CTLA4-Ig融合蛋白誘導獼猴同種異體肝移植免疫耐受的實驗研究_《中國普外基礎與臨床雜志》

作者：

胡明道 ¹ , 趙戀峰 ¹ , 于恒海 ¹ , 唐繼紅 ¹ , 黃明 ¹ , 劉峰 ¹ , 周玉凱 ¹ ,  李立 ²

1.昆明醫學院第二附屬醫院肝膽外科（昆明 650101）;;
2.昆明市第一人民醫院暨昆明醫學院附屬甘美醫院肝移植中心(昆明 650011);

關鍵詞：

細胞毒性T淋巴細胞相關抗原4 獼猴肝移植免疫耐受

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目的探討細胞毒性T淋巴細胞相關抗原4（CTLA4Ig）融合蛋白對同種異體肝臟移植免疫耐受的誘導作用及機理。方法利用大型哺乳動物獼猴作為研究對象，建立同種異體原位肝臟移植模型。同種異體原位肝臟移植對照組及CTLA4-Ig組各5只。觀察術后生存時間，檢測肝功能、IL-2、IL-10、排斥反應的病理學分級和術后肝臟細胞凋亡指數。
結果對照組平均存活時間為6.57 d，CTLA4-Ig組平均存活時間為14.92 d (P lt;0.05)。肝功能變化: 對照組術后ALT明顯升高，Alb則明顯降低; CTLA4-Ig組ALT及Alb均維持于正常穩定水平。細胞因子變化：術后3 d起，對照組循環血中IL-2表達水平相對較高，而CTLA4-Ig組IL-10的表達水平較對照組高。移植物病理排斥反應分級: 在移植術后CTLA4-Ig組排斥反應程度明顯比對照組輕。對照組術后3 d起肝臟細胞凋亡指數較CTLA4-Ig組明顯升高。
結論 CTLA4-Ig融合蛋白可誘導移植后免疫耐受，延長受體生存時間。細胞因子IL-2或者IL-10可作為監測移植排斥反應或者免疫耐受的實驗室指標之一。

引用本文： 胡明道,趙戀峰,于恒海,唐繼紅,黃明,劉峰,周玉凱,李立. CTLA4-Ig融合蛋白誘導獼猴同種異體肝移植免疫耐受的實驗研究. 中國普外基礎與臨床雜志, 2010, 17(1): 40-45. doi: 復制

1.	唐波, 肖曙峰, 張捷, 等. 穿孔素mRNA 表達與大鼠肝移植急性排斥反應的關系 [J]. 中國普外基礎與臨床雜志, 2009; 16(8): 617621.
2.	徐明清, 嚴律南, 茍興華, 等. 鋅指蛋白A20 促進同種異體大鼠小體積移植肝再生并抑制急性排斥 [J]. 中國普外基礎與臨床雜志, 2008; 15(8): 572578.
3.	劉世呈, 李靖. 肝細胞移植的研究進展 [J]. 中國普外基礎與臨床雜志, 2008; 15(2): 109111.
4.	鄭樹森. 肝臟移植 [M]. 第1版. 北京: 人民衛生出版社, 2001: 12.
5.	Kemnitze J, Ringe B, Cohnert TR, et al. Bile duct injury as a part of diagnostic criteria for liver allograft rejection [J]. Hum Pathol, 1989; 20(2): 132143.
6.	Jenkins MK, Burrell E, Ashwell JD. Antigen presentation by resting B cells: effectiveness at inducing T cell proliferation is determined by costimulatory signals, not T cell receptor occupany [J]. J Immunol, 1990; 144(5): 15851590.
7.	Judge JA, Tang A, Spain JM, et al. The in vivo mechanisms of action of CTLA4Ig [J]. J Immunol, 1996; 156(6): 22942299.
8.	Tu Y, Rehman A, Flye MW. CTLA4 treatment prolongs rat orthotopic liver graft survival [J]. Transplant Proc, 1997; 29(12): 10361037.
9.	陳忠華, 陳實. 移植免疫學 [M]. 第1版. 武漢: 湖北科學技術出版社, 1998: 298312.
10.	Lu S, Yu Y, Gao Y, et al. Immunological inhibition of transplanted liver allografts by adenoassociated virus vector encoding CTLA4Ig in rats [J]. Hepatobiliary Pancreat Dis Int, 2008; 7(3): 258263.
11.	Kanaya K, Tsuchida Y, Inobe M, et al. Combined gene therapy with adenovirus vectors containing CTLA4Ig and CD40Ig prolongs survival of composite tissue allografts in rat model [J].Transplantation, 2003; 75(3): 275281.
12.	Gong N, Pleyer U, Vogt K, et al. Local overexpression of nerve growth factor in rat corneal transplants improves allograft survival [J]. Invest Ophthalmol Vis Sci, 2007; 48(3): 10431052.
13.	Jiang GP, Hu ZH, Zheng SS, et al. Adenovirus mediated CTLA4Ig gene inhibits infiltration of immune cells and cell apoptosis in rats after liver transplantation [J]. World J Gastroenterol, 2005; 11(7): 10651069.
14.	Schmitz V, Neumann UP, Fischer U, et al. Induction of longterm graft acceptance by a combination treatment of donor splenocytes and CTLA4Ig in a high responder rat liver transplantation model [J]. Transpl Int, 2005; 18(10): 11871196.
15.	Iwasaki N, Gohda T, Yoshioka C, et al. Feasibility of immunosuppression in composite tissue allografts by systemic administration of CTLA4Ig [J].Transplantation, 2002; 15; 73(3): 334340.
16.	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.
17.	Olthoff KM, Judge TA, Gelman AE, et al. Adenovirusmediated gene transfer into coldpreserved liver allografts:survival pattern and unresponsiveness followins transduction with CTLA4Ig [J]. Nat Med, 1998; 4 (2): 194200.
18.	唐映梅, 何曉順, 陳規劃, 等. 肝移植術后早期肝功能的動態變化及其對預后的價值 [J]. 中華內科雜志, 2005; 44(4): 268271.
19.	Yard BA, KooymansCouthino M, Paape ME, et al. Analysis of cytokine production by graftinfiltrating cells isolated from rejecting renal allografts [J]. Transplantation, 1994; 57(1): 153158.
20.	Benigni A, Tomasoni S, Turka LA, et al. Adenoassociated virusmediated CTLA4Ig gene transfer protects MHCmismatched renal allografts from chronic rejection [J]. J Am Soc Nephrol, 2006; 17(6): 16651672.
21.	Wang YF, Xu AG, Hua YB, et al. Effect of local CTLA4Ig gene transfection on acute rejection of small bowel allografts in rats [J]. World J Gastroenterol, 2004; 10(6): 885888.
22.	Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. Ⅳ. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones [J]. J Exp Med, 1989; 170(6): 20812095.
23.	Chen Y, Chen J, Liu Z, et al. Relationship between TH1/TH2 cytokines and immune tolerance in liver transplantation in rats [J]. Transplant Proc, 2008; 40(8): 26912695.
24.	Chen B, Kapturczak MH, Joseph R, et al. Adenoassociated viral vectormediated interleukin10 prolongs allograft survival in a rat kidney transplantation model [J]. Am J Transplant, 2007; 7(5): 11121120.
25.	Cao H, Liu H, Wu ZY. Effects of combined immune therapy on survival and Th1/Th2 cytokine balance in rat orthotopic liver transplantation [J]. Chin Med J (Engl), 2007; 120(20): 18091812.
26.	Woodle ES, Kulkarni S. Programmed cell death [J]. Transplantation, 1998; 66(6): 681691.
27.	Krams SM, Martinez OM. Apoptosis as a mechanism of tissue injury in liver allograft rejection [J]. Semin Liver Dis, 1998; 18(2): 153167.

1. 唐波, 肖曙峰, 張捷, 等. 穿孔素mRNA 表達與大鼠肝移植急性排斥反應的關系 [J]. 中國普外基礎與臨床雜志, 2009; 16(8): 617621.
2. 徐明清, 嚴律南, 茍興華, 等. 鋅指蛋白A20 促進同種異體大鼠小體積移植肝再生并抑制急性排斥 [J]. 中國普外基礎與臨床雜志, 2008; 15(8): 572578.
3. 劉世呈, 李靖. 肝細胞移植的研究進展 [J]. 中國普外基礎與臨床雜志, 2008; 15(2): 109111.
4. 鄭樹森. 肝臟移植 [M]. 第1版. 北京: 人民衛生出版社, 2001: 12.
5. Kemnitze J, Ringe B, Cohnert TR, et al. Bile duct injury as a part of diagnostic criteria for liver allograft rejection [J]. Hum Pathol, 1989; 20(2): 132143.
6. Jenkins MK, Burrell E, Ashwell JD. Antigen presentation by resting B cells: effectiveness at inducing T cell proliferation is determined by costimulatory signals, not T cell receptor occupany [J]. J Immunol, 1990; 144(5): 15851590.
7. Judge JA, Tang A, Spain JM, et al. The in vivo mechanisms of action of CTLA4Ig [J]. J Immunol, 1996; 156(6): 22942299.
8. Tu Y, Rehman A, Flye MW. CTLA4 treatment prolongs rat orthotopic liver graft survival [J]. Transplant Proc, 1997; 29(12): 10361037.
9. 陳忠華, 陳實. 移植免疫學 [M]. 第1版. 武漢: 湖北科學技術出版社, 1998: 298312.
10. Lu S, Yu Y, Gao Y, et al. Immunological inhibition of transplanted liver allografts by adenoassociated virus vector encoding CTLA4Ig in rats [J]. Hepatobiliary Pancreat Dis Int, 2008; 7(3): 258263.
11. Kanaya K, Tsuchida Y, Inobe M, et al. Combined gene therapy with adenovirus vectors containing CTLA4Ig and CD40Ig prolongs survival of composite tissue allografts in rat model [J].Transplantation, 2003; 75(3): 275281.
12. Gong N, Pleyer U, Vogt K, et al. Local overexpression of nerve growth factor in rat corneal transplants improves allograft survival [J]. Invest Ophthalmol Vis Sci, 2007; 48(3): 10431052.
13. Jiang GP, Hu ZH, Zheng SS, et al. Adenovirus mediated CTLA4Ig gene inhibits infiltration of immune cells and cell apoptosis in rats after liver transplantation [J]. World J Gastroenterol, 2005; 11(7): 10651069.
14. Schmitz V, Neumann UP, Fischer U, et al. Induction of longterm graft acceptance by a combination treatment of donor splenocytes and CTLA4Ig in a high responder rat liver transplantation model [J]. Transpl Int, 2005; 18(10): 11871196.
15. Iwasaki N, Gohda T, Yoshioka C, et al. Feasibility of immunosuppression in composite tissue allografts by systemic administration of CTLA4Ig [J].Transplantation, 2002; 15; 73(3): 334340.
16. 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.
17. Olthoff KM, Judge TA, Gelman AE, et al. Adenovirusmediated gene transfer into coldpreserved liver allografts:survival pattern and unresponsiveness followins transduction with CTLA4Ig [J]. Nat Med, 1998; 4 (2): 194200.
18. 唐映梅, 何曉順, 陳規劃, 等. 肝移植術后早期肝功能的動態變化及其對預后的價值 [J]. 中華內科雜志, 2005; 44(4): 268271.
19. Yard BA, KooymansCouthino M, Paape ME, et al. Analysis of cytokine production by graftinfiltrating cells isolated from rejecting renal allografts [J]. Transplantation, 1994; 57(1): 153158.
20. Benigni A, Tomasoni S, Turka LA, et al. Adenoassociated virusmediated CTLA4Ig gene transfer protects MHCmismatched renal allografts from chronic rejection [J]. J Am Soc Nephrol, 2006; 17(6): 16651672.
21. Wang YF, Xu AG, Hua YB, et al. Effect of local CTLA4Ig gene transfection on acute rejection of small bowel allografts in rats [J]. World J Gastroenterol, 2004; 10(6): 885888.
22. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. Ⅳ. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones [J]. J Exp Med, 1989; 170(6): 20812095.
23. Chen Y, Chen J, Liu Z, et al. Relationship between TH1/TH2 cytokines and immune tolerance in liver transplantation in rats [J]. Transplant Proc, 2008; 40(8): 26912695.
24. Chen B, Kapturczak MH, Joseph R, et al. Adenoassociated viral vectormediated interleukin10 prolongs allograft survival in a rat kidney transplantation model [J]. Am J Transplant, 2007; 7(5): 11121120.
25. Cao H, Liu H, Wu ZY. Effects of combined immune therapy on survival and Th1/Th2 cytokine balance in rat orthotopic liver transplantation [J]. Chin Med J (Engl), 2007; 120(20): 18091812.
26. Woodle ES, Kulkarni S. Programmed cell death [J]. Transplantation, 1998; 66(6): 681691.
27. Krams SM, Martinez OM. Apoptosis as a mechanism of tissue injury in liver allograft rejection [J]. Semin Liver Dis, 1998; 18(2): 153167.

《中國普外基礎與臨床雜志》

CTLA4-Ig融合蛋白誘導獼猴同種異體肝移植免疫耐受的實驗研究

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《中國普外基礎與臨床雜志》

CTLA4-Ig融合蛋白誘導獼猴同種異體肝移植免疫耐受的實驗研究

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

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