他克莫司撤藥誘發大鼠肝移植急性排斥反應的病理學觀察與分析_《中國普外基礎與臨床雜志》

作者：

李鑄 ,  李立 , 冉江華 , 張升寧 , 劉靜 , 劉滇生 , 李來邦 , 陳娟

昆明市第一人民醫院(昆明醫學院附屬甘美醫院)肝膽胰一病區(昆明 650011);

關鍵詞：

大鼠動物模型原位肝移植術急性排斥反應他克莫司

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目的建立大鼠肝移植急性排斥反應動物模型，觀察大鼠肝移植術后他克莫司撤藥誘發受體急性排斥反應的肝臟動態病理學變化，為臨床肝移植術后他克莫司停藥或者用藥不規律所致急性排斥反應的預測和評估提供理論依據。方法通過Kamada二袖套法，建立雄性DA大鼠至Lewis大鼠的原位肝移植模型60例。受體大鼠術前1 d和術后7 d內飼喂治療劑量的他克莫司，之后半量遞減至停藥。分別于術后7、14、21及28 d處死部分受體大鼠，獲取肝組織標本，觀察受體大鼠肝臟大體和鏡下的動態病理學改變，并進行排斥活動指數評分，同時觀察受體大鼠的術后生存時間。結果受體大鼠術后7 d內由于受他克莫司的保護，肝臟未出現典型的急性排斥反應表現，至術后14 d由于他克莫司的減量及撤出，迅速發生肝臟的急性排斥反應，術后14、21及28 d排斥活動指數評分分別為（3.7±0.9）分、（6.3±0.9）分和（8.1±0.7）分。受體術后生存時間為（20.85±0.71） d，中位生存期為21 d。結論通過圍手術期短期飼喂治療劑量他克莫司并逐漸減量至撤藥誘發肝移植大鼠急性排斥反應模型術后的急性排斥反應,動態觀察該實驗條件下排斥反應發生的時限和嚴重程度，對臨床肝移植術后類似情況下所發生的急性排斥反應具有一定的預測價值和嚴重程度評估價值。

引用本文： 李鑄,李立,冉江華,張升寧,劉靜,劉滇生,李來邦,陳娟. 他克莫司撤藥誘發大鼠肝移植急性排斥反應的病理學觀察與分析. 中國普外基礎與臨床雜志, 2010, 17(12): 1253-1257. doi: 復制

1.	Lee S, Charters AC, Chandler JG, et al. A technique for orthotopic liver transplantation in the rat [J]. Transplantation, 1973; 16(6): 664-669.
2.	Lee S, Charters AC 3rd, Orloff MJ. Simplified technic for orthotopic liver transplantation in the rat [J]. Am J Surg, 1975; 130(1): 38-40.
3.	Kamada N, Calne RY. A surgical experience with five hundred thirty liver transplants in the rat [J]. Surgery, 1983; 93(1 Pt 1 ): 64-69.
4.	王文濤, 嚴律南, 曾勇, 等. 大鼠肝移植模型的制作和膽道外引流方法的改進 [J]. 中國普外基礎與臨床雜志, 2002； 9(3): 161-163.
5.	Spiegel HU, Palmes D. Surgical techniques of orthotopic rat liver transplantation [J]. J Invest Surg, 1998; 11(2): 83-96.
6.	姜明山，韓德恩. 不同品系大鼠之間原位肝移植的實驗觀察 [J]. 中華實驗外科雜志, 2004; 21(4): 428-429.
7.	Zimmermann FA, Davies HS, Knoll PP, et al. Orthotopic liver allografts in the rat. The influence of strain combination on the fate of the graft [J]. Transplantation, 1984; 37(4): 406-410.
8.	Solez K. History of the Banff classification of allograft pathology as it approaches its 20th year [J]. Curr Opin Organ Transplant, 2010; 15(1): 49-51.
9.	Furness PN. The BANFF classification: a pan-European study [J]. Transplant Proc, 2002; 34(6): 2485.
10.	Hroldt BS, Burattin M, Gunson BK, et al. Does the Banff rejection activity index predict outcome in patients with early acute cellular rejection following liver transplantation? [J]. Liver Transpl, 2006; 12(7): 1144-1151.
11.	Demirhan B, Bileziki B, Haberal AN, et al. Hepatic parenchymal changes and histologic eosinophilia as predictors of subsequent acute liver allograft rejection [J]. Liver Transpl, 2008; 14(2): 214-219.
12.	Bryan CF, Newman JT, Nery J, et al. Quantitative and functional profile of the immune system after liver transplantation [J]. Transplant Proc, 1987; 19(5): 4340-4344.
13.	Schlitt HJ, Nashan B, Krick P, et al. Intragraft immune events after human liver transplantation. Correlation with clinical signs of acute rejection and influence of immunosuppression [J]. Transplantation, 1992; 54(2): 273-278.
14.	Kwekkeboom J, Zondervan PE, Kuijpers MA, et al. Fine-needle aspiration cytology in the diagnosis of acute rejection after liver transplantation [J]. Br J Surg, 2003; 90(2): 246-247.
15.	Hckerstedt K, Lautenschlager I, Ahonen J, et al. Diagnosis of acute rejection in liver transplantation [J]. J Hepatol, 1988; 6(2): 217-221.
16.	Nashan B, Saliba F, Durand F, et al. Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients [J]. Liver Transpl, 2009; 15(2): 136-147.
17.	Lerut J, Mathys J, Verbaandert C, et al. Tacrolimus monotherapy in liver transplantation: one-year results of a prospective, randomized, double-blind, placebo-controlled study [J]. Ann Surg, 2008; 248(6): 956-967.
18.	Zimmermann FA, Butcher GW, Davies HS, et al. Techniques for orthotopic liver transplantation in the rat and some studies of the immunologic responses to fully allogeneic liver grafts [J]. Transplant Proc, 1979; 11(1): 571-577.
19.	陸炯炯，杜雋銘, 　周學平, 等. 大鼠原位肝移植術后排斥反應病理動態變化 [J]. 上海交通大學學報(醫學版), 2007; 27（4）： 475-477.
20.	Neuberger J, Adams DH. What is the significance of acute liver allograft rejection? [J]. J Hepatol, 1998; 29(1): 143-150.
21.	Mor E, Solomon H, Gibbs JF, et al. Acute cellular rejection following liver transplantation: clinical pathologic features and effect on outcome [J]. Semin Liver Dis, 1992; 12(1): 28-40.
22.	Bartlett AS, Ramadas R, Furness S, et al. The natural history of acute histologic rejection without biochemical graft dysfunction in orthotopic liver transplantation: a systematic review [J]. Liver Transpl, 2002; 8(12): 1147-1153.
23.	李立，張升寧，冉江華, 等. 受體來源未成熟樹突狀細胞誘導大鼠肝移植免疫低反應性的實驗研究 [J]. 中國普外基礎與臨床雜志, 2009; 16(1): 32-38.
24.	Wavamunno MD, Chapman JR. Individualization of immunosuppression: concepts and rationale [J]. Curr Opin Organ Transplant, 2008; 13(6): 604-608.
25.	Karabulut AB, Ara C. Melatonin ameliorates tacrolimus (FK-506)’s induced immunosupressive effect in rat liver [J]. Transplant Proc, 2009; 41(5): 1875-1877.
26.	魏曉平，李立. 他克莫司與環孢素A在器官移植中的應用比較 [J]. 中國普外基礎與臨床雜志, 2003; 10(4): 415-418.
27.	馬秋野, 孫峰, 武步強, 等. 肝移植術后他克莫司血藥濃度與尿α1微球蛋白及微量白蛋白的相關性研究 [J]. 中國普外基礎與臨床雜志, 2006; 13(3): 334-335.

1. Lee S, Charters AC, Chandler JG, et al. A technique for orthotopic liver transplantation in the rat [J]. Transplantation, 1973; 16(6): 664-669.
2. Lee S, Charters AC 3rd, Orloff MJ. Simplified technic for orthotopic liver transplantation in the rat [J]. Am J Surg, 1975; 130(1): 38-40.
3. Kamada N, Calne RY. A surgical experience with five hundred thirty liver transplants in the rat [J]. Surgery, 1983; 93(1 Pt 1 ): 64-69.
4. 王文濤, 嚴律南, 曾勇, 等. 大鼠肝移植模型的制作和膽道外引流方法的改進 [J]. 中國普外基礎與臨床雜志, 2002； 9(3): 161-163.
5. Spiegel HU, Palmes D. Surgical techniques of orthotopic rat liver transplantation [J]. J Invest Surg, 1998; 11(2): 83-96.
6. 姜明山，韓德恩. 不同品系大鼠之間原位肝移植的實驗觀察 [J]. 中華實驗外科雜志, 2004; 21(4): 428-429.
7. Zimmermann FA, Davies HS, Knoll PP, et al. Orthotopic liver allografts in the rat. The influence of strain combination on the fate of the graft [J]. Transplantation, 1984; 37(4): 406-410.
8. Solez K. History of the Banff classification of allograft pathology as it approaches its 20th year [J]. Curr Opin Organ Transplant, 2010; 15(1): 49-51.
9. Furness PN. The BANFF classification: a pan-European study [J]. Transplant Proc, 2002; 34(6): 2485.
10. Hroldt BS, Burattin M, Gunson BK, et al. Does the Banff rejection activity index predict outcome in patients with early acute cellular rejection following liver transplantation? [J]. Liver Transpl, 2006; 12(7): 1144-1151.
11. Demirhan B, Bileziki B, Haberal AN, et al. Hepatic parenchymal changes and histologic eosinophilia as predictors of subsequent acute liver allograft rejection [J]. Liver Transpl, 2008; 14(2): 214-219.
12. Bryan CF, Newman JT, Nery J, et al. Quantitative and functional profile of the immune system after liver transplantation [J]. Transplant Proc, 1987; 19(5): 4340-4344.
13. Schlitt HJ, Nashan B, Krick P, et al. Intragraft immune events after human liver transplantation. Correlation with clinical signs of acute rejection and influence of immunosuppression [J]. Transplantation, 1992; 54(2): 273-278.
14. Kwekkeboom J, Zondervan PE, Kuijpers MA, et al. Fine-needle aspiration cytology in the diagnosis of acute rejection after liver transplantation [J]. Br J Surg, 2003; 90(2): 246-247.
15. Hckerstedt K, Lautenschlager I, Ahonen J, et al. Diagnosis of acute rejection in liver transplantation [J]. J Hepatol, 1988; 6(2): 217-221.
16. Nashan B, Saliba F, Durand F, et al. Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients [J]. Liver Transpl, 2009; 15(2): 136-147.
17. Lerut J, Mathys J, Verbaandert C, et al. Tacrolimus monotherapy in liver transplantation: one-year results of a prospective, randomized, double-blind, placebo-controlled study [J]. Ann Surg, 2008; 248(6): 956-967.
18. Zimmermann FA, Butcher GW, Davies HS, et al. Techniques for orthotopic liver transplantation in the rat and some studies of the immunologic responses to fully allogeneic liver grafts [J]. Transplant Proc, 1979; 11(1): 571-577.
19. 陸炯炯，杜雋銘, 　周學平, 等. 大鼠原位肝移植術后排斥反應病理動態變化 [J]. 上海交通大學學報(醫學版), 2007; 27（4）： 475-477.
20. Neuberger J, Adams DH. What is the significance of acute liver allograft rejection? [J]. J Hepatol, 1998; 29(1): 143-150.
21. Mor E, Solomon H, Gibbs JF, et al. Acute cellular rejection following liver transplantation: clinical pathologic features and effect on outcome [J]. Semin Liver Dis, 1992; 12(1): 28-40.
22. Bartlett AS, Ramadas R, Furness S, et al. The natural history of acute histologic rejection without biochemical graft dysfunction in orthotopic liver transplantation: a systematic review [J]. Liver Transpl, 2002; 8(12): 1147-1153.
23. 李立，張升寧，冉江華, 等. 受體來源未成熟樹突狀細胞誘導大鼠肝移植免疫低反應性的實驗研究 [J]. 中國普外基礎與臨床雜志, 2009; 16(1): 32-38.
24. Wavamunno MD, Chapman JR. Individualization of immunosuppression: concepts and rationale [J]. Curr Opin Organ Transplant, 2008; 13(6): 604-608.
25. Karabulut AB, Ara C. Melatonin ameliorates tacrolimus (FK-506)’s induced immunosupressive effect in rat liver [J]. Transplant Proc, 2009; 41(5): 1875-1877.
26. 魏曉平，李立. 他克莫司與環孢素A在器官移植中的應用比較 [J]. 中國普外基礎與臨床雜志, 2003; 10(4): 415-418.
27. 馬秋野, 孫峰, 武步強, 等. 肝移植術后他克莫司血藥濃度與尿α1微球蛋白及微量白蛋白的相關性研究 [J]. 中國普外基礎與臨床雜志, 2006; 13(3): 334-335.

《中國普外基礎與臨床雜志》

他克莫司撤藥誘發大鼠肝移植急性排斥反應的病理學觀察與分析

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《中國普外基礎與臨床雜志》

他克莫司撤藥誘發大鼠肝移植急性排斥反應的病理學觀察與分析

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