阻断间接识别途径抑制同种异体移植慢性排异的实验研究
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摘要
目的：
1．建立体外培养、扩增受体C3H小鼠骨髓源性树突状细胞(BM-DC)的方法，并对其进行鉴定；观察其对供体C57BL／6小鼠可溶性抗原提呈的有效性。同时探讨B7反义肽(B7 antisense peptide，B7AP)抑制单向混合淋巴细胞反应的作用，并明确B7AP显著抑制单向混合淋巴细胞反应的最适工作浓度。
2．通过体外供体抗原间接识别反应体系，观察B7AP预处理的负载供体抗原的受体树突状细胞(dendritic cell，DC)诱导针对供体抗原的特异性免疫低反应；同时通过体内实验进一步观察其可行性，并对其机制进行初步分析。
3．建立同种异基因小鼠颈总动脉原位移植模型(C57BL／6→C3H)，观察阻断间接识别途径对移植动脉慢性排异的影响，并初步探讨此种效应的局部机制。
方法：
1．体外分离受体C3H小鼠骨髓细胞，在重组小鼠粒细胞-巨噬细胞集落刺激因子(rmGM-CSF)和肿瘤坏死因子-α(rmTNF-α)的刺激下，手法筛选、培养扩增受体小鼠骨髓源性树突状细胞；通过细胞形态、功能、表面分子表达对其进行鉴定。在培养过程中加入制备的供体C57BL／6小鼠可溶性抗原，通过与受体C3H小鼠脾脏T细胞进行单向混合淋巴细胞反应，观察受体DC负载供体抗原的有效性。进一步利用不同浓度的B7AP与负载供体抗原的受体DC进行充分孵育，并与受体脾脏T细胞进行单向混合淋巴细胞反应(MLR)，建立B7AP浓度对数值与单向混合淋巴细胞反应cpm值(每分钟液闪数)的曲线，应用统计学方法寻找B7AP显著抑制单向混合淋巴细胞反应的最适工作浓度。
2．建立体外供体抗原间接识别反应体系，利用B7AP预处理的负载供体抗原的受体DC与受体T细胞行初次单向混合淋巴细胞反应，收集反应后受体T细胞，与负载供体抗原、第三供体抗原的受体DC和供体DC行再次单向混合淋巴细胞反应，观察反应后受体T细胞针对间接途径提呈的供体抗原、第三供体抗原以及直接途径提呈的供体抗原的免疫活性。同时通过B7AP封闭的负载供体抗原的受体DC对受体小鼠进行预处理后，分离受体脾脏T细胞与负载供体抗原、第三供体抗原的受体DC和供体DC行再次单向混合淋巴细胞反应，了解B7AP封闭的负载供体抗原的受体DC体内有效性，并分别在早期和2月时对受体小鼠进行供体抗原刺激后取脾脏进行细胞因子和淋巴细胞凋亡(apoptosis)分析，初步探讨免疫耐受的其他可能机制。
3．建立小鼠同种异基因颈总动脉原位移植模型(C57BL／6→C3H)，通过术前3天对受体小鼠进行股静脉注射B7AP预处理的负载供体抗原的受体DC，2月后取移植动脉进行病理分析，观察移植动脉内膜增生情况，作计算机图像分析，并通过对移植动脉的免疫组化分析，初步了解此效应的局部机制。
结果：
1．在rmGM-CSF和TNF-α刺激下，可从受体C3H小鼠骨髓前体细胞培养扩增出大量的成熟DC。形态学符合成熟DC，表面高表达CD80、CD86、MHC-Ⅱ类抗原，功能上具有强烈的刺激不同品系小鼠T细胞增殖的能力。
2．在培养过程中加入供体抗原的受体DC具有显著刺激受体T细胞增殖的能力。
3．B7AP预处理后的负载供体抗原的受体DC能够有效减弱对受体T细胞的刺激增殖作用，并且在反义肽终浓度为10mg／L，或者与DC孵育时浓度为20mg／L时，能够保证DC表面B7分子被完全封闭。
4．再次单向混合淋巴细胞反应结果显示，B7AP预处理的负载供体抗原的受体DC能够诱导产生针对供体抗原的免疫低反应，但仍然保持对第三抗原的免疫反应。
5．体内实验也显示B7AP封闭的负载供体抗原的受体DC对受体小鼠进行预处理后，受体脾脏分离T细胞也能产生针对供体抗原的免疫低反应，同时受体在受到供体抗原刺激后脾脏细胞因子mRNA半定量RT-PCR结果显示Th2分泌细胞因子IL-10明显升高，而Th1分泌细胞因子IL-2、IFN-γ减弱，此种效应在一定时间内可以维持；但是受体脾脏淋巴细胞凋亡无改变。
6．体内外实验均发现阻断间接识别途径形成的预处理受体T细胞仍能产生对直接途径提呈的供体抗原的免疫反应。
7．成功建立同种异基因小鼠颈总动脉原位移植模型(C57BL／6→C3H)。
8．2月时取移植动脉，制作病理切片HE染色，观察见预处理小鼠组移植动脉内膜增生不明显，计算机图像分析系统分析显示预处理组小鼠移植动脉内膜相对厚度为0.071±0.034，而对照组的移植动脉相对内膜厚度为0.179±0.056，两者差别具有统计学意义；同时移植动脉壁TGF-β1免疫组化分析显示预处理组TGF-β1的表达相对于对照组明显减弱，与动脉内膜增生程度一致。
结论
1．C3H小鼠骨髓前体细胞在rmGM-CSF和TNF-α的刺激下，可以扩增培养大量成熟DC。
2．受体C3H小鼠的成熟DC能够有效的提呈供体C57BL／6小鼠可溶性抗原。
3．负载供体抗原的受体C3H小鼠DC经B7AP预处理后能够抑制其和受体小鼠T细胞的单向混合淋巴细胞反应。
4．B7AP预处理的负载供体抗原的受体DC能够诱导针对供体抗原的特异性免疫低反应，同时可能通过诱导Th1→Th2免疫偏移来加强这种效应。
5．阻断间接途径产生的受体T细胞的特异性免疫低反应不影响其对直接途径提呈的供体抗原的免疫反应。
6．B7AP预处理的负载供体抗原的受体DC能够有效抑制小鼠同种异基因颈总动脉原位移植(C57BL／6→C3H)后移植动脉的内膜增生，TGF-β1在局部可能发挥一定的作用。
7．B7AP阻断间接识别途径能够有效抑制同种异体移植慢性排异反应。
Objectives: 1. To establish the method of culturing and propagation of the recipient mouse bone marrow-derived dendritic cells(BM-DC) in vitro and verify its validity of donor soluble antigen presentation. Also to investigate the effect of the inhibition of the one-way mixed lymphocyte reaction (MLR) by B7 antisense peptide(B7AP) and find the most suitable B7AP concentration of marked inhibition to one-way MLR. 2. To investigate donor-specific immune hyporesponsiveness induced by the B7AP-pretreated donor antigen-loaded recipient derived DC using the the response system of the recipient-donor indirect pathway in vitro, then to observe the validity in vivo and analyze the mechanism initially. 3. To investigate the effect and its regional mechanism of chronic rejection of the transplanted artery via the blockade of indirect recognition after establishing the allogeneic murine model of carotid artery orthotopic transplantation.
Methods: 1. The recipient C3H BM-DC were generated by culturing bone marrow precursors with recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and tumor necrosis factor-alpha (TNF-α). BM-DC were identified by the cell morphous、function and the expression of the molecules on the cell surface. In the culturing process, donor C57BL/6 soluble antigens were added, then the validity of the recipient DC loading the donor antigen was investigated by the one-way MLR using the spleen T cells of the recipient C3H and the cultured recipient DC. Also the MLRs of the cultured recipient DC and the T cells of the recipient spleen were performed after the cultured recipient DC were incubated with B7APs of different concentrations, to display the curve of the logarithm of the B7AP concentrations and the CPMs of the MLRs and to find the most suitable concentration of the B7APs associated with marked inhibition on the one-way MLR. 2. The response system in vitro of the donor antigen indirect presentation to the recipient was established. The primary one-way MLR of the B7AP-pretreated donor antigen-loaded recipient DC and the recipient spleen T cells were taken , then the secondary MLR of the collected recipient T cells after the primary MLR and the donor-antigen or the third antigen loaded recipient DC or donor DC to investigate its immunological competence. Also the recipient spleen T cells were isolated after the recipient was pretreated by the B7AP-pretreated donor antigen-loaded recipient DC and the MLR was taken with the donor antigen or the third party antigen loaded recipient DC or donor DC to identify the vadility of the B7AP-pretreated donor antigen-loaded recipient DC in vivo. Meanwhile the cytokine genes(IL-2, IL-10, and INF-γmRNA) and the lymphocyte apoptosis of the recipient spleen were analyzed to find the other possible mechanism of the immune tolerance initially after stimulated by the donor antigen in the earlier period or 2 months later. 3. The reciepient was pretreated by B7AP-blocked donor antigen-loaded recipient DCs, then the allogeneic murine model of carotid artery orthotopic transplantation was established (C57BL/6→C3H) . The transplanted artery was harvested to be analyzed pathologically after 2 months. Also the TGF-β1 immunohistochemistry analysis of the transplanted artery were performed to find the regional mechanism of the immune tolerance.
Results: 1. Under the stimulation of the rmGM-CSF and TNF-α, large number of the mature BM-DC were propagated from the mouse bone marrow. They match with the DC morphologically, highly express the CD80、CD86n MHC- II on their surface and stimulate the proliferation of the other strain's T cells intensively. 2. The recipient DC which were cultured by adding the donor antigen could stimulate the proliferation of the recipient T cells significantly. 3. B7AP-pretreated donor antigen-loaded recipient DC could effectively inhibit the proliferation of the recipient T cells and it was sure that the B7 molecular could be fully blocked when the concentration of B7AP was 10mg/L or 20mg/L incubated with DC. 4. The result of the secondary MLR showed B7AP-pretreated donor antigen-loaded recipient DC could induce the immune hyporeponsiveness to the donor antigen, but immune responsiveness to the third party antigen. 5. The experiment in vivo also showed the recipient spleen T cells would hyporesponse to the donor antigen after the recipient was pretreated by the B7AP-blocked donor antigen-loaded recipient DC. Meanwhile after stimulated by donor antigen, the Th2 cytokines (IL-10) mRNA of the recipient spleen were up-regulated and the Th1 cytokine (IL-2、IFN-γ) mRNA were down-regulated, which was maintained in some time, but the apoptosis of the recipient spleen lymphocytes were not changed. 6. The recipient T cells pretreated by the blockade of indirect recognition were hyperresponsive to the donor antigen presented via direct recognition. 7. We successfully established the allogeneic murine model of carotid artery orthotopic transplantation. 8. The transplanted artery was harvested in 2 month and the intimal proliferative lesion was observed pathologically. The result showed the relative thickness of the intima pretreated was 0.071±0.034, but 0.179±0.056 of the control group. The difference was statistically significant. The TGF-β1 in the artery wall pretreated was low-expressed by the immunohistochemical analysis, which was matched with the levels of intimal proliferative lesion.
Conclusions: 1. A large quantity of mature DC was propagated from mouse bone marrow precursors under rmGM-CSF and TNF-αstimulation. 2. The recipient DC could present the donor antigen effectively. 3. The donor-loaded recipient DC pretreated by the B7AP could inhibit the one-way MLR with the recipient T cells. 4. The B7AP-pretreated donor antigen-loaded recipient DC could induce the specific hyporesponsiveness to the donor antigen, which may be enhanced by the immune deviation (Th1→Th2). 5. The specific hyporesponsiveness of the recipient T cells to the donor antigen via the blockade of the indirect recognition would not take effect on its response to the donor antigen via direct recognition. 6. The B7AP-pretreated donor antigen-loaded recipient DC could effectively inhibit the intimal proliferative lesion of the transplanted artery in the allogeneic murine model of carotid artery orthotopic transplantation, and the TGF-β1 may play a regionnal role. 7. Blockade of indirect recognition by B7AP can effectively inhibit chronic allograft rejection.
1．建立体外培养、扩增受体C3H小鼠骨髓源性树突状细胞(BM-DC)的方法，并对其进行鉴定；观察其对供体C57BL／6小鼠可溶性抗原提呈的有效性。同时探讨B7反义肽(B7 antisense peptide，B7AP)抑制单向混合淋巴细胞反应的作用，并明确B7AP显著抑制单向混合淋巴细胞反应的最适工作浓度。
2．通过体外供体抗原间接识别反应体系，观察B7AP预处理的负载供体抗原的受体树突状细胞(dendritic cell，DC)诱导针对供体抗原的特异性免疫低反应；同时通过体内实验进一步观察其可行性，并对其机制进行初步分析。
3．建立同种异基因小鼠颈总动脉原位移植模型(C57BL／6→C3H)，观察阻断间接识别途径对移植动脉慢性排异的影响，并初步探讨此种效应的局部机制。
方法：
1．体外分离受体C3H小鼠骨髓细胞，在重组小鼠粒细胞-巨噬细胞集落刺激因子(rmGM-CSF)和肿瘤坏死因子-α(rmTNF-α)的刺激下，手法筛选、培养扩增受体小鼠骨髓源性树突状细胞；通过细胞形态、功能、表面分子表达对其进行鉴定。在培养过程中加入制备的供体C57BL／6小鼠可溶性抗原，通过与受体C3H小鼠脾脏T细胞进行单向混合淋巴细胞反应，观察受体DC负载供体抗原的有效性。进一步利用不同浓度的B7AP与负载供体抗原的受体DC进行充分孵育，并与受体脾脏T细胞进行单向混合淋巴细胞反应(MLR)，建立B7AP浓度对数值与单向混合淋巴细胞反应cpm值(每分钟液闪数)的曲线，应用统计学方法寻找B7AP显著抑制单向混合淋巴细胞反应的最适工作浓度。
2．建立体外供体抗原间接识别反应体系，利用B7AP预处理的负载供体抗原的受体DC与受体T细胞行初次单向混合淋巴细胞反应，收集反应后受体T细胞，与负载供体抗原、第三供体抗原的受体DC和供体DC行再次单向混合淋巴细胞反应，观察反应后受体T细胞针对间接途径提呈的供体抗原、第三供体抗原以及直接途径提呈的供体抗原的免疫活性。同时通过B7AP封闭的负载供体抗原的受体DC对受体小鼠进行预处理后，分离受体脾脏T细胞与负载供体抗原、第三供体抗原的受体DC和供体DC行再次单向混合淋巴细胞反应，了解B7AP封闭的负载供体抗原的受体DC体内有效性，并分别在早期和2月时对受体小鼠进行供体抗原刺激后取脾脏进行细胞因子和淋巴细胞凋亡(apoptosis)分析，初步探讨免疫耐受的其他可能机制。
3．建立小鼠同种异基因颈总动脉原位移植模型(C57BL／6→C3H)，通过术前3天对受体小鼠进行股静脉注射B7AP预处理的负载供体抗原的受体DC，2月后取移植动脉进行病理分析，观察移植动脉内膜增生情况，作计算机图像分析，并通过对移植动脉的免疫组化分析，初步了解此效应的局部机制。
结果：
1．在rmGM-CSF和TNF-α刺激下，可从受体C3H小鼠骨髓前体细胞培养扩增出大量的成熟DC。形态学符合成熟DC，表面高表达CD80、CD86、MHC-Ⅱ类抗原，功能上具有强烈的刺激不同品系小鼠T细胞增殖的能力。
2．在培养过程中加入供体抗原的受体DC具有显著刺激受体T细胞增殖的能力。
3．B7AP预处理后的负载供体抗原的受体DC能够有效减弱对受体T细胞的刺激增殖作用，并且在反义肽终浓度为10mg／L，或者与DC孵育时浓度为20mg／L时，能够保证DC表面B7分子被完全封闭。
4．再次单向混合淋巴细胞反应结果显示，B7AP预处理的负载供体抗原的受体DC能够诱导产生针对供体抗原的免疫低反应，但仍然保持对第三抗原的免疫反应。
5．体内实验也显示B7AP封闭的负载供体抗原的受体DC对受体小鼠进行预处理后，受体脾脏分离T细胞也能产生针对供体抗原的免疫低反应，同时受体在受到供体抗原刺激后脾脏细胞因子mRNA半定量RT-PCR结果显示Th2分泌细胞因子IL-10明显升高，而Th1分泌细胞因子IL-2、IFN-γ减弱，此种效应在一定时间内可以维持；但是受体脾脏淋巴细胞凋亡无改变。
6．体内外实验均发现阻断间接识别途径形成的预处理受体T细胞仍能产生对直接途径提呈的供体抗原的免疫反应。
7．成功建立同种异基因小鼠颈总动脉原位移植模型(C57BL／6→C3H)。
8．2月时取移植动脉，制作病理切片HE染色，观察见预处理小鼠组移植动脉内膜增生不明显，计算机图像分析系统分析显示预处理组小鼠移植动脉内膜相对厚度为0.071±0.034，而对照组的移植动脉相对内膜厚度为0.179±0.056，两者差别具有统计学意义；同时移植动脉壁TGF-β1免疫组化分析显示预处理组TGF-β1的表达相对于对照组明显减弱，与动脉内膜增生程度一致。
结论
1．C3H小鼠骨髓前体细胞在rmGM-CSF和TNF-α的刺激下，可以扩增培养大量成熟DC。
2．受体C3H小鼠的成熟DC能够有效的提呈供体C57BL／6小鼠可溶性抗原。
3．负载供体抗原的受体C3H小鼠DC经B7AP预处理后能够抑制其和受体小鼠T细胞的单向混合淋巴细胞反应。
4．B7AP预处理的负载供体抗原的受体DC能够诱导针对供体抗原的特异性免疫低反应，同时可能通过诱导Th1→Th2免疫偏移来加强这种效应。
5．阻断间接途径产生的受体T细胞的特异性免疫低反应不影响其对直接途径提呈的供体抗原的免疫反应。
6．B7AP预处理的负载供体抗原的受体DC能够有效抑制小鼠同种异基因颈总动脉原位移植(C57BL／6→C3H)后移植动脉的内膜增生，TGF-β1在局部可能发挥一定的作用。
7．B7AP阻断间接识别途径能够有效抑制同种异体移植慢性排异反应。
Objectives: 1. To establish the method of culturing and propagation of the recipient mouse bone marrow-derived dendritic cells(BM-DC) in vitro and verify its validity of donor soluble antigen presentation. Also to investigate the effect of the inhibition of the one-way mixed lymphocyte reaction (MLR) by B7 antisense peptide(B7AP) and find the most suitable B7AP concentration of marked inhibition to one-way MLR. 2. To investigate donor-specific immune hyporesponsiveness induced by the B7AP-pretreated donor antigen-loaded recipient derived DC using the the response system of the recipient-donor indirect pathway in vitro, then to observe the validity in vivo and analyze the mechanism initially. 3. To investigate the effect and its regional mechanism of chronic rejection of the transplanted artery via the blockade of indirect recognition after establishing the allogeneic murine model of carotid artery orthotopic transplantation.
Methods: 1. The recipient C3H BM-DC were generated by culturing bone marrow precursors with recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) and tumor necrosis factor-alpha (TNF-α). BM-DC were identified by the cell morphous、function and the expression of the molecules on the cell surface. In the culturing process, donor C57BL/6 soluble antigens were added, then the validity of the recipient DC loading the donor antigen was investigated by the one-way MLR using the spleen T cells of the recipient C3H and the cultured recipient DC. Also the MLRs of the cultured recipient DC and the T cells of the recipient spleen were performed after the cultured recipient DC were incubated with B7APs of different concentrations, to display the curve of the logarithm of the B7AP concentrations and the CPMs of the MLRs and to find the most suitable concentration of the B7APs associated with marked inhibition on the one-way MLR. 2. The response system in vitro of the donor antigen indirect presentation to the recipient was established. The primary one-way MLR of the B7AP-pretreated donor antigen-loaded recipient DC and the recipient spleen T cells were taken , then the secondary MLR of the collected recipient T cells after the primary MLR and the donor-antigen or the third antigen loaded recipient DC or donor DC to investigate its immunological competence. Also the recipient spleen T cells were isolated after the recipient was pretreated by the B7AP-pretreated donor antigen-loaded recipient DC and the MLR was taken with the donor antigen or the third party antigen loaded recipient DC or donor DC to identify the vadility of the B7AP-pretreated donor antigen-loaded recipient DC in vivo. Meanwhile the cytokine genes(IL-2, IL-10, and INF-γmRNA) and the lymphocyte apoptosis of the recipient spleen were analyzed to find the other possible mechanism of the immune tolerance initially after stimulated by the donor antigen in the earlier period or 2 months later. 3. The reciepient was pretreated by B7AP-blocked donor antigen-loaded recipient DCs, then the allogeneic murine model of carotid artery orthotopic transplantation was established (C57BL/6→C3H) . The transplanted artery was harvested to be analyzed pathologically after 2 months. Also the TGF-β1 immunohistochemistry analysis of the transplanted artery were performed to find the regional mechanism of the immune tolerance.
Results: 1. Under the stimulation of the rmGM-CSF and TNF-α, large number of the mature BM-DC were propagated from the mouse bone marrow. They match with the DC morphologically, highly express the CD80、CD86n MHC- II on their surface and stimulate the proliferation of the other strain's T cells intensively. 2. The recipient DC which were cultured by adding the donor antigen could stimulate the proliferation of the recipient T cells significantly. 3. B7AP-pretreated donor antigen-loaded recipient DC could effectively inhibit the proliferation of the recipient T cells and it was sure that the B7 molecular could be fully blocked when the concentration of B7AP was 10mg/L or 20mg/L incubated with DC. 4. The result of the secondary MLR showed B7AP-pretreated donor antigen-loaded recipient DC could induce the immune hyporeponsiveness to the donor antigen, but immune responsiveness to the third party antigen. 5. The experiment in vivo also showed the recipient spleen T cells would hyporesponse to the donor antigen after the recipient was pretreated by the B7AP-blocked donor antigen-loaded recipient DC. Meanwhile after stimulated by donor antigen, the Th2 cytokines (IL-10) mRNA of the recipient spleen were up-regulated and the Th1 cytokine (IL-2、IFN-γ) mRNA were down-regulated, which was maintained in some time, but the apoptosis of the recipient spleen lymphocytes were not changed. 6. The recipient T cells pretreated by the blockade of indirect recognition were hyperresponsive to the donor antigen presented via direct recognition. 7. We successfully established the allogeneic murine model of carotid artery orthotopic transplantation. 8. The transplanted artery was harvested in 2 month and the intimal proliferative lesion was observed pathologically. The result showed the relative thickness of the intima pretreated was 0.071±0.034, but 0.179±0.056 of the control group. The difference was statistically significant. The TGF-β1 in the artery wall pretreated was low-expressed by the immunohistochemical analysis, which was matched with the levels of intimal proliferative lesion.
Conclusions: 1. A large quantity of mature DC was propagated from mouse bone marrow precursors under rmGM-CSF and TNF-αstimulation. 2. The recipient DC could present the donor antigen effectively. 3. The donor-loaded recipient DC pretreated by the B7AP could inhibit the one-way MLR with the recipient T cells. 4. The B7AP-pretreated donor antigen-loaded recipient DC could induce the specific hyporesponsiveness to the donor antigen, which may be enhanced by the immune deviation (Th1→Th2). 5. The specific hyporesponsiveness of the recipient T cells to the donor antigen via the blockade of the indirect recognition would not take effect on its response to the donor antigen via direct recognition. 6. The B7AP-pretreated donor antigen-loaded recipient DC could effectively inhibit the intimal proliferative lesion of the transplanted artery in the allogeneic murine model of carotid artery orthotopic transplantation, and the TGF-β1 may play a regionnal role. 7. Blockade of indirect recognition by B7AP can effectively inhibit chronic allograft rejection.
引文
1. Hart DN. DC: unique leukocyte population which control the primary immune response[J]. Blood, 1997, 90(9): 3245-3287.
2. Fairchild P J, Waldmann H. DCs and prospects for transplantation tolerance[J]. Curr Opin Immunol, 2000, 12(5): 528-635.
3. Lechler R, Ng WF, Steinman RM. DCs in transplantation—friend or foe? [J] Immunity, 2001, 14(4): 357-368
4. Ling V, Wu PW, Finnerty HF, et al. Cutting edge: identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor[J]. J Immunol, 2000, 164(4): 1653-1657.
5. Banchereau J, Steinman RM. DCs and the control of immunity[J]. Nature, 1998, 392(6673): 245-252.
6. Onodera K, Chandraker A, Volk HD, et al. Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2[J]. Transplantation, 1999, 68(2): 288-293.
7. Gimmi CD, Freeman GJ, Gribben JG, et al. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation[J]. Proc Natl Acad Sci U S A, 1993, 90(14): 6586-6590.
8. Harding FA, McArthur JG, Gross JA, et al. CD28-mediated signalling costimulates murine T cells and prevents induction of anergy in T-cell clones[J]. Nature, 1992, 356(6370): 607-609
9. von Bubnoff D, de la Salle H, Wessendorf J, et al. Antigen-presenting cells and tolerance induction[J]. Allergy, 2002, 57(1): 2-8.
10. Game DS, Lechler RI. Pathways of allorecognition: implication for transplantation tolerance. Transpl Immunol, 2002, 10(2-3): 101-108.
11. Hornick P. Direct and indirect allorecognition[J]. Methods Mol Biol, 2006, 333: 145-156.
12. Ochando JC, Krieger NR, Bromberg JS. Direct versus indirect allorecognition: Visualization of dendritic cell distribution and interactions during rejection and tolerization[J]. Am J Transplant, 2006, 6(10): 2488-2496.
13. Takayama T, Nishioka Y, Lu L, et al. Retroviral delivery of viral interleukin-10 into myeloid DCs markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness[J].Transplantation, 1998, 66(12): 1567-1574.
14. Chen Z, Lu L, Li J, et al. Transfection with genes encoding CTLA4Ig mediated by adenoassociated virus vectors prolongs survival of heart allografts[J]. Transplant Proc, 2001, 33(1-2): 604.
15．叶闻斐，何球藻．未成熟树突细胞诱导同种免疫低应答性的研究[J]．中国免疫学杂志，2000，16(11)：578-580．
16．于平，熊思东，何球藻，等．未成熟树突细胞诱导异体嵌合体的形成[J]．中国免疫学杂志，2002，18(4)：223-227．
17. Sheng Sun D, Iwagaki H, Ozaki M, et al. Prolonged survival of donor-specific rat intestinal allograft by administration of bone-marrow-derived immature dendritic cells[J]. Transpl Immunol, 2005, 14(1): 17-20.
18. Garrovillo M, Ali A, Oluwole SF. Indirect allorecognition in acquired thymic tolerance: induction of donor-specific tolerance to rat cardiac allografts by allopeptide-pulsed host DCs[J]. Transplantation, 1999, 68(12): 1827-1834.
19. Ali A, Garrovillo M, Jin MX, et al. Major histocompatibility complex class Ⅰ peptide-pulsed host DCs induce antigen-specific acquired thymic tolerance to islet cells[J]. Transplantation, 2000, 69(2): 221-226.
20. Tiao MM, Lu L, Tao R, et al. Prolongation of cardiac allograft survival by systemic administration of immature recipient dendritic cells deficient in NF-kappaB activity[J]. Ann Surg, 2005, 241(3): 497-505.
21. Xu DL, Liu Y, Tan JM, et al. Marked prolongation of murine cardiac allograft survival using recipient immature dendritic cells pulsed with donor-derived apoptotic cells. Scand J Immunol, 2004, 59(6): 536-544.
22. DePaz HA, Oluwole OO, Adeyeri AO, et al. Immature rat myeloid DCs generated in low-dose granulocyte macrophage-colony stimulating factor prolong donorspecific rat cardiac allograft survival [J]. Transplantation, 2003, 75(4): 521-528.
23. Lu L, Li W, Zhong C, et al. Increased apopotosis of immunoreactive host cells and augmented donor leukocyte chimerism, not sustained inhibition of B7 molecule expression expression are associated with prolonged cardiac allograft survival in mice preconditioned with immature donor DCs plus anti-CD40L mAb[J]. Transplantation, 1999, 68(6): 747-757.
24. Lee WC, Zhong C, Qian S, et al. Phenotype, function, and in vivo migration and survival of allogeneic DC progenitors genetically engineered to express TGF-beta[J]. Transplantation, 1998, 66(12): 1810-1817.
25. Takayama T, Morelli AE, Robbins PD, et al. Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid DCs that induce allosntigen-specific T cell anergy in vitro[J]. Gene Ther, 2000, 7(15): 1265-1273.
26. Li WM, Liu W, Gao C, et al. Antigen-specific tolerance induced by IL-10 gene modified immature dendritic cells in experimental autoimmune myocarditis in rats[J]. Chin Med J (Engl), 2006, 119(19): 1646-1652.
27. Liu N, Duan TD, Zheng N. Effects of TGF-betal, gene modified donor dendritic cells on immune repulsion[J]. Sichuan Da Xue Xue Bao Yi Xue Ban, 2006, 37(5): 721-725.
28. Yoshimura S, Bondeson J, Brennan FM, et al. Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of DCs with proteasome inhibitor PSI[J]. Eur J Immunol, 2001, 31(6): 1883-1893
29．陈晋，熊思东，张瑞华，等．B7反义肽抑制同种异基因移植排斥反应的研究[J]．中国免疫学杂志，2003，19(7)：468-472
30．项建斌，程峰，陈宗祐，等．异体小鼠颈动脉移植慢性排斥模型的制作[J]．复旦学报医学版，2006，33(2)：222-224．
1. Hart DN. DC: unique leukocyte population which control the primary immune response[J]. Blood, 1997, 90(9): 3245-3287.
2. Banchereau J, Steinman RM. DCs and the control of immunity[J]. Nature, 1998, 392(6673): 245-252.
3. von Bubnoff D, de la Salle H, Wessendorf J, et al. Antigen-presenting cells and tolerance induction[J]. Allergy, 2002, 57(1): 2-8.
4. Tseng SX, Ostugi M, Gorski K, et al. B7-DC, a new DC molecule with potent costimulatory properties for T cells[J]. J Exp Med, 2001, 193(7): 839-846.
5. Boussiotis VA, Freeman GJ, Gray G, et al. B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance[J]. J Exp Med, 1993, 178(5): 1753-1763.
6．陈晋，熊思东，张瑞华，等．B7反义肽抑制同种异基因移植排斥反应的研究[J]．中国免疫学杂志，2003，19(7)：468-472．
7. Steinman RM and Cohn IA. Identification of a novel cell type in peripheral lymphoid organs of mice[J]. J Exp Med, 1973, 137(5): 1142-1162.
8. Hart DN, Hill GR. DC immunotherapy for ancer; Application to low-grade lymphoma and multiply myeloma[J]. Immunol Cell Biol, 1999, 77(5): 451-459.
9. Kock F, Heufler C, Kanpgen E, et al. Tumor necrosis factor alpha maintains the ciability of murine epidermal Langerhans cells in culture, but in contrast to granulocyte/macrophage colony-stimulating factor, without inducing their functional maturation[J]. J Exp Med, 1990, 171(1): 159-171.
10．孙祖玥，赵勇．树突状细胞诱导移植免疫耐受[A]．见：移植免疫耐受[M]．赵勇主编．北京：中国医药科技出版社，2005：85-86．
11. Hanada K, Tsunoda R, Hamada H. GM-CSF-induced in vivo expansion of splenic dndritic cells and their strong costimulation activity[J]. J Leukoc Biol, 1996, 60(2): 181-190.
12. Ferlazzo G, Klein J, Paliard X, et al. Dendritic cells generated from CD34+ progenitor cells with flt3 ligand, c-kit ligand, GM-CSF, IL-4, and TNF-alpha are functional antigen-presenting cells resembling mature monocyte-derived dendritic cells[J]. J Immunother, 2000, 23 (1): 48-58.
13. Inaba K, Inaba M, Romani N, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor[J]. J Exp Med, 1992, 176(6): 1693-1702.
14．许化溪，严俊．实验动物免疫细胞功能功能的测定[A]．见：现代免疫学实验技术[M]．沈关心，周如麟主编．湖北：湖北科学技术出版社，1998：328-341．
15. Norbury CC, Chambers BJ, Proscott AR, et al. Constitutive macropinocytosis allows TAP-dependent major histocompatibility complex class-1 presentation of exogenous soluble antigen by bone marrow-derived DCs[J]. Eur J Immunol, 1997, 27(1): 280-288.
16. Carl GF, Vries JM, Lesterhuis EJ, et al. DC immunotherapy: mapping the way[J]. Nature Med, 2004, 10 (5): 475-480.
17. Bonham CA, Peng L, Liang X, et al. Marked prolongation of cardiac allograft survival by DCs genectically engineered with NF-KB oligodeoxyribonucleotide decoys and adenoviral vectors CTLA4-Ig[J]. J Immunol, 2002, 169(6): 3382-3391.
1. Ensminger SM, Spriewald BM, Witzke O, et al. Indirect allorecog-nition can play an important role in the development of transplant arteriosclerosis[J]. Transplantation, 2002, 73(2): 279-286.
2. Hornick P. Direct and indirect allorecognition[J]. Methods Mol Biol, 2006, 333: 145-156.
3. Jenkins MK, Ashwell JD, Schwartz RH. Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells[J]. J Immunol, 1988, 140(10): 3324-3330.
4. Onodera K, Chandraker A, Volk HD, et al. Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2[J]. Transplantation, 1999, 68(2): 288-293
5. Gimmi CD, Freeman GJ, Gribben JG, et al. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation[J]. Proc Natl Acad Sci U S A, 1993, 90(14): 6586-6590.
6. Harding FA, McArthur JG, Gross JA, et al. CD28-mediated signalling costimulates murine T cells and prevents induction of anergy in T-cell clones[J]. Nature, 1992, 356(6370): 607-609.
7．于平，熊思东，何球藻，等．未成熟树突状细胞诱导异体嵌合体的形成[J]．中国免疫学杂志，2002，18(4)：223-227
8. Vella JP, Spadafora-Ferreira M, Murphy B, et al. Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction[J]. Transplantation, 1997, 64(6): 795-800.
9. Lee RS, Yamada K, Houser SL, et al. Indirect allorecognition promotes the development of cardiac allograft vasculopathy[J]. Proc Natl Acad Sci U S A, 2001, 98(6): 3276-3281.
10. Mandelbrot DA, Furukawa Y, McAdam AJ, et al. Expression of B7 molecules in recipient, not donor, mice determines the survival of cardiac allografts[J]. J Immunol, 1999, 163(7): 3753-3757.
11. Ochando JC, Krieger NR, Bromberg JS. Direct versus indirect allorecognition: Visualization of dendritic cell distribution and interactions during rejection and tolerization[J]. Am J Transplant, 2006, 6(10): 2488-2496.
12. Hillebrands JL, Raue HP, Klatter FA, et al. Intrathymic immune modulation prevents acute rejection but not the development of graft arteriosclerosis (chronic rejection) [J]. Transplantation, 2001, 71 (7): 914-924.
13. Takayama T, Nishioka Y, Lu L, et al. Retroviral delivery of viral interleukin-10 into myeloid DCs markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness[J]. Transplantation, 1998, 66(12): 1567-1574.
14. Chen Z, Lu L, Li J, et al. Transfection with genes encoding CTLA4Ig mediated by adenoassociated virus vectors prolongs survival of heart allografts[J]. Transplant Proc, 2001, 33(1-2): 604.
15. van der Merwe PA, Bodian DL, Daenke S, et al. CD80(BT-1)binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med.1997, 185(3): 393-403.
16. Greene J, Wang M, Liu Y E, Raymond LA, et al. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase4. J Biol Chem, 1996, 271(48): 30375-30380.
17. Yi-qun Z, Lorre K, de Boer M, et al. B7-blocking agents, alone or in combination with cyclosporin A, induce antigen-specific anergy of human memory T cells[J]. J Immunol, 1997, 158(10): 4734-4740
18. Gebhardt BM, Hodkin M, Varnell ED, et al. Protection of corneal allografts by CTLA4-Ig[J]. Cornea, 1999, 18(3): 314-320.
19. Guillot C, Mathieu P, Coathalem H, et al. Tolerance to cardiac allografts via local and systemic mechanisms after adenovirus-mediated CTLA4Ig expression[J]. J Immunol, 2000, 164(10): 5258-5268.
20. Tomasoni S, Azzollini N, Casiraghi F, et al . CTLA4-Ig gene transfer prolongs survival and induces donor specific tolerance in a rat renal allograft[J]. J Am Soc Nephrol, 2000, 11 (4): 747-752.
21. Kurlberg G, Haglind E, Schon K, et al. Blockade of the B7-CD28 pathway by CTLA4-Ig counteracts rejection and prolongs survival in small bowel transplantation[J]. Scand J Immunol, 2000, 51 (3): 224-230.
22. Han B, Hu Y. Effects of CTLA4-Ig gene-modified dendritic cells on the corneal allografts[J]. J Huazhong Univ Sci Technolog Med Sci, 2006, 26(3): 366-368.
23. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig[J]. N Engl J Med, 2003, 349(20): 1907-1915
24．黄赤兵，吴军，张艮，等．用负载供体抗原的致耐受性树突状细胞延长大鼠移 植肾存活[J]．第三军医大学学报，2003，25(21)：1906-1908．
25. Woodward JE, Zotola LB, Schaefer AT, et al. Blockade of the CD28/B7 pathway is required for the establishment of donor cell chimerism in CD40 ligand-deficent recipients[J]. Transplant Proc, 2001, 33(1-2): 115.
26. Steurer W, Oellinger R, Perwanger F, et al. Prolonged allograft survival following ex vivo blockade of costimulatory signals B7-1/2 and CD40[J]. Transplant Proc, 2001, 33(1-2): 274-275.
27. Yu XZ, Bidwell SJ, Martin PJ, et al. CD28-specific antibody prevents graftversus-host disease in mice[J]. J Immunol, 2000, 164(9): 4564-4568.
28. Yu XZ, Carpenter P, Anasetti C. Advances in transplantation tolerance[J]. Lancet, 2001, 357: 1959-1963.
29．陈晋，熊思东，张瑞华，等．B7反义肽抑制同种异基因移植排斥反应的研究[J]．中国免疫学杂志，2003，19(7)：468-472．
30. Metzler WJ, Bajorath J, Fenderson W, et al. Solution structure of human CTLA4 and delineation of a CD80/ CD86 binding site conserved in CD28[J]. Nature Structural Biol, 1997, 4(7): 527-532.
31. Tao R, Wang L, Chen CH, et al. Mechanistic insights into achievement of cardiac allograft long-term survival by treatment with immature dendritic cells and sub-dose sirolimus[J]. J Heart Lung Transplant, 2006, 25(3): 310-319.
32. Xu H, Chen T, Wang HQ, et al. Combination treatment with donor interleukin12p35 silenced dendritic cells and cyclosporine induces long-term survival of intestinal allografts in rats[J]. Transplant Proc, 2007, 39(1): 286-288.
33. Valujskikh A, Fedoseyeva E, Benichou G, et al. Development of autoimmunity after skin graft rejection via an indirect alloresponse[J]. Transplantation, 2002, 73 (7): 1130-1137.
34. Lu L, Qian S, Hepshberger PA, et al. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation[J]. J Immunol, 1997, 158(12): 5676-5684.
35. Golshayan D, Jiang S, Tsang J, et al. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance[J]. Blood, 2007, 109(2): 827-835.
36. Xu H, Chen T, Wang HQ, et al. Prolongation of rat intestinal allograft survival by administration of donor interleukin-12 p35-silenced bone marrow-derived dendritic cells[J]. Transplant Proc, 2006, 38(5): 1561-1563.
37. Gao Q, Chen N, Rouse TM, et al. The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance [J]. Transplantation, 1996, 62(12): 1847-1854.
38. Mosmann TR, Sad S. The expanding universe of T2cell subsets: Th1, Th2 and more[J]. Immuno Today, 1996, 17(3): 138-146.
39. Taylor PA, Panoskalitsis-Mortari A, Noelle RJ, et al. Analysis of the requirements for the induction of CD4+ T cell alloantigen hyporesponsiveness by ex vivo anti-CD40 ligand antibody[J]. J Immunol, 2000, 164(2): 612-622.
1. Vella JP, Spadafora-Ferreira M, Murphy B, et al. Indirect allo recogni-tion of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction[J]. Transplantation, 1997, 64(6): 795-800.
2. Ensminger SM, Spriewald BM, Witzke O, et al. Indirect allorecognition can play an important role in the development of transplant arteriosclerosis[J]. Transplantation, 2002, 73(2): 279-286.
3. Lee RS, Yamada K, Houser SL, et al.Indirect allorecognition promotes the development of cardiac allograft vasculopathy[J]. Proc Natl Acad Sci U S A, 2001, 98(6): 3276-3281.
4. Motomura N, Lou H, Maurice P, et al. Acceleration of arteriosclerosis of the rat aorta allograft by insulin growth factor-I[J]. Transplantation, 1997, 63(7): 932-936.
5．李幼平，冯莉，唐强，等．慢性移植物失功机制及干预[A]．见：移植免疫生物学[M]．李幼平主编．北京：高等教育出版社，2006：253-254．
6. Game DS, Lechler RI. Pathways of allorecognition: implication for transplantation tolerance. Transpl Immunol, 2002, 10(2-3): 101-108.
7. Mirenda V, Berton I, Read J, et al. Modified dendritic cells coexpressing self and allogeneic major histocompatability complex molecules: an efficientway to induce indirect pathway regulation[J]. J Am Soc Nephrology, 2004, 15(4): 987-997.
8. Mandelbrot DA, Furukawa Y, McAdam A J, et al. Expression of B7 molecules in recipient, not donor, mice determines the survival of cardiac allografts[J]. J Immunol, 1999, 163(7): 3753-3757.
9. Takayama T, Nishioka Y, Lu L, et al. Retroviral delivery of viral interleukin-10 into myeloid DCs markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness[J]. Transplantation, 1998, 66(12): 1567-1574.
10. Chen Z, Lu L, Li J, et al. Transfection with genes encoding CTLA4Ig mediated by adenoassociated virus vectors prolongs survival of heart allografts[J]. Transplant Proc, 2001, 33(1-2): 604.
11．叶闻斐，何球藻．未成熟树突细胞诱导同种免疫低应答性的研究[J]．中国免疫学杂志，2000，16(11)：578-580．
12．于平，熊思东，何球藻，等．未成熟树突细胞诱导异体嵌合体的形成[J]．中国 免疫学杂志，2002，18(4)：223-227．
13. Sheng Sun D, Iwagaki H, Ozaki M, et al. Prolonged survival of donor-specific rat intestinal allograft by administration of bone-marrow-derived immature dendritic cells[J]. Transpl Immunol, 2005, 14(1): 17-20.
14. Garrovillo M, Ali A, Oluwole SF. Indirect allorecognition in acquired thymic tolerance: induction of donor-specific tolerance to rat cardiac allografts by allopeptide-pulsed host DCs[J]. Transplantation, 1999, 68(12): 1827-1834.
15. Ali A, Garrovillo M, Jin MX, et al. Major histocompatibility complex class Ⅰ peptide-pulsed host DCs induce antigen-specific acquired thymic tolerance to islet cells[J]. Transplantation, 2000, 69(2): 221-226.
16. Tiao MM, Lu L, Tao R, et al. Prolongation of cardiac allograft survival by systemic administration of immature recipient dendritic cells deficient in NF-kappaB activity[J]. Ann Surg, 2005, 241 (3): 497-505.
17. Xu DL, Liu Y, Tan JM, et al. Marked prolongation of murine cardiac allograft survival using recipient immature dendritic cells pulsed with donor-derived apoptotic cells[J]. Scand J Immunol, 2004, 59(6): 536-544.
18．黄赤兵，吴军，张艮，等．用负载供体抗原的致耐受性树突状细胞延长大鼠移植肾存活[J]．第三军医大学学报，2003，25(21)：1906-1908．
19. Woodward JE, Zotola LB, Schaefer AT, et al. Blockade of the CD28/B7 pathway is required for the establishment of donor cell chimerism in CD40 ligand-deficent recipients[J]. Transplant Proc, 2001, 33(1-2): 115.
20. Steurer W, Oellinger R, Perwanger F, et al. Prolonged allograft survival following ex vivo blockade of costimulatory signals B7-1/2 and CD40[J]. Transplant Proc, 2001, 33(1-2): 274-275.
21. Yu XZ, Bidwell SJ, Martin PJ, et al. CD28-specific antibody prevents graft-versus-host disease in mice[J]. J Immunol, 2000, 164(9): 4564-4568.
22. Yu XZ, Carpenter P, Anasetti C. Advances in transplantation tolerance[J]. Lancet, 2001, 357: 1959-1963.
23. Gao LH, Zheng SS, Zhu YF, et al. A rat model of chronic allograft liver rejection[J]. Transplant Proc, 2005, 37(5): 2327-2332.
24. Junaid A, Kren SM, Rosenberg ME, et al. Physiological and structural responses to chronic experimental renal allograft injury[J]. Am J Physiol, 1994; 267(6 Pt 2): F1102-1106
25. Johnson P, Carpenter M, Hirsch G, et al. Recipient cells form the intimal proliferative lesion in the rat aortic model of allograft arteriosclerosis[J]. Am J Transplant, 2002, 2(3): 207-214.
26. Koulack J, McAlister VC, Giacomantonio CA, et al. Development of a mouse aortic transplant model of chronic rejection[J]. Microsurgery, 1995, 16(2): 110-113.
27．项建斌，程峰，陈宗祐，等．异体小鼠颈动脉移植慢性排斥模型的制作[J]．复旦学报医学版，2006，33(2)：222-224．
28. Tao R, Wang L, Chen CH, et al. Mechanistic insights into achievement of cardiac allograft long-term survival by treatment with immature dendritic cells and sub-dose sirolimus[J]. J Heart Lung Transplant, 2006, 25(3): 310-319.
29. Xu H, Chen T, Wang HQ, et al. Combination treatment with donor interleukin-12 p35 silenced dendritic cells and cyclosporine induces long-term survival of intestinal allografts in rats[J]. Transplant Proc, 2007, 39(1): 286-288.
30. Aziz T, Hasleton P, HannA W, et al. J Transforming growth factor beta in relation to cardiac allograft vasculopathy after heart transplantation[J]. Thorac Cardiovasc Surg, 2000, 119(4pt1): 700-708.
1. Steinman RM and Cohn IA. Identification of a novel cell type in peripheral lymphoid organs of mice[J]. J Exp Med, 1973, 137(5): 1142-1162.
2. Hart DN. Dendritic cell: unique leukocyte population which control the primary immune response[J]. Blood, 1997, 90(9): 3245-3287.
3．郑峻松，吴军，肖光夏．树突状细胞与移植免疫耐受的研究[J]．中华烧伤杂志，2003，19(6)：382-383．
4. Heinemann EH, Hinrich J. Follicular dendritic like cells derived from human monocytes[J]. J Immunol, 2005, 6(23): 2171-2172.
5. Cella M, Sallusto F, Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells[J]. Curr Opin Immunol. 1997; 9(1): 10-16.
6. Steinman RM, Inaba K. Myeloid dendritic cells[J]. J Leukoc Biol, 1999, 66(2): 205-208.
7. Carl GF, Vries JM, Lesterhuis EJ, et al. Dendritic cell immunotherapy: mapping the way[J]. Nature Med, 2004, 10(5): 475-480.
8. Jonuleit H, Schmitt E, Steinbrink K, et al. Dendritic cells as a tool to induce anergic and regulatory T cells[J]. Trends Immunol, 2001, 2(7): 394-395.
9. DePaz HA, Oluwole OO, Adeyeri AO, et al. Immature rat myeloid dendritic cells generated in low-dose granulocytemacrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival[J]. Transplantation, 2003, 75(4): 521-528.
10. Nabeyama K, Yasunami Y, Toyofuku A, et al. Beneficial effects of costimulatory blockade with anti-inducible costimulator antibody in conjunction with CTLA4Ig on prevention of islet xenograft rejection from rat to mouse[J]. Transplantation, 2004, 78(11): 1590-1596.
11. Linal L, Weicheng L, Cuiping Z, et al. Increased apopotosis of immunoreactive host cells and augmented donor leukocyte chimerism, not sustained inhibition of B7 molecule expression are associated with prolonged cardiac allograft survival in mice preconditioned with immature donor dendritic cells plus anti-CD40LmAb[J]. Transplantation, 1999, 68(6): 747-757.
12. Lan YY, Wang Z, Raimondi G, et al. Alternatively activated dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig[J]. J Immunol, 2006, 177(9): 5868-5877.
13. Kalinski P, Hilkens CM, Snijders A, et al. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells[J]. J Immunol, 1997, 159(1): 28-35
14. Min WP, Gorezynski R, Huang XY, et al. Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival [J]. J Immunol, 2000, 164(1): 161-167.
15. Gorezynski RM, Bransom J, Cettral M, et al. Synergy induction of increased renal allograft survival after portal vein infusion of dendritic cells transduced to express TGF-β and IL-10 along with administration of CHO cells expressing the regulatorymolecule OX22[J]. Clin Immunol, 2000, 95 (3): 182-189.
16. Wang Q, Liu Y, Wang J, et al. Induction of allospecific tolerance by immature dendritic cells genetically modified to express soluble TNF receptor. J Immunol, 2006, 177(4): 2175-2185.
17. Hackstein H, Thomson AW. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs[J]. Nat Rev Immunol, 2004, 4(1): 24-34.
18. Yoshimura S, Bondeson J, Brennan FM, et al. Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI[J]. Eur J Immunol, 2001, 31 (6): 1883-1893.
19. Rohn TA, Boes M, Wohers D, et al. Upregulation of the CLIP self peptide on mature dendritic cells antagonizes T helper type 1 polarization[J]. Nat Immunol, 2004, 5(9): 909-918.
20. Zwickey HL, Unternaehrer J J, Mellman I. Presentation of self-antigens on MHC class Ⅱ molecules during dendritic cell maturation[J]. Int Immunol, 2006, 18(1): 199-209.
21. Inaba K, Hosono M, Inaba M. Thymic dendritic cells and B cells: isolation and function[J]. Int Rev Immunol, 1990, 6(2-3): 117-126.
22. Fiedor P, Jin MX, Hardy MA, et al. Dependence of acquired systemic tolerance to rat islet allografts induced by intrathymic soluble alloantigens on host responsiveness, MHC differences, and transient immunosuppression in the high responder recipient[J]. Transplantation, 1997, 63(2): 279-283.
23. Onodera K, Chandraker A, Volk HD, et al. Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2[J].Transplantation, 1999, 68(2): 288-293.
24. von Bubnoff D, de la Salle H, Wessendorf J, et al. Antigen-presenting cells and tolerance induction[J]. Allergy, 2002, 57(1): 2-8.
25. Lechler R, Chai JG, Marelli-Berg F, et al. The contributions of T-cell anergy to peripheral T-cell tolerance[J]. Immunology, 2001, 103(3): 262-269.
26. Gao JX, Madrenas J, Zeng W, et al. CD40-deficient dendritic cells producing interleukin-10, but not interleukin-12, induce T-cell hyporesponsiveness in vitro and prevent acute allograft rejection[J]. Immunology, 1999, 98(2): 159-170.
27. Woodward JE, Bayer AL, Chavin KD, et al. T-cell alterations in cardiac allograft recipients after B7 (CD80 and CD86) blockade[J]. Transplantation, 1998, 66(1): 14-20.
28. Takayama T, Nishioka Y, Lu L,et al. Retroviral delivery of viral interleukin-10 into myeloid dendritic cells markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness[J]. Transplantation, 1998, 66 (12): 1567-1574.
29. Hopken UE, Lehmann I, Droese J, et al. The ratio between dendritic cells and T cells determines the outcome of their encounter: proliferation versus deletion[J]. Eur J Immunol, 2005, 35(10): 2851-2863.
30. Kurts C, Heath WR, Kosaka H, et al. The peripheral deletion of autoreactive CDS+ T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1) [J]. J Exp Med, 1998, 188(2): 415-420.
31. Lu L, Qian S, Hepshberger PA, et al. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation[J]. J Immunol, 1997, 158(12): 5676-5684.
32. Roncarolo MG; Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells[J]. J Exp Med, 2001, 193(2): F5-9.
33. Chen W. Dendritic cells and (CD4+)CD25+ T regulatory cells: crosstalk between two professionals in immunity versus tolerance[J]. Front Biosci, 2006,11: 1360-1370
34. Inaba K. Dendritic cells as antigen-presenting cells in vivo[J]. Immunol Cell Biol, 1997, 75(2):206-208.
35. Adam R, McMaster P, Grady JO, et al. Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry[J]. Liver Transpl, 2005, 9 (12): 1231-1243.
36. Jiang S, Tsang J, Game DS,et al. Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity: Potential reagents to promote donor-specific transplantation tolerance[J]. Transplantation, 2006, 82(12): 1738-1743.
37. Golshayan D, Jiang S, Tsang J,et al.In vitro-expanded donor alloantigen-specific CD4+CD25+regulatory T cells promote experimental transplantation tolerance[J]. Blood, 2007, 109(2): 827-835.
38. Kato T, Nariuchi H. Polarization of naive CD4+ T cells toward the Thl subset by CTLA-4 costimulation[J]. J Immunol, 2000, 164 (7): 3554-3562.
39. Oosterwegel MA, Mandelbrot DA, Boyd SD, et al. The role of CTLA-4 in regulating Th2 differentiation[J]. J Immunol, 1999, 163(5): 2634-2639.
40. Xu H, Chen T, Wang HQ, et al. Prolongation of rat intestinal allograft survival by administration of donor interleukin-12 p35-silenced bone marrow-derived dendritic cells[J].Transplant Proc, 2006, 38(5): 1561-1563.
2. Fairchild P J, Waldmann H. DCs and prospects for transplantation tolerance[J]. Curr Opin Immunol, 2000, 12(5): 528-635.
3. Lechler R, Ng WF, Steinman RM. DCs in transplantation—friend or foe? [J] Immunity, 2001, 14(4): 357-368
4. Ling V, Wu PW, Finnerty HF, et al. Cutting edge: identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor[J]. J Immunol, 2000, 164(4): 1653-1657.
5. Banchereau J, Steinman RM. DCs and the control of immunity[J]. Nature, 1998, 392(6673): 245-252.
6. Onodera K, Chandraker A, Volk HD, et al. Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2[J]. Transplantation, 1999, 68(2): 288-293.
7. Gimmi CD, Freeman GJ, Gribben JG, et al. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation[J]. Proc Natl Acad Sci U S A, 1993, 90(14): 6586-6590.
8. Harding FA, McArthur JG, Gross JA, et al. CD28-mediated signalling costimulates murine T cells and prevents induction of anergy in T-cell clones[J]. Nature, 1992, 356(6370): 607-609
9. von Bubnoff D, de la Salle H, Wessendorf J, et al. Antigen-presenting cells and tolerance induction[J]. Allergy, 2002, 57(1): 2-8.
10. Game DS, Lechler RI. Pathways of allorecognition: implication for transplantation tolerance. Transpl Immunol, 2002, 10(2-3): 101-108.
11. Hornick P. Direct and indirect allorecognition[J]. Methods Mol Biol, 2006, 333: 145-156.
12. Ochando JC, Krieger NR, Bromberg JS. Direct versus indirect allorecognition: Visualization of dendritic cell distribution and interactions during rejection and tolerization[J]. Am J Transplant, 2006, 6(10): 2488-2496.
13. Takayama T, Nishioka Y, Lu L, et al. Retroviral delivery of viral interleukin-10 into myeloid DCs markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness[J].Transplantation, 1998, 66(12): 1567-1574.
14. Chen Z, Lu L, Li J, et al. Transfection with genes encoding CTLA4Ig mediated by adenoassociated virus vectors prolongs survival of heart allografts[J]. Transplant Proc, 2001, 33(1-2): 604.
15．叶闻斐，何球藻．未成熟树突细胞诱导同种免疫低应答性的研究[J]．中国免疫学杂志，2000，16(11)：578-580．
16．于平，熊思东，何球藻，等．未成熟树突细胞诱导异体嵌合体的形成[J]．中国免疫学杂志，2002，18(4)：223-227．
17. Sheng Sun D, Iwagaki H, Ozaki M, et al. Prolonged survival of donor-specific rat intestinal allograft by administration of bone-marrow-derived immature dendritic cells[J]. Transpl Immunol, 2005, 14(1): 17-20.
18. Garrovillo M, Ali A, Oluwole SF. Indirect allorecognition in acquired thymic tolerance: induction of donor-specific tolerance to rat cardiac allografts by allopeptide-pulsed host DCs[J]. Transplantation, 1999, 68(12): 1827-1834.
19. Ali A, Garrovillo M, Jin MX, et al. Major histocompatibility complex class Ⅰ peptide-pulsed host DCs induce antigen-specific acquired thymic tolerance to islet cells[J]. Transplantation, 2000, 69(2): 221-226.
20. Tiao MM, Lu L, Tao R, et al. Prolongation of cardiac allograft survival by systemic administration of immature recipient dendritic cells deficient in NF-kappaB activity[J]. Ann Surg, 2005, 241(3): 497-505.
21. Xu DL, Liu Y, Tan JM, et al. Marked prolongation of murine cardiac allograft survival using recipient immature dendritic cells pulsed with donor-derived apoptotic cells. Scand J Immunol, 2004, 59(6): 536-544.
22. DePaz HA, Oluwole OO, Adeyeri AO, et al. Immature rat myeloid DCs generated in low-dose granulocyte macrophage-colony stimulating factor prolong donorspecific rat cardiac allograft survival [J]. Transplantation, 2003, 75(4): 521-528.
23. Lu L, Li W, Zhong C, et al. Increased apopotosis of immunoreactive host cells and augmented donor leukocyte chimerism, not sustained inhibition of B7 molecule expression expression are associated with prolonged cardiac allograft survival in mice preconditioned with immature donor DCs plus anti-CD40L mAb[J]. Transplantation, 1999, 68(6): 747-757.
24. Lee WC, Zhong C, Qian S, et al. Phenotype, function, and in vivo migration and survival of allogeneic DC progenitors genetically engineered to express TGF-beta[J]. Transplantation, 1998, 66(12): 1810-1817.
25. Takayama T, Morelli AE, Robbins PD, et al. Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid DCs that induce allosntigen-specific T cell anergy in vitro[J]. Gene Ther, 2000, 7(15): 1265-1273.
26. Li WM, Liu W, Gao C, et al. Antigen-specific tolerance induced by IL-10 gene modified immature dendritic cells in experimental autoimmune myocarditis in rats[J]. Chin Med J (Engl), 2006, 119(19): 1646-1652.
27. Liu N, Duan TD, Zheng N. Effects of TGF-betal, gene modified donor dendritic cells on immune repulsion[J]. Sichuan Da Xue Xue Bao Yi Xue Ban, 2006, 37(5): 721-725.
28. Yoshimura S, Bondeson J, Brennan FM, et al. Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of DCs with proteasome inhibitor PSI[J]. Eur J Immunol, 2001, 31(6): 1883-1893
29．陈晋，熊思东，张瑞华，等．B7反义肽抑制同种异基因移植排斥反应的研究[J]．中国免疫学杂志，2003，19(7)：468-472
30．项建斌，程峰，陈宗祐，等．异体小鼠颈动脉移植慢性排斥模型的制作[J]．复旦学报医学版，2006，33(2)：222-224．
1. Hart DN. DC: unique leukocyte population which control the primary immune response[J]. Blood, 1997, 90(9): 3245-3287.
2. Banchereau J, Steinman RM. DCs and the control of immunity[J]. Nature, 1998, 392(6673): 245-252.
3. von Bubnoff D, de la Salle H, Wessendorf J, et al. Antigen-presenting cells and tolerance induction[J]. Allergy, 2002, 57(1): 2-8.
4. Tseng SX, Ostugi M, Gorski K, et al. B7-DC, a new DC molecule with potent costimulatory properties for T cells[J]. J Exp Med, 2001, 193(7): 839-846.
5. Boussiotis VA, Freeman GJ, Gray G, et al. B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance[J]. J Exp Med, 1993, 178(5): 1753-1763.
6．陈晋，熊思东，张瑞华，等．B7反义肽抑制同种异基因移植排斥反应的研究[J]．中国免疫学杂志，2003，19(7)：468-472．
7. Steinman RM and Cohn IA. Identification of a novel cell type in peripheral lymphoid organs of mice[J]. J Exp Med, 1973, 137(5): 1142-1162.
8. Hart DN, Hill GR. DC immunotherapy for ancer; Application to low-grade lymphoma and multiply myeloma[J]. Immunol Cell Biol, 1999, 77(5): 451-459.
9. Kock F, Heufler C, Kanpgen E, et al. Tumor necrosis factor alpha maintains the ciability of murine epidermal Langerhans cells in culture, but in contrast to granulocyte/macrophage colony-stimulating factor, without inducing their functional maturation[J]. J Exp Med, 1990, 171(1): 159-171.
10．孙祖玥，赵勇．树突状细胞诱导移植免疫耐受[A]．见：移植免疫耐受[M]．赵勇主编．北京：中国医药科技出版社，2005：85-86．
11. Hanada K, Tsunoda R, Hamada H. GM-CSF-induced in vivo expansion of splenic dndritic cells and their strong costimulation activity[J]. J Leukoc Biol, 1996, 60(2): 181-190.
12. Ferlazzo G, Klein J, Paliard X, et al. Dendritic cells generated from CD34+ progenitor cells with flt3 ligand, c-kit ligand, GM-CSF, IL-4, and TNF-alpha are functional antigen-presenting cells resembling mature monocyte-derived dendritic cells[J]. J Immunother, 2000, 23 (1): 48-58.
13. Inaba K, Inaba M, Romani N, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor[J]. J Exp Med, 1992, 176(6): 1693-1702.
14．许化溪，严俊．实验动物免疫细胞功能功能的测定[A]．见：现代免疫学实验技术[M]．沈关心，周如麟主编．湖北：湖北科学技术出版社，1998：328-341．
15. Norbury CC, Chambers BJ, Proscott AR, et al. Constitutive macropinocytosis allows TAP-dependent major histocompatibility complex class-1 presentation of exogenous soluble antigen by bone marrow-derived DCs[J]. Eur J Immunol, 1997, 27(1): 280-288.
16. Carl GF, Vries JM, Lesterhuis EJ, et al. DC immunotherapy: mapping the way[J]. Nature Med, 2004, 10 (5): 475-480.
17. Bonham CA, Peng L, Liang X, et al. Marked prolongation of cardiac allograft survival by DCs genectically engineered with NF-KB oligodeoxyribonucleotide decoys and adenoviral vectors CTLA4-Ig[J]. J Immunol, 2002, 169(6): 3382-3391.
1. Ensminger SM, Spriewald BM, Witzke O, et al. Indirect allorecog-nition can play an important role in the development of transplant arteriosclerosis[J]. Transplantation, 2002, 73(2): 279-286.
2. Hornick P. Direct and indirect allorecognition[J]. Methods Mol Biol, 2006, 333: 145-156.
3. Jenkins MK, Ashwell JD, Schwartz RH. Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells[J]. J Immunol, 1988, 140(10): 3324-3330.
4. Onodera K, Chandraker A, Volk HD, et al. Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2[J]. Transplantation, 1999, 68(2): 288-293
5. Gimmi CD, Freeman GJ, Gribben JG, et al. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation[J]. Proc Natl Acad Sci U S A, 1993, 90(14): 6586-6590.
6. Harding FA, McArthur JG, Gross JA, et al. CD28-mediated signalling costimulates murine T cells and prevents induction of anergy in T-cell clones[J]. Nature, 1992, 356(6370): 607-609.
7．于平，熊思东，何球藻，等．未成熟树突状细胞诱导异体嵌合体的形成[J]．中国免疫学杂志，2002，18(4)：223-227
8. Vella JP, Spadafora-Ferreira M, Murphy B, et al. Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction[J]. Transplantation, 1997, 64(6): 795-800.
9. Lee RS, Yamada K, Houser SL, et al. Indirect allorecognition promotes the development of cardiac allograft vasculopathy[J]. Proc Natl Acad Sci U S A, 2001, 98(6): 3276-3281.
10. Mandelbrot DA, Furukawa Y, McAdam AJ, et al. Expression of B7 molecules in recipient, not donor, mice determines the survival of cardiac allografts[J]. J Immunol, 1999, 163(7): 3753-3757.
11. Ochando JC, Krieger NR, Bromberg JS. Direct versus indirect allorecognition: Visualization of dendritic cell distribution and interactions during rejection and tolerization[J]. Am J Transplant, 2006, 6(10): 2488-2496.
12. Hillebrands JL, Raue HP, Klatter FA, et al. Intrathymic immune modulation prevents acute rejection but not the development of graft arteriosclerosis (chronic rejection) [J]. Transplantation, 2001, 71 (7): 914-924.
13. Takayama T, Nishioka Y, Lu L, et al. Retroviral delivery of viral interleukin-10 into myeloid DCs markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness[J]. Transplantation, 1998, 66(12): 1567-1574.
14. Chen Z, Lu L, Li J, et al. Transfection with genes encoding CTLA4Ig mediated by adenoassociated virus vectors prolongs survival of heart allografts[J]. Transplant Proc, 2001, 33(1-2): 604.
15. van der Merwe PA, Bodian DL, Daenke S, et al. CD80(BT-1)binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med.1997, 185(3): 393-403.
16. Greene J, Wang M, Liu Y E, Raymond LA, et al. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase4. J Biol Chem, 1996, 271(48): 30375-30380.
17. Yi-qun Z, Lorre K, de Boer M, et al. B7-blocking agents, alone or in combination with cyclosporin A, induce antigen-specific anergy of human memory T cells[J]. J Immunol, 1997, 158(10): 4734-4740
18. Gebhardt BM, Hodkin M, Varnell ED, et al. Protection of corneal allografts by CTLA4-Ig[J]. Cornea, 1999, 18(3): 314-320.
19. Guillot C, Mathieu P, Coathalem H, et al. Tolerance to cardiac allografts via local and systemic mechanisms after adenovirus-mediated CTLA4Ig expression[J]. J Immunol, 2000, 164(10): 5258-5268.
20. Tomasoni S, Azzollini N, Casiraghi F, et al . CTLA4-Ig gene transfer prolongs survival and induces donor specific tolerance in a rat renal allograft[J]. J Am Soc Nephrol, 2000, 11 (4): 747-752.
21. Kurlberg G, Haglind E, Schon K, et al. Blockade of the B7-CD28 pathway by CTLA4-Ig counteracts rejection and prolongs survival in small bowel transplantation[J]. Scand J Immunol, 2000, 51 (3): 224-230.
22. Han B, Hu Y. Effects of CTLA4-Ig gene-modified dendritic cells on the corneal allografts[J]. J Huazhong Univ Sci Technolog Med Sci, 2006, 26(3): 366-368.
23. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig[J]. N Engl J Med, 2003, 349(20): 1907-1915
24．黄赤兵，吴军，张艮，等．用负载供体抗原的致耐受性树突状细胞延长大鼠移 植肾存活[J]．第三军医大学学报，2003，25(21)：1906-1908．
25. Woodward JE, Zotola LB, Schaefer AT, et al. Blockade of the CD28/B7 pathway is required for the establishment of donor cell chimerism in CD40 ligand-deficent recipients[J]. Transplant Proc, 2001, 33(1-2): 115.
26. Steurer W, Oellinger R, Perwanger F, et al. Prolonged allograft survival following ex vivo blockade of costimulatory signals B7-1/2 and CD40[J]. Transplant Proc, 2001, 33(1-2): 274-275.
27. Yu XZ, Bidwell SJ, Martin PJ, et al. CD28-specific antibody prevents graftversus-host disease in mice[J]. J Immunol, 2000, 164(9): 4564-4568.
28. Yu XZ, Carpenter P, Anasetti C. Advances in transplantation tolerance[J]. Lancet, 2001, 357: 1959-1963.
29．陈晋，熊思东，张瑞华，等．B7反义肽抑制同种异基因移植排斥反应的研究[J]．中国免疫学杂志，2003，19(7)：468-472．
30. Metzler WJ, Bajorath J, Fenderson W, et al. Solution structure of human CTLA4 and delineation of a CD80/ CD86 binding site conserved in CD28[J]. Nature Structural Biol, 1997, 4(7): 527-532.
31. Tao R, Wang L, Chen CH, et al. Mechanistic insights into achievement of cardiac allograft long-term survival by treatment with immature dendritic cells and sub-dose sirolimus[J]. J Heart Lung Transplant, 2006, 25(3): 310-319.
32. Xu H, Chen T, Wang HQ, et al. Combination treatment with donor interleukin12p35 silenced dendritic cells and cyclosporine induces long-term survival of intestinal allografts in rats[J]. Transplant Proc, 2007, 39(1): 286-288.
33. Valujskikh A, Fedoseyeva E, Benichou G, et al. Development of autoimmunity after skin graft rejection via an indirect alloresponse[J]. Transplantation, 2002, 73 (7): 1130-1137.
34. Lu L, Qian S, Hepshberger PA, et al. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation[J]. J Immunol, 1997, 158(12): 5676-5684.
35. Golshayan D, Jiang S, Tsang J, et al. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance[J]. Blood, 2007, 109(2): 827-835.
36. Xu H, Chen T, Wang HQ, et al. Prolongation of rat intestinal allograft survival by administration of donor interleukin-12 p35-silenced bone marrow-derived dendritic cells[J]. Transplant Proc, 2006, 38(5): 1561-1563.
37. Gao Q, Chen N, Rouse TM, et al. The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance [J]. Transplantation, 1996, 62(12): 1847-1854.
38. Mosmann TR, Sad S. The expanding universe of T2cell subsets: Th1, Th2 and more[J]. Immuno Today, 1996, 17(3): 138-146.
39. Taylor PA, Panoskalitsis-Mortari A, Noelle RJ, et al. Analysis of the requirements for the induction of CD4+ T cell alloantigen hyporesponsiveness by ex vivo anti-CD40 ligand antibody[J]. J Immunol, 2000, 164(2): 612-622.
1. Vella JP, Spadafora-Ferreira M, Murphy B, et al. Indirect allo recogni-tion of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction[J]. Transplantation, 1997, 64(6): 795-800.
2. Ensminger SM, Spriewald BM, Witzke O, et al. Indirect allorecognition can play an important role in the development of transplant arteriosclerosis[J]. Transplantation, 2002, 73(2): 279-286.
3. Lee RS, Yamada K, Houser SL, et al.Indirect allorecognition promotes the development of cardiac allograft vasculopathy[J]. Proc Natl Acad Sci U S A, 2001, 98(6): 3276-3281.
4. Motomura N, Lou H, Maurice P, et al. Acceleration of arteriosclerosis of the rat aorta allograft by insulin growth factor-I[J]. Transplantation, 1997, 63(7): 932-936.
5．李幼平，冯莉，唐强，等．慢性移植物失功机制及干预[A]．见：移植免疫生物学[M]．李幼平主编．北京：高等教育出版社，2006：253-254．
6. Game DS, Lechler RI. Pathways of allorecognition: implication for transplantation tolerance. Transpl Immunol, 2002, 10(2-3): 101-108.
7. Mirenda V, Berton I, Read J, et al. Modified dendritic cells coexpressing self and allogeneic major histocompatability complex molecules: an efficientway to induce indirect pathway regulation[J]. J Am Soc Nephrology, 2004, 15(4): 987-997.
8. Mandelbrot DA, Furukawa Y, McAdam A J, et al. Expression of B7 molecules in recipient, not donor, mice determines the survival of cardiac allografts[J]. J Immunol, 1999, 163(7): 3753-3757.
9. Takayama T, Nishioka Y, Lu L, et al. Retroviral delivery of viral interleukin-10 into myeloid DCs markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness[J]. Transplantation, 1998, 66(12): 1567-1574.
10. Chen Z, Lu L, Li J, et al. Transfection with genes encoding CTLA4Ig mediated by adenoassociated virus vectors prolongs survival of heart allografts[J]. Transplant Proc, 2001, 33(1-2): 604.
11．叶闻斐，何球藻．未成熟树突细胞诱导同种免疫低应答性的研究[J]．中国免疫学杂志，2000，16(11)：578-580．
12．于平，熊思东，何球藻，等．未成熟树突细胞诱导异体嵌合体的形成[J]．中国 免疫学杂志，2002，18(4)：223-227．
13. Sheng Sun D, Iwagaki H, Ozaki M, et al. Prolonged survival of donor-specific rat intestinal allograft by administration of bone-marrow-derived immature dendritic cells[J]. Transpl Immunol, 2005, 14(1): 17-20.
14. Garrovillo M, Ali A, Oluwole SF. Indirect allorecognition in acquired thymic tolerance: induction of donor-specific tolerance to rat cardiac allografts by allopeptide-pulsed host DCs[J]. Transplantation, 1999, 68(12): 1827-1834.
15. Ali A, Garrovillo M, Jin MX, et al. Major histocompatibility complex class Ⅰ peptide-pulsed host DCs induce antigen-specific acquired thymic tolerance to islet cells[J]. Transplantation, 2000, 69(2): 221-226.
16. Tiao MM, Lu L, Tao R, et al. Prolongation of cardiac allograft survival by systemic administration of immature recipient dendritic cells deficient in NF-kappaB activity[J]. Ann Surg, 2005, 241 (3): 497-505.
17. Xu DL, Liu Y, Tan JM, et al. Marked prolongation of murine cardiac allograft survival using recipient immature dendritic cells pulsed with donor-derived apoptotic cells[J]. Scand J Immunol, 2004, 59(6): 536-544.
18．黄赤兵，吴军，张艮，等．用负载供体抗原的致耐受性树突状细胞延长大鼠移植肾存活[J]．第三军医大学学报，2003，25(21)：1906-1908．
19. Woodward JE, Zotola LB, Schaefer AT, et al. Blockade of the CD28/B7 pathway is required for the establishment of donor cell chimerism in CD40 ligand-deficent recipients[J]. Transplant Proc, 2001, 33(1-2): 115.
20. Steurer W, Oellinger R, Perwanger F, et al. Prolonged allograft survival following ex vivo blockade of costimulatory signals B7-1/2 and CD40[J]. Transplant Proc, 2001, 33(1-2): 274-275.
21. Yu XZ, Bidwell SJ, Martin PJ, et al. CD28-specific antibody prevents graft-versus-host disease in mice[J]. J Immunol, 2000, 164(9): 4564-4568.
22. Yu XZ, Carpenter P, Anasetti C. Advances in transplantation tolerance[J]. Lancet, 2001, 357: 1959-1963.
23. Gao LH, Zheng SS, Zhu YF, et al. A rat model of chronic allograft liver rejection[J]. Transplant Proc, 2005, 37(5): 2327-2332.
24. Junaid A, Kren SM, Rosenberg ME, et al. Physiological and structural responses to chronic experimental renal allograft injury[J]. Am J Physiol, 1994; 267(6 Pt 2): F1102-1106
25. Johnson P, Carpenter M, Hirsch G, et al. Recipient cells form the intimal proliferative lesion in the rat aortic model of allograft arteriosclerosis[J]. Am J Transplant, 2002, 2(3): 207-214.
26. Koulack J, McAlister VC, Giacomantonio CA, et al. Development of a mouse aortic transplant model of chronic rejection[J]. Microsurgery, 1995, 16(2): 110-113.
27．项建斌，程峰，陈宗祐，等．异体小鼠颈动脉移植慢性排斥模型的制作[J]．复旦学报医学版，2006，33(2)：222-224．
28. Tao R, Wang L, Chen CH, et al. Mechanistic insights into achievement of cardiac allograft long-term survival by treatment with immature dendritic cells and sub-dose sirolimus[J]. J Heart Lung Transplant, 2006, 25(3): 310-319.
29. Xu H, Chen T, Wang HQ, et al. Combination treatment with donor interleukin-12 p35 silenced dendritic cells and cyclosporine induces long-term survival of intestinal allografts in rats[J]. Transplant Proc, 2007, 39(1): 286-288.
30. Aziz T, Hasleton P, HannA W, et al. J Transforming growth factor beta in relation to cardiac allograft vasculopathy after heart transplantation[J]. Thorac Cardiovasc Surg, 2000, 119(4pt1): 700-708.
1. Steinman RM and Cohn IA. Identification of a novel cell type in peripheral lymphoid organs of mice[J]. J Exp Med, 1973, 137(5): 1142-1162.
2. Hart DN. Dendritic cell: unique leukocyte population which control the primary immune response[J]. Blood, 1997, 90(9): 3245-3287.
3．郑峻松，吴军，肖光夏．树突状细胞与移植免疫耐受的研究[J]．中华烧伤杂志，2003，19(6)：382-383．
4. Heinemann EH, Hinrich J. Follicular dendritic like cells derived from human monocytes[J]. J Immunol, 2005, 6(23): 2171-2172.
5. Cella M, Sallusto F, Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells[J]. Curr Opin Immunol. 1997; 9(1): 10-16.
6. Steinman RM, Inaba K. Myeloid dendritic cells[J]. J Leukoc Biol, 1999, 66(2): 205-208.
7. Carl GF, Vries JM, Lesterhuis EJ, et al. Dendritic cell immunotherapy: mapping the way[J]. Nature Med, 2004, 10(5): 475-480.
8. Jonuleit H, Schmitt E, Steinbrink K, et al. Dendritic cells as a tool to induce anergic and regulatory T cells[J]. Trends Immunol, 2001, 2(7): 394-395.
9. DePaz HA, Oluwole OO, Adeyeri AO, et al. Immature rat myeloid dendritic cells generated in low-dose granulocytemacrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival[J]. Transplantation, 2003, 75(4): 521-528.
10. Nabeyama K, Yasunami Y, Toyofuku A, et al. Beneficial effects of costimulatory blockade with anti-inducible costimulator antibody in conjunction with CTLA4Ig on prevention of islet xenograft rejection from rat to mouse[J]. Transplantation, 2004, 78(11): 1590-1596.
11. Linal L, Weicheng L, Cuiping Z, et al. Increased apopotosis of immunoreactive host cells and augmented donor leukocyte chimerism, not sustained inhibition of B7 molecule expression are associated with prolonged cardiac allograft survival in mice preconditioned with immature donor dendritic cells plus anti-CD40LmAb[J]. Transplantation, 1999, 68(6): 747-757.
12. Lan YY, Wang Z, Raimondi G, et al. Alternatively activated dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig[J]. J Immunol, 2006, 177(9): 5868-5877.
13. Kalinski P, Hilkens CM, Snijders A, et al. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells[J]. J Immunol, 1997, 159(1): 28-35
14. Min WP, Gorezynski R, Huang XY, et al. Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival [J]. J Immunol, 2000, 164(1): 161-167.
15. Gorezynski RM, Bransom J, Cettral M, et al. Synergy induction of increased renal allograft survival after portal vein infusion of dendritic cells transduced to express TGF-β and IL-10 along with administration of CHO cells expressing the regulatorymolecule OX22[J]. Clin Immunol, 2000, 95 (3): 182-189.
16. Wang Q, Liu Y, Wang J, et al. Induction of allospecific tolerance by immature dendritic cells genetically modified to express soluble TNF receptor. J Immunol, 2006, 177(4): 2175-2185.
17. Hackstein H, Thomson AW. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs[J]. Nat Rev Immunol, 2004, 4(1): 24-34.
18. Yoshimura S, Bondeson J, Brennan FM, et al. Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI[J]. Eur J Immunol, 2001, 31 (6): 1883-1893.
19. Rohn TA, Boes M, Wohers D, et al. Upregulation of the CLIP self peptide on mature dendritic cells antagonizes T helper type 1 polarization[J]. Nat Immunol, 2004, 5(9): 909-918.
20. Zwickey HL, Unternaehrer J J, Mellman I. Presentation of self-antigens on MHC class Ⅱ molecules during dendritic cell maturation[J]. Int Immunol, 2006, 18(1): 199-209.
21. Inaba K, Hosono M, Inaba M. Thymic dendritic cells and B cells: isolation and function[J]. Int Rev Immunol, 1990, 6(2-3): 117-126.
22. Fiedor P, Jin MX, Hardy MA, et al. Dependence of acquired systemic tolerance to rat islet allografts induced by intrathymic soluble alloantigens on host responsiveness, MHC differences, and transient immunosuppression in the high responder recipient[J]. Transplantation, 1997, 63(2): 279-283.
23. Onodera K, Chandraker A, Volk HD, et al. Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2[J].Transplantation, 1999, 68(2): 288-293.
24. von Bubnoff D, de la Salle H, Wessendorf J, et al. Antigen-presenting cells and tolerance induction[J]. Allergy, 2002, 57(1): 2-8.
25. Lechler R, Chai JG, Marelli-Berg F, et al. The contributions of T-cell anergy to peripheral T-cell tolerance[J]. Immunology, 2001, 103(3): 262-269.
26. Gao JX, Madrenas J, Zeng W, et al. CD40-deficient dendritic cells producing interleukin-10, but not interleukin-12, induce T-cell hyporesponsiveness in vitro and prevent acute allograft rejection[J]. Immunology, 1999, 98(2): 159-170.
27. Woodward JE, Bayer AL, Chavin KD, et al. T-cell alterations in cardiac allograft recipients after B7 (CD80 and CD86) blockade[J]. Transplantation, 1998, 66(1): 14-20.
28. Takayama T, Nishioka Y, Lu L,et al. Retroviral delivery of viral interleukin-10 into myeloid dendritic cells markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness[J]. Transplantation, 1998, 66 (12): 1567-1574.
29. Hopken UE, Lehmann I, Droese J, et al. The ratio between dendritic cells and T cells determines the outcome of their encounter: proliferation versus deletion[J]. Eur J Immunol, 2005, 35(10): 2851-2863.
30. Kurts C, Heath WR, Kosaka H, et al. The peripheral deletion of autoreactive CDS+ T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1) [J]. J Exp Med, 1998, 188(2): 415-420.
31. Lu L, Qian S, Hepshberger PA, et al. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation[J]. J Immunol, 1997, 158(12): 5676-5684.
32. Roncarolo MG; Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells[J]. J Exp Med, 2001, 193(2): F5-9.
33. Chen W. Dendritic cells and (CD4+)CD25+ T regulatory cells: crosstalk between two professionals in immunity versus tolerance[J]. Front Biosci, 2006,11: 1360-1370
34. Inaba K. Dendritic cells as antigen-presenting cells in vivo[J]. Immunol Cell Biol, 1997, 75(2):206-208.
35. Adam R, McMaster P, Grady JO, et al. Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry[J]. Liver Transpl, 2005, 9 (12): 1231-1243.
36. Jiang S, Tsang J, Game DS,et al. Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity: Potential reagents to promote donor-specific transplantation tolerance[J]. Transplantation, 2006, 82(12): 1738-1743.
37. Golshayan D, Jiang S, Tsang J,et al.In vitro-expanded donor alloantigen-specific CD4+CD25+regulatory T cells promote experimental transplantation tolerance[J]. Blood, 2007, 109(2): 827-835.
38. Kato T, Nariuchi H. Polarization of naive CD4+ T cells toward the Thl subset by CTLA-4 costimulation[J]. J Immunol, 2000, 164 (7): 3554-3562.
39. Oosterwegel MA, Mandelbrot DA, Boyd SD, et al. The role of CTLA-4 in regulating Th2 differentiation[J]. J Immunol, 1999, 163(5): 2634-2639.
40. Xu H, Chen T, Wang HQ, et al. Prolongation of rat intestinal allograft survival by administration of donor interleukin-12 p35-silenced bone marrow-derived dendritic cells[J].Transplant Proc, 2006, 38(5): 1561-1563.