CTLA4-1gG在糖尿病大鼠胰腺移植中的作用研究
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摘要
【目的】探讨细胞毒性T淋巴细胞相关抗原4免疫蛋白(cytotoxicity T lymphocyte-associated 4-immunoglobulin G，CTLA4-IgG)对同种异体大鼠胰腺移植排斥反应的影响。
【方法】 予Wistar大鼠静脉注射链脲霉素(streptozotocin，STZ)诱导制成Ⅰ型糖尿病模型，以其为胰腺移植的受者，并随机分为对照组和实验组，各16例。正常SD大鼠为供者。整块切取供者胰十二指肠，保留带有腹腔干和肠系膜上动脉的腹主动脉段。切除受者左肾，保留右肾，将供者门静脉和受者左肾静脉应用套管法行端端吻合；供者腹主动脉段与受者肾下腹主动脉行端侧吻合；供者十二指肠与受者空肠行侧侧吻合。实验组分别于术中、术后1—7d腹腔注射CTLA4-IgG；对照组分别于术中术后1—7d腹腔注射无菌柠檬酸缓冲液。两组受者术后1—7d每日监测血糖观察移植物功能性存活情况，ELISA检测术后3、7d血清IL-2浓度，术后7d取移植物标本行病理学检查并处死。
【结果】 胰腺移植后糖尿病大鼠受者血糖恢复正常，术后6d，对照组血糖10.6±1.87mmol／L，实验组血糖8.0±0.60mmol／L，两组相比差异有统计学意义(P＜0.01)。实验组术后3、7d血清IL-2浓度分别为
Objective : To evaluate the effect of CTLA4-IgG on the immunological tolerance of pancreaticoduodenal transplantation model in allogenic rats.
Methods: The diabetes Wistar rats as recipients were induced by intravenous administration streptozotocin (STZ) in a single dose of 60mg/ kg of body weight via penis dorsal vein. The diabetes rats were randomly assigned to control group (n = 16) and transplantation group (n=16). Pancreaticoduodenal transplantations were done with the SD rats as donors,then the graft including duodenum and pancreas were harvested enbloc, while the abdominal aorta segment including the coeliac artery and mesentery artery were kept intact. In the recipient operations, the left kidneys was removed while the right kidney was kept intact, the recipient left renal vein was anastomosed with the donor portal vein by end-to-end fashion, the recipient abdominal aorta was anastomosed with the donor proximal end of donor abdominal aorta by lateral-to-end fashion, and the recipient small intestine was anastomosed with the donor duodenum by lateral-to-lateral fashion. The operation group were administered via celiac injection with CTLA4-IgG during operation and after operation(from the 1st day to 7th day) The control group were administered via celiac injection with axenic citric acid puffer solution in the same way as the operation group .Blood glucose of the two recipient groups were investigated daily after transplantation for 7 days, The graft functional survive interval (GFSI) was recorded synchronously. The concentration of IL-2 was observed with ELISA on the 3rd, 7th day after operation. Pancreas tissue biopsies were done on the 3rd,
【方法】 予Wistar大鼠静脉注射链脲霉素(streptozotocin，STZ)诱导制成Ⅰ型糖尿病模型，以其为胰腺移植的受者，并随机分为对照组和实验组，各16例。正常SD大鼠为供者。整块切取供者胰十二指肠，保留带有腹腔干和肠系膜上动脉的腹主动脉段。切除受者左肾，保留右肾，将供者门静脉和受者左肾静脉应用套管法行端端吻合；供者腹主动脉段与受者肾下腹主动脉行端侧吻合；供者十二指肠与受者空肠行侧侧吻合。实验组分别于术中、术后1—7d腹腔注射CTLA4-IgG；对照组分别于术中术后1—7d腹腔注射无菌柠檬酸缓冲液。两组受者术后1—7d每日监测血糖观察移植物功能性存活情况，ELISA检测术后3、7d血清IL-2浓度，术后7d取移植物标本行病理学检查并处死。
【结果】 胰腺移植后糖尿病大鼠受者血糖恢复正常，术后6d，对照组血糖10.6±1.87mmol／L，实验组血糖8.0±0.60mmol／L，两组相比差异有统计学意义(P＜0.01)。实验组术后3、7d血清IL-2浓度分别为
Objective : To evaluate the effect of CTLA4-IgG on the immunological tolerance of pancreaticoduodenal transplantation model in allogenic rats.
Methods: The diabetes Wistar rats as recipients were induced by intravenous administration streptozotocin (STZ) in a single dose of 60mg/ kg of body weight via penis dorsal vein. The diabetes rats were randomly assigned to control group (n = 16) and transplantation group (n=16). Pancreaticoduodenal transplantations were done with the SD rats as donors,then the graft including duodenum and pancreas were harvested enbloc, while the abdominal aorta segment including the coeliac artery and mesentery artery were kept intact. In the recipient operations, the left kidneys was removed while the right kidney was kept intact, the recipient left renal vein was anastomosed with the donor portal vein by end-to-end fashion, the recipient abdominal aorta was anastomosed with the donor proximal end of donor abdominal aorta by lateral-to-end fashion, and the recipient small intestine was anastomosed with the donor duodenum by lateral-to-lateral fashion. The operation group were administered via celiac injection with CTLA4-IgG during operation and after operation(from the 1st day to 7th day) The control group were administered via celiac injection with axenic citric acid puffer solution in the same way as the operation group .Blood glucose of the two recipient groups were investigated daily after transplantation for 7 days, The graft functional survive interval (GFSI) was recorded synchronously. The concentration of IL-2 was observed with ELISA on the 3rd, 7th day after operation. Pancreas tissue biopsies were done on the 3rd,
引文
1．Alan D．Cherrington．糖尿病过去现在和将来．国外医学内分泌学分册，2005；25(5)：附录3—5．
2．常向云．糖尿病流行现状及防治对策．全科医学临床与教育，2004；2 (1)：49—50．
3. Fahim Zaman, Kenneth D. Abreo, Steven Levine, et al. Pancreatic Transplantation: Evaluation and Management. Journal of Intensive Care Medicine 2004; 19(3): 127—139.
4．包军胜．同期胰肾联合移植的进展．国外医学移植与血液净化分册．2004：2(1)：27—31．
5. Sutherland DE, Gruessner RW, Gruessner AC. Pancreas transplantation for treatment of diabetes mellitus. World j Surg. 2001; 25: 487-496.
6. Pancreas transplantation for patients with type 1 diabetes: American Diabetes Association. Diabetes Care. 2000; 23: 117
7. Kennedy WR, Navarro X, Goetz FC, Sutherland DE, Najarian. IS. Effects of pancreatic transplantation on diabetic neuropathy. NEg1J Med. 1990; 22: 1031-1037.
8. Ojo A, Meier-Kriesche HU, Hanson J, et al. The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation. 2001; 71: 82-90.
9. Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE. Pancreas and islet transplantation for patients with diabetes. Diabetes Care, 2000; 23: 112-116.
10. Suthanthiran M, Strom TB. Renal Transplantation. N Eng J Med, 1994; 331: 365-376.
11. Schreiber S, Crabtree G. The mechanism of action of cyclosporine A and FK 506. Immunol Today, 1992; 13: 136-142.
12. Chung 1, Kuo CI, Crabtree GR, Bienis J. Rapamycin-FKBP specifically blocks growth dependent activation of and signalling, by the 70kd S6 protein kinases. Cell, 1992; 69.
13. Brazelton T. Morris R. Molecular mechanisms of action of new xenobiotic immunosuppessive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Current Opinion in Immunology. 1996, 8: 710-720.
14. Norman D. Mechanisms of action and overview of OKT3. Therapeutic Drug Manitoring, 1995, 17: 615-620.
15．Victo Mdong，Laurence A．T细胞同种异体活化的共刺激信号通路．移植免疫生物学．2000，61．
16. Krensky A, Weiss A, Crabtree G; et al. T-lymphocyte-antigen interactions in transplant rejection. N Engl Med, 1990; 322: 510-7.
17. Jenkins M K, Ashwell J D, Schwartz R H, et al. Allogeneic none-T spleen cells restore the responsiveness of normal T cell clones stimulate with antigen and chemically modified antigen presenting cells. [J]. J. immunol, 1988; 140(10): 3 324-3 330.
18. Mueller D L Jenkins M K, Schwartz R H. An accessory cell derived costimulatory signal acts independently of protein kinase C activation to allow T cell proliferation and prevent the induction of unresponsiveness [J]. J. Immunol, 1989; 142(4): 2 617-2 624.
19. Schwartz R H. A cell culture model for T lymphocyte clonal anergy[J]. Science, 1990; 248(4 961): 1 349-1 356.
20. Freeman GJ, Freeman A S, Sege J M et al .B7 a new member of the Ig superfamily with unique expression in activated and neoplastic B cells. [J]. J. Immunol, 1989, 143 (1):2 714-2 721.
21. Janeway CA, Bottomry K.Signals and signs for lymphocyte response. Cell,1994;76:275-85.
22. Linsley PS, Brady W, UrnesM, Grosmaire LS, damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J ExP Med, 1991, 174:561-569.
23. Walunas TL. Leasehow DJ,Bakker CY, et al. TLA-4 can function as a negative regulator of T cell activation. Immunity, 1994, 1:405-413.
24. Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activatin. J eXP Med, 1996; 183: 2541- 2550.
25. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA4. Science, 1995; 270:985-988.
26. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regualtory role of CtlA-4. Immunity, 1995; 3:541-547.
27. Fraser JD. Irving BA. Crabtree GR, Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science, 1991 Jan 18; 251(4991): 313-6.
28. Davidson J, Wilkinson A, Dantal J, et al. New-onset diabetes after transplantation: 2003 international consensus guidelines. Transplantation. 2003; 75(10): SS, 3-24.
29. Peter P, Nuttall SL, Kendall MJ. Insulin resistance--the new goal! J Clin Pharm Ther. 2003; 28(3): 167-74.
30. Friedrich J, Charpentier K, Marsh CL, et al. Outcomes with the selective use of enteric exocrine drainage in pancreas transplantation. Transplant Proc. 2004; 36(10): 3101-4.
31. Gruessner AC, Suthedand DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of May 2003. Clin Transpl, 2003: 21-51.
32．刘忠，关凤林，沈忠义等．异基因大鼠全胰十二指肠移植急性排斥反应的病理变化．中国普通外科杂志，2002；311(3)：165-7．
33．王为忠，刘小南，李开宗等．大鼠单纯胰腺移植技术。中国普外基础与临床杂志，2005；12(2)：148．
34．薛武军，田普训，播晓鸣，等．肾移植1140例次总结．中华器官移植杂志，2001；22：198-200．
35．董隽，敖建华，肖序仁，等．肾移植受者术后发生恶性肿瘤的分析．中华器官移植杂志，2001；22：214-215．
36．孟慧林，杨德安，李香铁，等．肾移植术后恶性肿瘤12例分析．中华器官移植杂志，2002，23：146—148．
37. Benz S, Obermaier R, Pfeffer F, et al. Impairment of microcirculation in the early reperfusion period correlates with the degree of graft pancreatitis in simultaneous pancreas-/kidney transplantation. Transplantation. 2001, 71: 759-763.
38. Benz S, Busing M, Kruger B, et al. Pancreas graft thrombosis: Is there a role for trypsin. Pancreas, 2004: 28(10): 75-79.
39．刘霆，张桂珍，卜丽莎，牟明成．STZ小剂量多次注射诱导大鼠胰岛素依赖性糖尿病动物模型探讨．2001，27(6)：578．
40．彭勇，龚建平甘霖。袖套法制作大鼠胰腺移植模型．肝胆胰外科杂志，2004，16(1)：7．
41. Nakhleh RE, Suthedand DE, Tzardis P, et al. Correlation of rejection of the duodenum with rejection of the pancreas in a pig model of pancreaticoduodenal transplantation. Transplantation, 1993; 56(6): 1353-1356.
42. Cook K, Sollinger HW, Warner T, et al. Pancreaticocystotomy: an alternative method for exocrine drainage of segmental pancreatic allografts.Transplantation, 1983; 35: 634—636.
43. Gruessner AC, Suthedand DER. Report for the International Pancreas Transplant Registry-2000. Transplant Proc, 2001; 33: 1643-1646.
1. Brunet J F, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamil-CTLA-4. Nature, 1987, 328: 267-270.
2. Janeway CA J r, Bottomly K. Signals and signs for lymphocyte responses. Cell, 1994, 76: 275-285.
3. Gause WC, Halvorson JM, Lu P, et al. The function of costimulatory molecules and the development of IL-4 producing T cells. Immunol Today, 1997, 18: 115-120.
4. Kita Y, Li XK, Ohba M, et al. Prolonged cardiac allograft survivalin rats systemically injected adenoviral vectors containing CTLA4Ig-gene. Transplantation, 1999, 68: 758-766.
5. Kita Y, Li XK, Ohba M, et al [J]. Transplantation, 1999, 68(6): 758-766.
6. Onodera K, Chandraker A, Volk HD, et al. [J]. Transplantation, 1999, 68(2): 288-293.
7. Lu L, Gambotto A, Lee WC, et al. Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolero genicity and survival in allogeneic recipients. Gene Ther, 1999, 6: 554-563.
8. Lu L, Lee WC, Takayama T, et al. [J]. J. Leukoc Biol, 1999, 66(2): 293-296.
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11. Linsley PS, Wallace PM, Johnosn J, et al. Immunosuppression invivo by a soluble form of the CTLA-4 T cell activation molecule. Science, 1992,257:792-795.
12. Lenschow DJ, Zeng Y, Thistlethwaite JR., et al. Longterm survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science, 1992, 257: 789-792.
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2．常向云．糖尿病流行现状及防治对策．全科医学临床与教育，2004；2 (1)：49—50．
3. Fahim Zaman, Kenneth D. Abreo, Steven Levine, et al. Pancreatic Transplantation: Evaluation and Management. Journal of Intensive Care Medicine 2004; 19(3): 127—139.
4．包军胜．同期胰肾联合移植的进展．国外医学移植与血液净化分册．2004：2(1)：27—31．
5. Sutherland DE, Gruessner RW, Gruessner AC. Pancreas transplantation for treatment of diabetes mellitus. World j Surg. 2001; 25: 487-496.
6. Pancreas transplantation for patients with type 1 diabetes: American Diabetes Association. Diabetes Care. 2000; 23: 117
7. Kennedy WR, Navarro X, Goetz FC, Sutherland DE, Najarian. IS. Effects of pancreatic transplantation on diabetic neuropathy. NEg1J Med. 1990; 22: 1031-1037.
8. Ojo A, Meier-Kriesche HU, Hanson J, et al. The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation. 2001; 71: 82-90.
9. Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE. Pancreas and islet transplantation for patients with diabetes. Diabetes Care, 2000; 23: 112-116.
10. Suthanthiran M, Strom TB. Renal Transplantation. N Eng J Med, 1994; 331: 365-376.
11. Schreiber S, Crabtree G. The mechanism of action of cyclosporine A and FK 506. Immunol Today, 1992; 13: 136-142.
12. Chung 1, Kuo CI, Crabtree GR, Bienis J. Rapamycin-FKBP specifically blocks growth dependent activation of and signalling, by the 70kd S6 protein kinases. Cell, 1992; 69.
13. Brazelton T. Morris R. Molecular mechanisms of action of new xenobiotic immunosuppessive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Current Opinion in Immunology. 1996, 8: 710-720.
14. Norman D. Mechanisms of action and overview of OKT3. Therapeutic Drug Manitoring, 1995, 17: 615-620.
15．Victo Mdong，Laurence A．T细胞同种异体活化的共刺激信号通路．移植免疫生物学．2000，61．
16. Krensky A, Weiss A, Crabtree G; et al. T-lymphocyte-antigen interactions in transplant rejection. N Engl Med, 1990; 322: 510-7.
17. Jenkins M K, Ashwell J D, Schwartz R H, et al. Allogeneic none-T spleen cells restore the responsiveness of normal T cell clones stimulate with antigen and chemically modified antigen presenting cells. [J]. J. immunol, 1988; 140(10): 3 324-3 330.
18. Mueller D L Jenkins M K, Schwartz R H. An accessory cell derived costimulatory signal acts independently of protein kinase C activation to allow T cell proliferation and prevent the induction of unresponsiveness [J]. J. Immunol, 1989; 142(4): 2 617-2 624.
19. Schwartz R H. A cell culture model for T lymphocyte clonal anergy[J]. Science, 1990; 248(4 961): 1 349-1 356.
20. Freeman GJ, Freeman A S, Sege J M et al .B7 a new member of the Ig superfamily with unique expression in activated and neoplastic B cells. [J]. J. Immunol, 1989, 143 (1):2 714-2 721.
21. Janeway CA, Bottomry K.Signals and signs for lymphocyte response. Cell,1994;76:275-85.
22. Linsley PS, Brady W, UrnesM, Grosmaire LS, damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J ExP Med, 1991, 174:561-569.
23. Walunas TL. Leasehow DJ,Bakker CY, et al. TLA-4 can function as a negative regulator of T cell activation. Immunity, 1994, 1:405-413.
24. Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activatin. J eXP Med, 1996; 183: 2541- 2550.
25. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA4. Science, 1995; 270:985-988.
26. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regualtory role of CtlA-4. Immunity, 1995; 3:541-547.
27. Fraser JD. Irving BA. Crabtree GR, Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science, 1991 Jan 18; 251(4991): 313-6.
28. Davidson J, Wilkinson A, Dantal J, et al. New-onset diabetes after transplantation: 2003 international consensus guidelines. Transplantation. 2003; 75(10): SS, 3-24.
29. Peter P, Nuttall SL, Kendall MJ. Insulin resistance--the new goal! J Clin Pharm Ther. 2003; 28(3): 167-74.
30. Friedrich J, Charpentier K, Marsh CL, et al. Outcomes with the selective use of enteric exocrine drainage in pancreas transplantation. Transplant Proc. 2004; 36(10): 3101-4.
31. Gruessner AC, Suthedand DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of May 2003. Clin Transpl, 2003: 21-51.
32．刘忠，关凤林，沈忠义等．异基因大鼠全胰十二指肠移植急性排斥反应的病理变化．中国普通外科杂志，2002；311(3)：165-7．
33．王为忠，刘小南，李开宗等．大鼠单纯胰腺移植技术。中国普外基础与临床杂志，2005；12(2)：148．
34．薛武军，田普训，播晓鸣，等．肾移植1140例次总结．中华器官移植杂志，2001；22：198-200．
35．董隽，敖建华，肖序仁，等．肾移植受者术后发生恶性肿瘤的分析．中华器官移植杂志，2001；22：214-215．
36．孟慧林，杨德安，李香铁，等．肾移植术后恶性肿瘤12例分析．中华器官移植杂志，2002，23：146—148．
37. Benz S, Obermaier R, Pfeffer F, et al. Impairment of microcirculation in the early reperfusion period correlates with the degree of graft pancreatitis in simultaneous pancreas-/kidney transplantation. Transplantation. 2001, 71: 759-763.
38. Benz S, Busing M, Kruger B, et al. Pancreas graft thrombosis: Is there a role for trypsin. Pancreas, 2004: 28(10): 75-79.
39．刘霆，张桂珍，卜丽莎，牟明成．STZ小剂量多次注射诱导大鼠胰岛素依赖性糖尿病动物模型探讨．2001，27(6)：578．
40．彭勇，龚建平甘霖。袖套法制作大鼠胰腺移植模型．肝胆胰外科杂志，2004，16(1)：7．
41. Nakhleh RE, Suthedand DE, Tzardis P, et al. Correlation of rejection of the duodenum with rejection of the pancreas in a pig model of pancreaticoduodenal transplantation. Transplantation, 1993; 56(6): 1353-1356.
42. Cook K, Sollinger HW, Warner T, et al. Pancreaticocystotomy: an alternative method for exocrine drainage of segmental pancreatic allografts.Transplantation, 1983; 35: 634—636.
43. Gruessner AC, Suthedand DER. Report for the International Pancreas Transplant Registry-2000. Transplant Proc, 2001; 33: 1643-1646.
1. Brunet J F, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamil-CTLA-4. Nature, 1987, 328: 267-270.
2. Janeway CA J r, Bottomly K. Signals and signs for lymphocyte responses. Cell, 1994, 76: 275-285.
3. Gause WC, Halvorson JM, Lu P, et al. The function of costimulatory molecules and the development of IL-4 producing T cells. Immunol Today, 1997, 18: 115-120.
4. Kita Y, Li XK, Ohba M, et al. Prolonged cardiac allograft survivalin rats systemically injected adenoviral vectors containing CTLA4Ig-gene. Transplantation, 1999, 68: 758-766.
5. Kita Y, Li XK, Ohba M, et al [J]. Transplantation, 1999, 68(6): 758-766.
6. Onodera K, Chandraker A, Volk HD, et al. [J]. Transplantation, 1999, 68(2): 288-293.
7. Lu L, Gambotto A, Lee WC, et al. Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolero genicity and survival in allogeneic recipients. Gene Ther, 1999, 6: 554-563.
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