共刺激通路联合阻断及同种反应性CD4~+记忆性T细胞对同种异体移植物存活影响及其机制研究
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摘要
第一部分小鼠腹部异位心脏移植模型的建立
目的探讨小鼠腹部异位心脏移植手术的技术方法及其改进,为进一步进行移植免疫学研究提供动物模型。方法采用供心主动脉与受体腹主动脉、供心肺动脉与受体下腔静脉端侧吻合方法对100例小鼠进行腹部异位心脏移植术,同时测量相关移植部位的重要结构。结果供心主动脉直径为(1.3±0.2)mm,供心肺动脉直径为(1.6±0.3)mm,受体下腔静脉直径为(2.4±0.4)mm,腹主动脉直径为(1.5±0.2)mm,腹腔大血管平均可利用长度为(6.0±1.0)mm。建模成功率为92%。供、受体手术时间分别为(8.0±1.0)min和(40.2±3.0)min;其中动脉吻合为(9.3±1.2)min,静脉吻合为(7.8±1.7)min。结论本组建立小鼠腹部异位心脏移植模型稳定可靠,适用于移植免疫学方面的研究。
第二部分联合阻断CD28/B7和CD40/CD40L共刺激通路对同种异体移植物存活影响及其机制研究
目的借助小鼠腹部异位心脏移植模型,采用共刺激信号阻断策略去诱导同种异体移植物出现免疫耐受,并探讨其机制。方法采用连续联合应用CTLA-4 Ig和MR1,研究其对同种异体移植物存活、Th1和Th2细胞因子分泌等其他相关机制的影响。结果共刺激信号联合阻断能明显延长同种移植物的存活时间(平均存活时间为43 d高于正常排斥对照组的8 d,P<0.01),其具体机制包括能明显抑制Th1和Th2细胞因子的分泌、能减少浸润至移植物内的CD4+和CD8+淋巴细胞的数量、能抑制移植物内穿孔素、颗粒酶B和FasL的表达。结论联合阻断CD28/B7和CD40/CD40L共刺激信号能明显抑制CD4+初始T细胞的活化,阻止其向Th1和Th2极化,明显减少移植物内CD4+和CD8+淋巴细胞的浸润数量,通过抑制移植物内穿孔素、颗粒酶B以及FasL表达来抑制CTLs对移植物的细胞毒作用,从而使同种异基因移植物存活时间延长。
第三部分同种反应性CD4+ Tm对同种异体移植物存活影响的初步研究
目的研究同种反应性CD4+ Tm对同种异体移植物存活的影响,并对其机制进行初步探讨。方法采用小鼠皮肤移植模型,通过免疫磁性分离技术分离出同种反应性CD4+ Tm,并进行表型和功能鉴定。通过尾静脉过继性输入,研究此细胞对同种移植物存活的影响,并探讨其初步机制。结果分离所得CD4+ Tm的活细胞百分率为(98.4±0.7)%,其中CD4+CD44+CD62L-CCR7-细胞比例约占95%,且其功能具有良好的供体特异性。在同种异基因抗原刺激下,CFSE标记的CD4+ Tm荧光强度逐渐下降。与未输注Tm的阴性对照组相比,Tm组同种移植物平均存活时间明显缩短,移植物内有较多CD4+ T淋巴细胞浸润,但分布局限于心肌的中环层。Tm组移植物内仅冠脉周围有少量颗粒酶B表达,其余地方未见明显表达,但有大量的FasL阳性细胞浸润,主要分布于心外膜及心内膜下,尤以血管周围较为明显。结论通过小鼠皮肤移植模型及免疫磁性分离技术,可制备高纯度无菌的CD4+ Tm,其细胞活力不受影响,作用具有良好的供体特异性,这为深入研究Tm在移植物免疫方面的作用奠定了基础。同种反应性CD4+ Tm能介导排斥反应,缩短同种异体移植物的存活时间,这其中以FasL-Fas为代表的非分泌性杀伤性途径可能在CD4+ Tm介导的移植物排斥过程中起主要作用。
Part I Establishment of ventral heterotopic heart transplantation in mice
Objective To explore the improved technique of mouse ventral heterotopic heart transplantation and build animal model on the study of transplantation immunity. Methods The donor heart aorta and the recipient ventral aorta, the donor pulmonary artery and the recipient inferior caval vein, were anastomosed by using the end-to-side suture technique respectively. At the same time, we measured the length of some transplantation-related parts.
Results The diameter of recipient inferior caval vein and ventral aorta was(2.4±0.4)mm,(1.5±0.2)mm respectively. The average length of ventral blood vessels which could be used was (6.0±1.0)mm. The succeeding rate was 92 %. The average time of donor operation and recipient operation was (8.0±1.0)min,(40.2±3.0)min respectively. The time of artery anastomosis and vena anastomosis was (9.3±1.2)min,(7.8±1.7)min respectively.
Conclusions The animal model was stable and could be used for the study of transplantation immunity.
Part II The mechanisms of survival prolongation of murine cardiac allografts using the treatment of CTLA-4 Ig and MR1
Objective The present study was undertaken to determine the role of costimulatory block therapy in murine cardiac transplant model and collect some evidences accounting for the mechanism of transplantation immunity.
Methods In our study, we blocked the CD28/B7 and CD154/CD40 costimulatory pathway by the transient administration of CTLA-4 Ig and MR1 antibody and then proceeded to study that how did the combination administration of CTLA-4 Ig/MR1 influence on survival time of allografts, deviation of Th1 and Th2 cytokines secretion and other mechanisms related to survival prolongation of allografts.
Results Costimulatory blockade can prolong the survival time of cardiac allografts (MST: 43 d for treated group vs. 8 d for untreated group, P<0.01). The costimulatory blockade therapy can downregulate the expression of both Th1 cytokine(IFN-γand IL-2)and Th2 cytokine(IL-4 and IL-10), reduce the quantities of graft-infiltrating CD4+ and CD8+ lymphocytes and inhibit the expression of both perforin/GrB and FasL in allografts.
Conclusions The combination administration of CTLA-4 Ig/MR1 can inhibit acute rejection reaction in murine cardiac allografts and prolong the survival time of cardiac grafts through several mechanisms including inhibition of the Th1 and Th2 cytokines expression, graft-infiltration of CD4+ and CD8+ T lymphocytes and both perforin/GrB and FasL-Fas mediated cytotoxicity.
Part III The role of alloreactive memory T cells in survival of allografts
Objective To study the role of alloreactive memory T cells in survival of allografts.
Methods To draw assistance from mouse skin transplantation model and separate the splenocytes of recipients. The CD4+ Tm were isolated by magnetic activated cell sorting(MACS). The activity and the purity of the isolated cells were detected. And then we transferred these cells into recipients, explored that how did these cells influence the survival of allografts.
Results The activity of the CD4+ memory T cells was (98.4±0.7)%. The proportion of CD4+CD44+CD62L-CCR7- lymphocytes were 95% approximately and its function was donor specific. When CFSE labelled Tm were transferred into recipents via tail vein injection 1 day before operation, the fluorescence intensity of these cells fell off gradually. The mean survival time of allografts in Tm group was shorter compared with negative group(no transferred Tm). There were more CD4+ lymphocytes infiltrating into the middle layer of allografts in Tm group compared with negative group. The level of granzyme B in allografts was very low and there were lots of graft-infiltrating FasL+ lymphocytes in Tm group, especially those locations near epicardium, endocardium and around the vessels.
Conclusions We could use Magnetic activated cell sorting isolation kit to isolate CD4+ memory T lymphocytes aiming at skin allograft effectively, which facilitates us to investigate the role of memory T cells in transplantation immunity. These alloreactive CD4+ Tm could mediate reject reaction and shorten the survival time of allografts. The main mechanisms of allografts rejection maybe contain FasL-Fas pathway mediated cell apoptosis.
目的探讨小鼠腹部异位心脏移植手术的技术方法及其改进,为进一步进行移植免疫学研究提供动物模型。方法采用供心主动脉与受体腹主动脉、供心肺动脉与受体下腔静脉端侧吻合方法对100例小鼠进行腹部异位心脏移植术,同时测量相关移植部位的重要结构。结果供心主动脉直径为(1.3±0.2)mm,供心肺动脉直径为(1.6±0.3)mm,受体下腔静脉直径为(2.4±0.4)mm,腹主动脉直径为(1.5±0.2)mm,腹腔大血管平均可利用长度为(6.0±1.0)mm。建模成功率为92%。供、受体手术时间分别为(8.0±1.0)min和(40.2±3.0)min;其中动脉吻合为(9.3±1.2)min,静脉吻合为(7.8±1.7)min。结论本组建立小鼠腹部异位心脏移植模型稳定可靠,适用于移植免疫学方面的研究。
第二部分联合阻断CD28/B7和CD40/CD40L共刺激通路对同种异体移植物存活影响及其机制研究
目的借助小鼠腹部异位心脏移植模型,采用共刺激信号阻断策略去诱导同种异体移植物出现免疫耐受,并探讨其机制。方法采用连续联合应用CTLA-4 Ig和MR1,研究其对同种异体移植物存活、Th1和Th2细胞因子分泌等其他相关机制的影响。结果共刺激信号联合阻断能明显延长同种移植物的存活时间(平均存活时间为43 d高于正常排斥对照组的8 d,P<0.01),其具体机制包括能明显抑制Th1和Th2细胞因子的分泌、能减少浸润至移植物内的CD4+和CD8+淋巴细胞的数量、能抑制移植物内穿孔素、颗粒酶B和FasL的表达。结论联合阻断CD28/B7和CD40/CD40L共刺激信号能明显抑制CD4+初始T细胞的活化,阻止其向Th1和Th2极化,明显减少移植物内CD4+和CD8+淋巴细胞的浸润数量,通过抑制移植物内穿孔素、颗粒酶B以及FasL表达来抑制CTLs对移植物的细胞毒作用,从而使同种异基因移植物存活时间延长。
第三部分同种反应性CD4+ Tm对同种异体移植物存活影响的初步研究
目的研究同种反应性CD4+ Tm对同种异体移植物存活的影响,并对其机制进行初步探讨。方法采用小鼠皮肤移植模型,通过免疫磁性分离技术分离出同种反应性CD4+ Tm,并进行表型和功能鉴定。通过尾静脉过继性输入,研究此细胞对同种移植物存活的影响,并探讨其初步机制。结果分离所得CD4+ Tm的活细胞百分率为(98.4±0.7)%,其中CD4+CD44+CD62L-CCR7-细胞比例约占95%,且其功能具有良好的供体特异性。在同种异基因抗原刺激下,CFSE标记的CD4+ Tm荧光强度逐渐下降。与未输注Tm的阴性对照组相比,Tm组同种移植物平均存活时间明显缩短,移植物内有较多CD4+ T淋巴细胞浸润,但分布局限于心肌的中环层。Tm组移植物内仅冠脉周围有少量颗粒酶B表达,其余地方未见明显表达,但有大量的FasL阳性细胞浸润,主要分布于心外膜及心内膜下,尤以血管周围较为明显。结论通过小鼠皮肤移植模型及免疫磁性分离技术,可制备高纯度无菌的CD4+ Tm,其细胞活力不受影响,作用具有良好的供体特异性,这为深入研究Tm在移植物免疫方面的作用奠定了基础。同种反应性CD4+ Tm能介导排斥反应,缩短同种异体移植物的存活时间,这其中以FasL-Fas为代表的非分泌性杀伤性途径可能在CD4+ Tm介导的移植物排斥过程中起主要作用。
Part I Establishment of ventral heterotopic heart transplantation in mice
Objective To explore the improved technique of mouse ventral heterotopic heart transplantation and build animal model on the study of transplantation immunity. Methods The donor heart aorta and the recipient ventral aorta, the donor pulmonary artery and the recipient inferior caval vein, were anastomosed by using the end-to-side suture technique respectively. At the same time, we measured the length of some transplantation-related parts.
Results The diameter of recipient inferior caval vein and ventral aorta was(2.4±0.4)mm,(1.5±0.2)mm respectively. The average length of ventral blood vessels which could be used was (6.0±1.0)mm. The succeeding rate was 92 %. The average time of donor operation and recipient operation was (8.0±1.0)min,(40.2±3.0)min respectively. The time of artery anastomosis and vena anastomosis was (9.3±1.2)min,(7.8±1.7)min respectively.
Conclusions The animal model was stable and could be used for the study of transplantation immunity.
Part II The mechanisms of survival prolongation of murine cardiac allografts using the treatment of CTLA-4 Ig and MR1
Objective The present study was undertaken to determine the role of costimulatory block therapy in murine cardiac transplant model and collect some evidences accounting for the mechanism of transplantation immunity.
Methods In our study, we blocked the CD28/B7 and CD154/CD40 costimulatory pathway by the transient administration of CTLA-4 Ig and MR1 antibody and then proceeded to study that how did the combination administration of CTLA-4 Ig/MR1 influence on survival time of allografts, deviation of Th1 and Th2 cytokines secretion and other mechanisms related to survival prolongation of allografts.
Results Costimulatory blockade can prolong the survival time of cardiac allografts (MST: 43 d for treated group vs. 8 d for untreated group, P<0.01). The costimulatory blockade therapy can downregulate the expression of both Th1 cytokine(IFN-γand IL-2)and Th2 cytokine(IL-4 and IL-10), reduce the quantities of graft-infiltrating CD4+ and CD8+ lymphocytes and inhibit the expression of both perforin/GrB and FasL in allografts.
Conclusions The combination administration of CTLA-4 Ig/MR1 can inhibit acute rejection reaction in murine cardiac allografts and prolong the survival time of cardiac grafts through several mechanisms including inhibition of the Th1 and Th2 cytokines expression, graft-infiltration of CD4+ and CD8+ T lymphocytes and both perforin/GrB and FasL-Fas mediated cytotoxicity.
Part III The role of alloreactive memory T cells in survival of allografts
Objective To study the role of alloreactive memory T cells in survival of allografts.
Methods To draw assistance from mouse skin transplantation model and separate the splenocytes of recipients. The CD4+ Tm were isolated by magnetic activated cell sorting(MACS). The activity and the purity of the isolated cells were detected. And then we transferred these cells into recipients, explored that how did these cells influence the survival of allografts.
Results The activity of the CD4+ memory T cells was (98.4±0.7)%. The proportion of CD4+CD44+CD62L-CCR7- lymphocytes were 95% approximately and its function was donor specific. When CFSE labelled Tm were transferred into recipents via tail vein injection 1 day before operation, the fluorescence intensity of these cells fell off gradually. The mean survival time of allografts in Tm group was shorter compared with negative group(no transferred Tm). There were more CD4+ lymphocytes infiltrating into the middle layer of allografts in Tm group compared with negative group. The level of granzyme B in allografts was very low and there were lots of graft-infiltrating FasL+ lymphocytes in Tm group, especially those locations near epicardium, endocardium and around the vessels.
Conclusions We could use Magnetic activated cell sorting isolation kit to isolate CD4+ memory T lymphocytes aiming at skin allograft effectively, which facilitates us to investigate the role of memory T cells in transplantation immunity. These alloreactive CD4+ Tm could mediate reject reaction and shorten the survival time of allografts. The main mechanisms of allografts rejection maybe contain FasL-Fas pathway mediated cell apoptosis.
引文
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1. Sayegh MH, Carpenter CB. Transplantation 50 years later-progress, challenges, and promises. N Engl J Med, 2004. 351(26): 2761-2766.
2. Meier-Kriesche HU, Schold JD, Srinivas TR, et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant, 2004, 4(3): 378-383.
3. Magee C, Pascual M. The growing problem of chronic renal failure after transplantation of a nonrenal organ. N Engl J Med, 2003, 349(10): 994-996.
4. Rothstein DM, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Immunol Rev, 2003, 196: 85-108.
5. Ferlazzo G, Semino C, Meta Metal. T lymphocytes express B7 family molecules following interaction with dendritic cells and acquire by stander costimulatory properties. Eur J Immunol, 2002, 32(11): 3092-3101.
6. Croft M. Costimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol, 2003, 3(8): 609-620.
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4. Ferlazzo G, Semino C, Meta Metal. T lymphocytes express B7 family moleculesfollowing interaction with dendritic cells and acquire by stander costimulatory properties. Eur J Immunol, 2002, 32(11): 3092-3101.
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1. van Besouw NM, van der Mast BJ, de Kuiper P, et al. Donor-specific T-cell reactivity identifies kidney transplant patients in whom immunosuppressive therapy can be safely reduced. Transplantation, 2000, 70: 136 - 143.
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13. de Groot-Kruseman HA, Baan CC, Zondervan PE, de Weger RA, Niesters HG, Balk AH, et al. Apoptotic death of infiltrating cells in human cardiac allografts is regulated by IL-2, FASL, and FLIP. Transplant Proc, 2004, 36(10): 3143-3148.
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1. Sayegh MH, Carpenter CB. Transplantation 50 years later-progress, challenges, and promises. N Engl J Med, 2004. 351(26): 2761-2766.
2. Meier-Kriesche HU, Schold JD, Srinivas TR, et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant, 2004, 4(3): 378-383.
3. Magee C, Pascual M. The growing problem of chronic renal failure after transplantation of a nonrenal organ. N Engl J Med, 2003, 349(10): 994-996.
4. Rothstein DM, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Immunol Rev, 2003, 196: 85-108.
5. Ferlazzo G, Semino C, Meta Metal. T lymphocytes express B7 family molecules following interaction with dendritic cells and acquire by stander costimulatory properties. Eur J Immunol, 2002, 32(11): 3092-3101.
6. Croft M. Costimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol, 2003, 3(8): 609-620.
7. Jacqueline MS, Jill EH, Barbara EB. CD28/CTLA-4 and CD80/CD86 Families. Immunol Res, 1999, 19: 1-24.
8. Carreno BM, Bennett F, Chau TA, et al. CTLA-4(CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. JImmunol, 2000, 165: 1352-1356.
9. Linsley PS, Brady W, Umes M, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med, 1991, 174: 561-569.
10. Lenschow DJ, Zeng Y, Hathcock KS, et al. Inhibition of transplant rejection following treatment with anti-B7-2 and anti-B7-1 antibodies. Transplantation, 1995, 60(10): 1171-1178.
11. Zheng XX, Sayegh MH, Zheng XG, et al. The role of donor and recipient B7-1(CD80) in allograft rejection. J Immunol, 1997, 159(3): 1169-1173.
12. Huloff A, Dittrich AU, Beier KC et al. ICOS is an inducible T cell costimulator structurally and functionally related to CD28. Nature, 1999, 6716(397): 263-266.
13. Harada H, Salama AD, Sho M, et al. The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. J Clin Invest, 2003, 112: 234-243.
14. Guo L, Li XK, Funeshima N, et al. Prolonged survival in rat liver transplantation with mouse monoclonal antibody against an inducible costiulator(ICOS). Transplantation, 2002, 73: 1027-1032.
15. Nanji SA, Hancock WW, Anderson CC, et al. Multiple combination therapies involving blockade of ICOS/B7RP-1 costimulation facilitate long-term islet allograft survival. Am J Transplant, 2004, 4(4): 526-536.
16. Dong HD, Zhu GF, Tamada K, et al. B7-H1, a third member of the B7 family, costimulates T cell proliferation and interleukin-10 secretion. Nat Med, 1999, 5(12): 1365-1369.
17. Latchman Y, Wood CR, Tatyana C, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001, 2(3): 261-268.
18. Tseng SY, Otsuji M, Gorsaki K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med, 2001, 193(7): 839-845.
19. Ozkaynak E, Wang L, Goodearl A, et al. Programmed death-1 targeting can promote allograft survival. J Immunol, 2002, 169(11): 546-553.
20. Gao W, Demirci G, Terry B, et al. Stimulating PD-1-negative signals concurrent with blocking CD154 costimulation induces long-term islet allograft survival. Transplantation, 2003, 76(6): 994-999.
21. Chapoval AI, Ni J, Lau JS, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol, 2001, 2(3): 269-274.
22. Suh WK, Gajewska BU, Okada H, et al. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol, 2003, 4(9): 899-906.
23. Ueno T, Clarkson MR, Habicht A, et al. Role of B7 homolog 3 (B7-H3) in a murine model of skin and cardiac allograft rejection. American Journal of Transplantation Supplement, 2005, 5(S11): 225-226.
24. Sedy JR, Gavrieli M, Potter KG, et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol, 2005, 6(1): 90-98.
25. Koho H, Paulie S, Ben Aissa H, et al. Monoclonal antibodies to antigens associated with transitional cell carcinoma of the human urinary bladder. Cancer Immunol Immunother, 1984, 17(3): 165-172.
26. Deng D, EI-Rifai W, Ji J, et al. Hypermethylation of metallothionein-3 CpG island in gastric carcinoma. Carcinogenesis, 2002, 24(1): 25-29.
27. Honey K, Cobbold SP, Waldmann H. CD40 ligand blockade induces CD40 T cell tolerance and linked suppression. Immunology, 1999, 163: 4805-4810.
28. Kanaya K, Tsuchida Y, Inobe M, et al. Combined gene therapy with adenovirus vectors containing CTLA-4 Ig and CD40 Ig prolongs survival of composite tissue allografts in rat model. Transplantation, 2003, 75: 275-281.
29. Jember AG, Zuberi R, Liu FT, et al. Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40. J Exp Med, 2001, 193: 387-392.
30. Nohara C, Akiba H, Nakijima A, et al. Amelioration of experimental autoimmune encephalomyelitis with anti-OX40 ligand monoclonal antibody: a critical role for OX40 ligand in migration, but not development, of pathogenic T cells. J Immunol, 2001, 166: 2108-2115.
31. Chitnis T, Najafian N, Abdallah KA, et al. CD28-independent induction of experimental autoimmune encephalomyelitis. J Clin Invest, 2001, 107: 575-583.
32. Yuan X, Salama AD, Dong V, et al. The role of the CD134-CD134 ligand costimulatory pathway in alloimmune responses in vivo. J Immunol, 2003, 170: 2949-2955.
33. Blazar BR, Sharpe A, Chen Al, et al. Ligation of OX40(CD134) regulates graft-versus-host (GVHD) and graft rejection in allogeneic bone marrow transplant recipients. Blood, 2003, 101: 3741-3748.
34. Cannons JL, Lau P, Ghumman B, et al. 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. J Immunol, 2001, 167: 1313-1324.
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