved by filtration released more insulin than Ficoll density gradient centrifugation(P＜0.05).(2) Hyperglycemia(BG＞16.7mmol/L) was induced by streptozotocin injection within 48 hours and it was corrected within 24 hours after islet transplantation(n=10) until rejection happened.
Conclusions:
The method of collagenase P perfusion by gallbladder puncture is convenient and high performance in obtaining mouse islet.The animal model of islet transplantation in streptozotocin induced diabetes mouse is stable and reliable.
PartⅡApplieation of trichosanthin in mouse islet allotransplantation
Objective:
To understand the inhibition effect of trichosanthin(TCS) to allograft rejection in mouse islet transplantation and investigate its possible mechanisms.To initially find the affect of TCS upon the islet function.
Methods:
(1) Control group(n=6) and TCS injection group(n=6) were set in mice with BALB/c to C57BL/6 islet transplantation.Blood glucose was tested in both groups daily to obtain the survival time of allografts.(2) Control group,TCS injection group, islet transplant group and transplant plus TCS group(n=5 in each group) were set.In all groups,T cell proliferation rate,IFN-γsecreting level and T cell ratio in peripheral lymph organs were detected to investigate mechanisms of trichosanthin in inhibiting rejection.(3) In vivo,we detected C peptide level secreted by islet graft before and after trichosanthin injection.In vitro,insulin release test was applied after islet culture with trichosanthin to comprehend whether trichosanthin could affect islet function.
Results:
(1) The mean survival time of islet allograft in TCS group was 12.2±1.7 days,and it was 9.7±1.4 days in control group,survival time was prolonged after trichosanthin injection(P＜0.05).(2) Donor antigen specific T cell proliferation rate and IFN-γ secreting level were depressed and regulatory T cell ratio in peripheral lymph organs was elevated after trichosanthin injection.(3) In vivo,C peptide levels were similar before and after trichosanthin injection.In vitro,insulin secreting level of islet was depressed after cultivation with trichosanthin(P＜0.05).
Conclusions:
Trichosanthin could inhibit allograft rejection in mouse islet transplantation. Inhibition of antigen specific T cell proliferation and up-regulation of regulatory T cell are possible mechanisms.Thrichosanthin could inhibit function of mouse islet when contact directly.
PartⅢStudying the role of IL-12p40 in allograft rejection of islet transplantation
Objective:
To comprehend the role of IL-12p40 gene in allograft rejection in mouse islet transplantation and investigate whether IL-12p40 gene deficiency induced Thl to Th2 immune deviation could lead to immune tolerance to islet allotransplantation.
Methods:
The survival time of islet allografts,infiltration of CD4~+ and CD8~+ T cell and expression levels of IL-4 and IFN-γin graft region were observed and compared between IL-12p40 knock-out(n=7) and wild type(n=6) recipients.
Results:
Mean survival time of islet allograft in recipients of IL-12p40 knock-out mice was 10.0±2.9 days,and it was 9.7±2.1 days in wild type recipients,there's no difference between them(P＞0.05).Infiltration of CD4~+ and CD8~+ T cell and expression levels of IL-4 and IFN-γin recipients of IL- 12p40 knock-out mice were similar to those in wild type recipients.
Conclusions:
Th1 to Th2 immune deviation existing in IL-12p40 deficient mouse recipient could not inhibit allograft rejection in islet transplantation and could not induce immune tolerance either.
We studied mechanisms and prevention methods of allograft rejection in mouse islet transplantation by means of drug intervention and gene knock-out.Initially applied trichosanthin which is component of Chinese medicine to inhibit allograft rejection in mouse islet transplantation and revealed its possible mechanisms.We also make it clear that IL-12p40 gene deficiency is not sufficient to induce tolerance to islet allograft.Our study is helpful for researchers to understand immune rejection and tolerance in islet transplantation,and it's positive to apply and investigate trichosanthin or other component of Chinese medicine in transplant area.
首先,我们建立了链脲佐菌素诱导的糖尿病小鼠进行肾被膜下胰岛移植的动物模型。在小鼠胰岛的获取上我们吸取了前人的经验并加以改进。然后我们进行了BALB/c小鼠对C57BL/6小鼠的同种胰岛移植,腹腔注射天花粉蛋白来干预受体小鼠的免疫反应,探讨天花粉蛋白对胰岛移植排斥反应的作用和可能的机制,并了解其对胰岛功能的影响。以IL-12p40基因敲除小鼠为移植受体,与野生型的受体相比较,来了解IL-12p40基因及其涉及的免疫环节在小鼠同种胰岛移植排斥中的作用和地位。
第一部分小鼠胰岛移植模型的建立
目的:
建立简便高效的小鼠胰岛获取方法和稳定的糖尿病小鼠胰岛移植动物模型。
方法:
(1)用改良的胆囊穿刺胶原酶P灌注法消化小鼠胰腺,了解操作难度和消化效果。分两组(n=6)比较Ficoll梯密度离心法和滤网过滤法纯化胰岛的效果。(2)用链脲佐菌素诱导小鼠糖尿病,行肾被膜下胰岛移植,观察糖尿病模型的稳定度及胰岛移植后小鼠血糖的纠正情况。
结果:
(1)改良的胆囊穿刺胶原酶P灌注方法简单、有效,胰腺消化充分,胰岛形态良好;胰岛纯化方法上,滤网过滤法获得的胰岛数量和纯度都比Ficoll梯密度离心法要高(P＜0.05),而操作时间则显著减少(P＜0.01)。胰岛素释放试验显示滤网过滤纯化的胰岛释放胰岛素的能力高于Ficoll梯密度离心法(P＜0.05)。(2)链脲佐菌素注射后48小时内小鼠血糖即升高至16.7mmol/L以上形成糖尿病,而胰岛移植(n=10)后第1天血糖即得到纠正,在发生排斥反应以前血糖都能维持正常水平。
结论:
胆囊穿刺胶原酶P灌注加滤过纯化的方法简便、高效,是获取小鼠胰岛的有效措施;链脲佐菌素诱导的糖尿病小鼠行肾被膜下胰岛移植是可靠的胰岛移植模型。
第二部分天花粉蛋白在小鼠同种胰岛移植中的应用
目的:
探讨天花粉蛋白(TCS)对小鼠同种胰岛移植排斥反应的抑制作用;探索这种抑制作用的可能机制;初步了解天花粉蛋白对胰岛功能的影响。
方法:
(1)行BALB/c小鼠至C57BL/6小鼠的同种异基因胰岛移植,随机分为天花粉蛋白腹腔注射组(n=6)和对照组(n=6),移植后每天测血糖,了解胰岛移植物存活时间。(2)设TCS组、胰岛移植组、胰岛移植+TCS组和空白对照组(每组n=5),检测各组T细胞增殖水平和分泌IFN-γ水平,及外周淋巴组织内T细胞的组成比例,探索天花粉蛋白的抑制作用机理。(3)体内实验,检测天花粉蛋白使用前、后胰岛移植物分泌C肽的水平;体外实验,胰岛培养时加入天花粉蛋白,做胰岛素释放试验并与对照组比较,了解其对胰岛功能的影响。
结果:
(1)天花粉蛋白腹腔注射组胰岛移植物存活时间为12.2±1.7天,对照组为9.7±1.4天,移植物存活时间有所延长(P＜0.05)。(2)天花粉蛋白注射后T细胞对供体特异性抗原刺激的增殖反应明显减弱(P＜0.05);分泌IFN-γ水平下降;外周淋巴组织内调节型T细胞比例上升。(3)体内实验,天花粉蛋白使用前、后C肽水平无明显改变;体外实验,胰岛培养时加入天花粉蛋白,胰岛分泌胰岛素的水平下降(P＜0.05)。
结论:
天花粉蛋白可以减缓小鼠同种胰岛移植的排斥反应;其机制可能与天花粉蛋白抑制小鼠的抗原特异性T细胞增殖及上调调节型T细胞有关。天花粉蛋白直接作用于胰岛,对胰岛的功能有抑制作用。
第三部分IL-12p40在胰岛移植排斥反应中作用的研究
目的:
了解IL-12p40基因在小鼠同种胰岛移植排斥反应中的作用,探索IL-12p40基因缺陷所导致的Th1向Th2的免疫偏离能否产生对同种胰岛移植的免疫耐受。
方法:
用IL-12p40基因敲除小鼠为受体行同种胰岛移植(n=7),与野生型受体(n=6)比较,观察胰岛移植物存活时间,移植区域CD4~+和CD8~+T细胞的浸润情况,以及细胞因子IL-4和IFN-γ的表达水平。
结果:
IL-12p40基因敲除受体胰岛移植物的存活时间为10.0±2.9天,对照组为9.7±2.1天,差异无统计学意义(P＞0.05);两组小鼠移植区域CD4~+和CD8~+T细胞的浸润情况,以及细胞因子IL-4和IFN-γ的表达水平都没有明显差异。
结论:
IL-12p40基因缺陷所导致的受体Th1向Th2的免疫偏离不能明显减弱小鼠同种胰岛移植的排斥反应,因此也无法诱导免疫耐受。
我们的实验从药物干预和基因敲除两方面来探讨小鼠同种胰岛移植排斥反应的发生机制及防治措施。初步探索了中药成分天花粉蛋白在对抗免疫排斥中的作用和机制,也明确了IL-12p40基因缺陷无法导致对同种胰岛移植物的免疫耐受。研究结果有助于加深对胰岛移植排斥反应及免疫耐受的认识,对在移植领域进一步研究应用天花粉蛋白或其他中药成分起到了积极作用。
Diabetes mellitus is one of the common chronic diseases with a lot of complications threatening health and life of patients.Although the application of insulin had saved lives of many diabetes patients,hypoglycemia is one of its adverse effects and complications of diabetes mellitus can not be controlled thoroughly.Islet transplantation is a new hopeful therapeutic measure in instead of insulin injection. Patients who accepted islet transplantation could get rid of insulin in some extent.But islet allograft could not be functional constantly,rejection toward allograft is the main reason.This study was interested in mechanisms of allograft rejection in islet transplantation.In order to prolong allograft survival of islet transplantation,we applied immunosuppressive drugs to recipient to prevent the rejection.
We established the model of streptozotocin induced diabetes mouse on the first step and then allogenic islets were transplanted beneath the capsule of the left kidney.We modified the method of pancreas digestion and islet purification based on previous studies.Then we studied the allo-transplantantion of islet from BALB/c mice to C57BL/6 mice.Trichosanthin was injected intraperitoneally to affect the immune response of recipient mice.Influence to function of islet and immunosuppressive effect was assessed and its mechanisms were investigated.In purpose of comprehend the role of IL-12p40 in allograft rejection of islet transplantation,we compared the immune rejections in recipients of IL-12p40 knock-out mice and wild type C57BL/6 mice.
PartⅠEstablishment of islet transplantation model in mouse
Objective:
To obtain a convenient and high performance method of harvesting mouse islet,and establish a stable model of islet transplantation in diabetes mouse.
Methods:
(1) Mouse pancreas was digested by collagenase P which was perfused by means of a gallbladder puncture.We observed the result of digestion and difficulty of operation. We compared the results of Ficoll density gradient centrifugation and filtration in islet purification(n=6 in each group).(2) We also performed islet transplantation in streptozotocin induced diabetes mice to observe the stability of diabetes model and correction of hyperglycemia after transplantation.
Results:
(1) The method of collagenase P perfusion by gallbladder puncture in pancreas digestion is easy and high performance.Filtration is better than Ficoll density gradient centrifugation in islet purification for quantity and purity of islets were elevated (P＜0.05),operating time was saved significantly(P＜0.01).Insulin release test showed that islets achieved by filtration released more insulin than Ficoll density gradient centrifugation(P＜0.05).(2) Hyperglycemia(BG＞16.7mmol/L) was induced by streptozotocin injection within 48 hours and it was corrected within 24 hours after islet transplantation(n=10) until rejection happened.
Conclusions:
The method of collagenase P perfusion by gallbladder puncture is convenient and high performance in obtaining mouse islet.The animal model of islet transplantation in streptozotocin induced diabetes mouse is stable and reliable.
PartⅡApplieation of trichosanthin in mouse islet allotransplantation
Objective:
To understand the inhibition effect of trichosanthin(TCS) to allograft rejection in mouse islet transplantation and investigate its possible mechanisms.To initially find the affect of TCS upon the islet function.
Methods:
(1) Control group(n=6) and TCS injection group(n=6) were set in mice with BALB/c to C57BL/6 islet transplantation.Blood glucose was tested in both groups daily to obtain the survival time of allografts.(2) Control group,TCS injection group, islet transplant group and transplant plus TCS group(n=5 in each group) were set.In all groups,T cell proliferation rate,IFN-γsecreting level and T cell ratio in peripheral lymph organs were detected to investigate mechanisms of trichosanthin in inhibiting rejection.(3) In vivo,we detected C peptide level secreted by islet graft before and after trichosanthin injection.In vitro,insulin release test was applied after islet culture with trichosanthin to comprehend whether trichosanthin could affect islet function.
Results:
(1) The mean survival time of islet allograft in TCS group was 12.2±1.7 days,and it was 9.7±1.4 days in control group,survival time was prolonged after trichosanthin injection(P＜0.05).(2) Donor antigen specific T cell proliferation rate and IFN-γ secreting level were depressed and regulatory T cell ratio in peripheral lymph organs was elevated after trichosanthin injection.(3) In vivo,C peptide levels were similar before and after trichosanthin injection.In vitro,insulin secreting level of islet was depressed after cultivation with trichosanthin(P＜0.05).
Conclusions:
Trichosanthin could inhibit allograft rejection in mouse islet transplantation. Inhibition of antigen specific T cell proliferation and up-regulation of regulatory T cell are possible mechanisms.Thrichosanthin could inhibit function of mouse islet when contact directly.
PartⅢStudying the role of IL-12p40 in allograft rejection of islet transplantation
Objective:
To comprehend the role of IL-12p40 gene in allograft rejection in mouse islet transplantation and investigate whether IL-12p40 gene deficiency induced Thl to Th2 immune deviation could lead to immune tolerance to islet allotransplantation.
Methods:
The survival time of islet allografts,infiltration of CD4~+ and CD8~+ T cell and expression levels of IL-4 and IFN-γin graft region were observed and compared between IL-12p40 knock-out(n=7) and wild type(n=6) recipients.
Results:
Mean survival time of islet allograft in recipients of IL-12p40 knock-out mice was 10.0±2.9 days,and it was 9.7±2.1 days in wild type recipients,there's no difference between them(P＞0.05).Infiltration of CD4~+ and CD8~+ T cell and expression levels of IL-4 and IFN-γin recipients of IL- 12p40 knock-out mice were similar to those in wild type recipients.
Conclusions:
Th1 to Th2 immune deviation existing in IL-12p40 deficient mouse recipient could not inhibit allograft rejection in islet transplantation and could not induce immune tolerance either.
We studied mechanisms and prevention methods of allograft rejection in mouse islet transplantation by means of drug intervention and gene knock-out.Initially applied trichosanthin which is component of Chinese medicine to inhibit allograft rejection in mouse islet transplantation and revealed its possible mechanisms.We also make it clear that IL-12p40 gene deficiency is not sufficient to induce tolerance to islet allograft.Our study is helpful for researchers to understand immune rejection and tolerance in islet transplantation,and it's positive to apply and investigate trichosanthin or other component of Chinese medicine in transplant area.
引文
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