吲哚胺2，3-双加氧酶抑制小鼠心脏移植排斥反应作用机制的研究
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摘要
本课题旨在研究吲哚胺2,3-双加氧酶(IDO)在小鼠异位心脏移植排斥反应中的抑制作用及其机制,采用转染IDO基因的供体小鼠树突细胞(IDO+C)与色氨酸代谢产物(TC)联合对受体进行干预,以期使增殖T细胞在DC传递抗原期间处于色氨酸饥饿且TC大量累积的状态中,造成T细胞增殖抑制或克隆删除,检验在此状态下抑制移植排斥反应的强度,为成功诱导免疫耐受提供实验基础。
第一部分IDO+DC和TC联合应用对T细胞的抑制作用
目的：研究IDO+DC和TC对体外培养T淋巴细胞的抑制作用。方法：通过携带IDO基因的腺病毒转染供体DC而获得IDO+DC。在体外实验中,获取受体脾CD4+T淋巴细胞,分别与供体DC、DC+TC、IDO+DC和IDO+DC+TC进行混合培养。在体内实验中,分别向受体注射供体DC、TC、IDO+DC及IDO+DC+TC,5天后获取受体脾CD4+T淋巴细胞,分别与供体DC进行混合培养。IDO+DC+TC注射组获取的受体脾CD4+T淋巴细胞再分别与供体DC和第三系DC进行混合培养。各组均检测T细胞凋亡率及增殖刺激指数(SI)。结果：在体外实验中,与IDO+DC+TC混合培养的受体T细胞SI明显降低,而T细胞凋亡率明显升高(P<0.01)。在体内实验中,注射IDO+DC+TC的受体T细胞SI亦明显降低,而T细胞凋亡率明显升高(P<0.01)。供体DC刺激的IDO+DC+TC注射组T细胞SI较第三系DC的SI低,而其T细胞凋亡率明显升高,差异均具有统计学意义(P<0.01)。结论：联合应用IDO+DC及TC较单独给予这两种干预因素对T淋巴细胞具有更强的抑制作用,并有可能诱导针对供体的抗原特异性免疫抑制。
第二部分小鼠同种异位心脏移植模型的建立
目的：建立稳定、可靠的小鼠同种异位心脏移植模型,为体内实验结果的准确性提供保障。方法：通过显微外科技术分两阶段建立该动物模型,第一阶段为模型制作训练阶段,第二阶段为稳定阶段,并对麻醉方式、供心处理等方面进行相应改进。结果：稳定阶段进行手术80例,手术成功率(91.25%)较训练阶段(29%)明显提高(P<0.01),且两阶段中无一动物死于麻醉意外。模型稳定阶段中,血管吻合失败率、移植心缺血时间及手术时间等较训练阶段均明显缩短(P<0.01)。结论：长期进行显微外科技术训练对避免实验动物的浪费和保障后续实验结果的准确性具有重要的意义。成功的麻醉是手术成功的前提,提高血管吻合质量是手术成功的关键,此模型稳定可靠,是研究器官移植排斥反应的理想动物模型。
第三部分IDO+DC和TC联合应用对小鼠异位心脏移植排斥反应的抑制作用及其机制研究
目的：研究联合应用供体IDO+DC和TC对移植排斥反应的抑制作用,探讨IDO抗排斥反应的作用机制。方法：术前给予受体不同干预,包括注射PBS、未转染DC、空病毒转染DC、CsA(10mg/kg/d)、TC、IDO+DC、IDO+DC+TC等。观察移植物存活时间。术后7天获取移植物行组织病理学检查、qRT-PCR检测细胞因子和IDO mRNA的表达水平、Western Blot及免疫组化染色检测IDO蛋白的表达水平。获取受体外周血行流式细胞学检测T细胞凋亡率。结果：与PBS组、未转染DC组、空病毒转染DC组比较,TC和IDO+DC组的供心生存期明显延长(P<0.01),病理分级程度下降(P<0.05),IDOmRNA和蛋白表达水平明显增高(P<0.01),TNF-amRNA的表达量降低(P<0.05),而IL-10mRNA和蛋白表达水平增高(P<0.05),且T细胞凋亡率明显升高(P<0.01)。与TC和IDO+DC组比较,IDO+DC+TC组供心生存期延长(P<0.05),IDOmRNA和蛋白表达水平增高(P<0.05),IL-2、IFN-γ、TNF-amRNA的表达量均降低(除与IDO+DC组相比IL-2mRNA下降无统计学差异,P<0.05),IL-10mRNA和蛋白表达水均增高(P<0.05),T细胞凋亡率明显升高(P<0.01),而病理分级程度虽有所降低但无统计学差异(P>0.05)。结论：术前注射转染IDO基因的供体DC及TC对小鼠心脏移植排斥反应的抑制作用较单独应用这两种干预因素更强,表明IDO通过色氨酸耗竭和色氨酸代谢产物累积两条途径同时发挥抗排斥作用。
第四部分IDO+DC和TC联合应用抑制排斥反应的抗原特异性研究
目的：观察联合应用转染IDO基因的供体DC和TC对小鼠心脏移植后皮肤移植排斥反应的抑制作用。方法：按第三部分方法建立IDO+DC+TC实验组,对其中供心存活超过30天的受体分别进行供体来源和第三系来源的皮肤移植,观察移植皮片的存活情况及病理学表现。结果：供体来源的移植皮片在术后两周仍存活,仅出现轻度的皮肤卷边和毛发脱落,皮下组织少量炎性细胞浸润。而第三系来源的移植皮片在术后十天已完全结痂、脱落,皮下组织大量炎性细胞浸润。结论：联合应用转染IDO基因的供体DC和TC可以延长供体来源移植皮肤的生存时间,提示术前注射IDO+DC+TC可诱导针对供体抗原的特异性免疫抑制,进而可能诱导免疫耐受。
Suppressive effect of indoleamine2,3-dioxygenase (IDO) on rejection of mice cardiac transplantation was studied in this experiment. Suppressive effect of transfected IDO positive dendritic cells (IDO+DC) and tryptophan catabolites (TC) were used to induce immune tolerance by suppressing T lymphocyte proliferation during the antigen presenting state of DC. Suppression of T lymphocytes proliferation or clone deletion was achieved when T lymphocytes underwent tryptophan starvation state with accumulation of TC. The suppressive effect on rejection of mice cardiac transplantation was evaluated, which provided experimental evidence for further research in the field of immune tolerance.
Part I Suppressive Effect of IDO+DC in Combination with TC on T Lymphocyte
Objective To evaluate the in vitro and in vivo suppressive effect of IDO+DC and TC on T lymphocyte. Method Adenovirus vector containing IDO gene was used to infect donor (C57BL/6) DC to obtain IDO+DC. In vitro, CD4+T lymphocytes were isolated from the spleen of untreated recipient (BALB/c) mouse, and then treated with either donor DC, TC with donor DC, IDO+DC or Co-administration of IDO+DC and TC. In vivo effect of treatments were examined by injection of either donor DC, TC, IDO+DC or Co-administration of IDO+DC and TC into recipient mouse, and CD4+T lymphocytes were isolated and harvested from the spleen five days after injection. Harvested CD4+T lymphocytes of the treated recipient mouse were mixed cultured with donor DC. Meanwhile, CD4+T lymphocytes harvested from recipient mouse treated with Co-administration of IDO+DC and TC were mixed cultured with tertiary origin DC from C3H/He mouse. T lymphocyte apoptosis rate (AR) and proliferation stimulation index (SI) were evaluated for both in vitro and in vivo effect of treatments. Result Both in vitro and in vivo effect of treatments with Co-administration of IDO+DC and TC showed significant decrease in T lymphocytes proliferation SI, and significant increase in T lymphocyte AR (P＜0.01). By using CD4+T lymphocytes from recipient mouse injected with Co-administration of IDO+DC and TC, mixed cultured with donor origin DC showed significant decrease in T lymphocyte SI, and significant increase in T lymphocyte AR (P<0.01) compare with that when mixed cultured with tertiary origin DC. Conclusion IDO+DC or TC alone is less effective comparing with combination administration of IDO+DC and TC, which showed stronger suppressing effect on T lymphocytes and might be able to induce antigen-specific immune suppression.
Part II Establishment of Heterotropic Cardiac Transplantation Model in Mice
Objective To establish a stable and reliable mouse heterotopic cardiac transplantation model for accurate in vivo results. Method Mouse heterotopic cardiac transplantation (HCT) model was established using C57BL/6mouse as the donor and BALB/c mouse as the recipient. Establishment of model was divided into two phases.100and80pairs of HCT were performed respectively in the training phase and stable phase. Anesthesia technique and method of harvesting the graft heart were also improved accordingly during both phases. Result Surgical success rate of HCT in stable phase (91.25%) was significantly increased when compared with that in training phase (29%)(P＜0.01), and no recipients were dead due to anesthesia in both phases. Vascular anastomosis failure rate, donor heart ischemia time and surgical time all showed significant improvement in stable phase when compare to those in traning phase (P<0.01). Conclusion Long-term training of microsurgical technique avoids wasting of experimental animals and at the same time ensures the quality of the model to be used for further experiments. Prerequisite for successful establishment of HCT model is successful anesthesia for the mouse, and ensuring the quality of vascular anastomosis is the key to successful establishment of HCT model. Mice HCT model is a stable and reliable model for further research in organ transplant rejection.
Part III Suppressive Effect of IDO+DC in Combination with TC on Rejection in Mice Heterotopic Cardiac Transplantation
Objective To examine the combination effect of IDO+DC and TC on transplantation rejection and possible anti-rejection mechanism. Method Donor mice were divided into two major groups, the control group and treatment group. Control group was further divided into four subgroups, including injection of PBS, untransfected DC, vector-virus DC, or Cyclosporine (10mg/kg/d). Treatment group was divided into three subgroups, including injection of TC, IDO+DC or Co-administration of IDO+DC and TC. Survival time of the donor heart in every groups was observed. Meanwhile, donor hearts were harvested7days post transplantation for different examinations, including pathological examination through H&E, mRNA expression of IDO and different cytokines through qRT-PCR, IDO protein expression through western blot and immunohistochemistry. Peripheral blood of recipient was also harvested for T lymphocyte apoptosis rate examination through FACS. Result Compared with PBS, untransfected DC, vector-virus DC control groups, IDO+DC and TC treatment significantly prolonged the survival time of donor hearts (P＜0.01). Pathological grading was significantly decreased (P<0.05). Boeh IDO mRNA and protein expression showed significant increase (P<0.01). mRNA expression of TNF-a was decreased (P＜0.05), while IL-10was significantly increased (P<0.01). Furthermore, the T lymphocyte apoptosis rate was also significantly increased (P＜0.01). Compared with treatment group with IDO+DC or TC alone, co-administration of IDO+DC and TC treatment significantly prolonged the survival time of the donor heart (P＜0.05). Both IDO mRNA and protein expression showed significant increase (P<0.05). mRNA expression of IL-2, IFN-γ, and TNF-a were significantly decreased (P＜0.05), with the exception for the IDO+DC treatment group of IL-2(P>0.05), and expression of IL-10was also significantly increased (P<0.05). Furthermore, the T lymphocyte apoptosis rate was significantly increased as well (P＜0.01). Pathological grading was decreased, but without significant difference (P>0.05). Conclusion Suppressive effect of co-administration of IDO+DC with TC was much more effective than administration of IDO+DC or TC alone, which suggested that IDO achieved immune suppressive effect through the pathway of tryptophan depletion and accumulation of TC.
Part IV Antigen-specific Suppressive Effect of IDO+DC in Combination with TC on Transplant Rejection
Objective To observe the suppressive effect of combination treatment with IDO+DC and TC on skin graft rejection of post cardiac transplantation mice. Method C57BL/6or C3H/He mouse was used as the donor, and BALB/c mouse treated with combination of IDO+DC (C57BL/6origin) and TC underwent HCT with donor heart survival>30days was used as the recipient to establish skin transplantation model. Then the condition of skin graft was monitored. Result Skin graft of C57BL/6origin survived>2weeks post transplantation, with mild skin curl and hair loss. Skin graft of C3H/He origin totally scab and fall off10days post transplantation. Conclusion Transplant rejection of skin graft decreased in mouse underwent treatment with combination of IDO+DC and TC, which indicated that combination treatment with IDO+DC and TC might induce antigen-specific immune tolerance.
第一部分IDO+DC和TC联合应用对T细胞的抑制作用
目的：研究IDO+DC和TC对体外培养T淋巴细胞的抑制作用。方法：通过携带IDO基因的腺病毒转染供体DC而获得IDO+DC。在体外实验中,获取受体脾CD4+T淋巴细胞,分别与供体DC、DC+TC、IDO+DC和IDO+DC+TC进行混合培养。在体内实验中,分别向受体注射供体DC、TC、IDO+DC及IDO+DC+TC,5天后获取受体脾CD4+T淋巴细胞,分别与供体DC进行混合培养。IDO+DC+TC注射组获取的受体脾CD4+T淋巴细胞再分别与供体DC和第三系DC进行混合培养。各组均检测T细胞凋亡率及增殖刺激指数(SI)。结果：在体外实验中,与IDO+DC+TC混合培养的受体T细胞SI明显降低,而T细胞凋亡率明显升高(P<0.01)。在体内实验中,注射IDO+DC+TC的受体T细胞SI亦明显降低,而T细胞凋亡率明显升高(P<0.01)。供体DC刺激的IDO+DC+TC注射组T细胞SI较第三系DC的SI低,而其T细胞凋亡率明显升高,差异均具有统计学意义(P<0.01)。结论：联合应用IDO+DC及TC较单独给予这两种干预因素对T淋巴细胞具有更强的抑制作用,并有可能诱导针对供体的抗原特异性免疫抑制。
第二部分小鼠同种异位心脏移植模型的建立
目的：建立稳定、可靠的小鼠同种异位心脏移植模型,为体内实验结果的准确性提供保障。方法：通过显微外科技术分两阶段建立该动物模型,第一阶段为模型制作训练阶段,第二阶段为稳定阶段,并对麻醉方式、供心处理等方面进行相应改进。结果：稳定阶段进行手术80例,手术成功率(91.25%)较训练阶段(29%)明显提高(P<0.01),且两阶段中无一动物死于麻醉意外。模型稳定阶段中,血管吻合失败率、移植心缺血时间及手术时间等较训练阶段均明显缩短(P<0.01)。结论：长期进行显微外科技术训练对避免实验动物的浪费和保障后续实验结果的准确性具有重要的意义。成功的麻醉是手术成功的前提,提高血管吻合质量是手术成功的关键,此模型稳定可靠,是研究器官移植排斥反应的理想动物模型。
第三部分IDO+DC和TC联合应用对小鼠异位心脏移植排斥反应的抑制作用及其机制研究
目的：研究联合应用供体IDO+DC和TC对移植排斥反应的抑制作用,探讨IDO抗排斥反应的作用机制。方法：术前给予受体不同干预,包括注射PBS、未转染DC、空病毒转染DC、CsA(10mg/kg/d)、TC、IDO+DC、IDO+DC+TC等。观察移植物存活时间。术后7天获取移植物行组织病理学检查、qRT-PCR检测细胞因子和IDO mRNA的表达水平、Western Blot及免疫组化染色检测IDO蛋白的表达水平。获取受体外周血行流式细胞学检测T细胞凋亡率。结果：与PBS组、未转染DC组、空病毒转染DC组比较,TC和IDO+DC组的供心生存期明显延长(P<0.01),病理分级程度下降(P<0.05),IDOmRNA和蛋白表达水平明显增高(P<0.01),TNF-amRNA的表达量降低(P<0.05),而IL-10mRNA和蛋白表达水平增高(P<0.05),且T细胞凋亡率明显升高(P<0.01)。与TC和IDO+DC组比较,IDO+DC+TC组供心生存期延长(P<0.05),IDOmRNA和蛋白表达水平增高(P<0.05),IL-2、IFN-γ、TNF-amRNA的表达量均降低(除与IDO+DC组相比IL-2mRNA下降无统计学差异,P<0.05),IL-10mRNA和蛋白表达水均增高(P<0.05),T细胞凋亡率明显升高(P<0.01),而病理分级程度虽有所降低但无统计学差异(P>0.05)。结论：术前注射转染IDO基因的供体DC及TC对小鼠心脏移植排斥反应的抑制作用较单独应用这两种干预因素更强,表明IDO通过色氨酸耗竭和色氨酸代谢产物累积两条途径同时发挥抗排斥作用。
第四部分IDO+DC和TC联合应用抑制排斥反应的抗原特异性研究
目的：观察联合应用转染IDO基因的供体DC和TC对小鼠心脏移植后皮肤移植排斥反应的抑制作用。方法：按第三部分方法建立IDO+DC+TC实验组,对其中供心存活超过30天的受体分别进行供体来源和第三系来源的皮肤移植,观察移植皮片的存活情况及病理学表现。结果：供体来源的移植皮片在术后两周仍存活,仅出现轻度的皮肤卷边和毛发脱落,皮下组织少量炎性细胞浸润。而第三系来源的移植皮片在术后十天已完全结痂、脱落,皮下组织大量炎性细胞浸润。结论：联合应用转染IDO基因的供体DC和TC可以延长供体来源移植皮肤的生存时间,提示术前注射IDO+DC+TC可诱导针对供体抗原的特异性免疫抑制,进而可能诱导免疫耐受。
Suppressive effect of indoleamine2,3-dioxygenase (IDO) on rejection of mice cardiac transplantation was studied in this experiment. Suppressive effect of transfected IDO positive dendritic cells (IDO+DC) and tryptophan catabolites (TC) were used to induce immune tolerance by suppressing T lymphocyte proliferation during the antigen presenting state of DC. Suppression of T lymphocytes proliferation or clone deletion was achieved when T lymphocytes underwent tryptophan starvation state with accumulation of TC. The suppressive effect on rejection of mice cardiac transplantation was evaluated, which provided experimental evidence for further research in the field of immune tolerance.
Part I Suppressive Effect of IDO+DC in Combination with TC on T Lymphocyte
Objective To evaluate the in vitro and in vivo suppressive effect of IDO+DC and TC on T lymphocyte. Method Adenovirus vector containing IDO gene was used to infect donor (C57BL/6) DC to obtain IDO+DC. In vitro, CD4+T lymphocytes were isolated from the spleen of untreated recipient (BALB/c) mouse, and then treated with either donor DC, TC with donor DC, IDO+DC or Co-administration of IDO+DC and TC. In vivo effect of treatments were examined by injection of either donor DC, TC, IDO+DC or Co-administration of IDO+DC and TC into recipient mouse, and CD4+T lymphocytes were isolated and harvested from the spleen five days after injection. Harvested CD4+T lymphocytes of the treated recipient mouse were mixed cultured with donor DC. Meanwhile, CD4+T lymphocytes harvested from recipient mouse treated with Co-administration of IDO+DC and TC were mixed cultured with tertiary origin DC from C3H/He mouse. T lymphocyte apoptosis rate (AR) and proliferation stimulation index (SI) were evaluated for both in vitro and in vivo effect of treatments. Result Both in vitro and in vivo effect of treatments with Co-administration of IDO+DC and TC showed significant decrease in T lymphocytes proliferation SI, and significant increase in T lymphocyte AR (P＜0.01). By using CD4+T lymphocytes from recipient mouse injected with Co-administration of IDO+DC and TC, mixed cultured with donor origin DC showed significant decrease in T lymphocyte SI, and significant increase in T lymphocyte AR (P<0.01) compare with that when mixed cultured with tertiary origin DC. Conclusion IDO+DC or TC alone is less effective comparing with combination administration of IDO+DC and TC, which showed stronger suppressing effect on T lymphocytes and might be able to induce antigen-specific immune suppression.
Part II Establishment of Heterotropic Cardiac Transplantation Model in Mice
Objective To establish a stable and reliable mouse heterotopic cardiac transplantation model for accurate in vivo results. Method Mouse heterotopic cardiac transplantation (HCT) model was established using C57BL/6mouse as the donor and BALB/c mouse as the recipient. Establishment of model was divided into two phases.100and80pairs of HCT were performed respectively in the training phase and stable phase. Anesthesia technique and method of harvesting the graft heart were also improved accordingly during both phases. Result Surgical success rate of HCT in stable phase (91.25%) was significantly increased when compared with that in training phase (29%)(P＜0.01), and no recipients were dead due to anesthesia in both phases. Vascular anastomosis failure rate, donor heart ischemia time and surgical time all showed significant improvement in stable phase when compare to those in traning phase (P<0.01). Conclusion Long-term training of microsurgical technique avoids wasting of experimental animals and at the same time ensures the quality of the model to be used for further experiments. Prerequisite for successful establishment of HCT model is successful anesthesia for the mouse, and ensuring the quality of vascular anastomosis is the key to successful establishment of HCT model. Mice HCT model is a stable and reliable model for further research in organ transplant rejection.
Part III Suppressive Effect of IDO+DC in Combination with TC on Rejection in Mice Heterotopic Cardiac Transplantation
Objective To examine the combination effect of IDO+DC and TC on transplantation rejection and possible anti-rejection mechanism. Method Donor mice were divided into two major groups, the control group and treatment group. Control group was further divided into four subgroups, including injection of PBS, untransfected DC, vector-virus DC, or Cyclosporine (10mg/kg/d). Treatment group was divided into three subgroups, including injection of TC, IDO+DC or Co-administration of IDO+DC and TC. Survival time of the donor heart in every groups was observed. Meanwhile, donor hearts were harvested7days post transplantation for different examinations, including pathological examination through H&E, mRNA expression of IDO and different cytokines through qRT-PCR, IDO protein expression through western blot and immunohistochemistry. Peripheral blood of recipient was also harvested for T lymphocyte apoptosis rate examination through FACS. Result Compared with PBS, untransfected DC, vector-virus DC control groups, IDO+DC and TC treatment significantly prolonged the survival time of donor hearts (P＜0.01). Pathological grading was significantly decreased (P<0.05). Boeh IDO mRNA and protein expression showed significant increase (P<0.01). mRNA expression of TNF-a was decreased (P＜0.05), while IL-10was significantly increased (P<0.01). Furthermore, the T lymphocyte apoptosis rate was also significantly increased (P＜0.01). Compared with treatment group with IDO+DC or TC alone, co-administration of IDO+DC and TC treatment significantly prolonged the survival time of the donor heart (P＜0.05). Both IDO mRNA and protein expression showed significant increase (P<0.05). mRNA expression of IL-2, IFN-γ, and TNF-a were significantly decreased (P＜0.05), with the exception for the IDO+DC treatment group of IL-2(P>0.05), and expression of IL-10was also significantly increased (P<0.05). Furthermore, the T lymphocyte apoptosis rate was significantly increased as well (P＜0.01). Pathological grading was decreased, but without significant difference (P>0.05). Conclusion Suppressive effect of co-administration of IDO+DC with TC was much more effective than administration of IDO+DC or TC alone, which suggested that IDO achieved immune suppressive effect through the pathway of tryptophan depletion and accumulation of TC.
Part IV Antigen-specific Suppressive Effect of IDO+DC in Combination with TC on Transplant Rejection
Objective To observe the suppressive effect of combination treatment with IDO+DC and TC on skin graft rejection of post cardiac transplantation mice. Method C57BL/6or C3H/He mouse was used as the donor, and BALB/c mouse treated with combination of IDO+DC (C57BL/6origin) and TC underwent HCT with donor heart survival>30days was used as the recipient to establish skin transplantation model. Then the condition of skin graft was monitored. Result Skin graft of C57BL/6origin survived>2weeks post transplantation, with mild skin curl and hair loss. Skin graft of C3H/He origin totally scab and fall off10days post transplantation. Conclusion Transplant rejection of skin graft decreased in mouse underwent treatment with combination of IDO+DC and TC, which indicated that combination treatment with IDO+DC and TC might induce antigen-specific immune tolerance.
引文
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