Cytotoxic T Lymphocyte-Associated Antigen 4 Fusion Protein Induces Immunotolerance of Orthotopic Liver Transplantation in Rhesus Monkeys_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HU Mingdao ¹ , ZHAO Lianfeng ¹ , YU Henghai ¹ , TANG Jihong ¹ , HUANG Ming ¹ , LIU Feng ¹ , ZHOU Yukai ¹ ,  LI Li ²

1.Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical College, Kunming 650101, China;;
2.Liver Transplantation Center, The First People’s Hospital of Kunming City and Affiliated Ganmei Hospital of Kunming Medical College, Kunming 650011, China;

Corresponding author：

LI Li, Email: lili@yahoo.com.cn

Keywords：

Cytotoxic T lymphocyte-associated antigen 4; Rhesus monkey; Liver transplantation; Immunotolerance

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Objective To explore the effect of cytotoxic T lymphocyte-associated antigen 4 (CTLA4-Ig) fusion protein on the function of orthotopic liver allograft.
Methods Orthotopic liver allograft models of rhesus monkeys were established in this study. The survival time, liver function and morphologic changes of graft were observed, respectively. The levels of IL-2 and IL-10 were detected by ELISA. Apoptosis was monitored by TUNEL.
Results The average survival of control group was 6.57 d, while the average survival of CTLA4-Ig group was 14.92 d, which was statistically prolonged (P lt;0.05). Serum ALT level was highly increased, and Alb level decreased obviously in control group. While the levels of ALT and Alb kept in normal in CTLA4-Ig group. After day 3-7, the expressions of IL-2 were highly expressed in control group, while the expressions of IL-10 in CTLA4-Ig group were higher than those of control group. The severity of rejection reaction after day 3 was weaker in CTLA4-Ig group than that of control group by histological assessment. The apoptosis index after day 3 in the liver cells was highly increased in control group as compared with the CTLA4-Ig group.
Conclusions CTLA4-Ig fusion protein therapy can induce immunotolerance and prolong the survival of recipients. The increasing of cytokines IL-2 or the decreasing of cytokines IL-10 may be one of the laboratory indexes in monitoring immunotolerance of transplantation.

Citation： HU Mingdao ,ZHAO Lianfeng,YU Henghai,TANG Jihong,HUANG Ming,LIU Feng,ZHOU Yukai,LI Li. Cytotoxic T Lymphocyte-Associated Antigen 4 Fusion Protein Induces Immunotolerance of Orthotopic Liver Transplantation in Rhesus Monkeys. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(1): 40-45. doi: Copy

1.	唐波, 肖曙峰, 张捷, 等. 穿孔素mRNA 表达与大鼠肝移植急性排斥反应的关系 [J]. 中国普外基础与临床杂志, 2009; 16(8): 617621.
2.	徐明清, 严律南, 苟兴华, 等. 锌指蛋白A20 促进同种异体大鼠小体积移植肝再生并抑制急性排斥 [J]. 中国普外基础与临床杂志, 2008; 15(8): 572578.
3.	刘世呈, 李靖. 肝细胞移植的研究进展 [J]. 中国普外基础与临床杂志, 2008; 15(2): 109111.
4.	郑树森. 肝脏移植 [M]. 第1版. 北京: 人民卫生出版社, 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.	陈忠华, 陈实. 移植免疫学 [M]. 第1版. 武汉: 湖北科学技术出版社, 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, 何晓顺, 陈规划, 等. 肝移植术后早期肝功能的动态变化及其对预后的价值 [J]. 中华内科杂志, 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, 张捷, 等. 穿孔素mRNA 表达与大鼠肝移植急性排斥反应的关系 [J]. 中国普外基础与临床杂志, 2009; 16(8): 617621.
2. 徐明清, 严律南, 苟兴华, 等. 锌指蛋白A20 促进同种异体大鼠小体积移植肝再生并抑制急性排斥 [J]. 中国普外基础与临床杂志, 2008; 15(8): 572578.
3. 刘世呈, 李靖. 肝细胞移植的研究进展 [J]. 中国普外基础与临床杂志, 2008; 15(2): 109111.
4. 郑树森. 肝脏移植 [M]. 第1版. 北京: 人民卫生出版社, 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. 陈忠华, 陈实. 移植免疫学 [M]. 第1版. 武汉: 湖北科学技术出版社, 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, 何晓顺, 陈规划, 等. 肝移植术后早期肝功能的动态变化及其对预后的价值 [J]. 中华内科杂志, 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.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Cytotoxic T Lymphocyte-Associated Antigen 4 Fusion Protein Induces Immunotolerance of Orthotopic Liver Transplantation in Rhesus Monkeys

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