• 昆明市第一人民醫(yī)院(昆明醫(yī)學(xué)院附屬甘美醫(yī)院)肝膽胰一病區(qū)(昆明 650011);

目的 建立大鼠肝移植急性排斥反應(yīng)動物模型，觀察大鼠肝移植術(shù)后他克莫司撤藥誘發(fā)受體急性排斥反應(yīng)的肝臟動態(tài)病理學(xué)變化，為臨床肝移植術(shù)后他克莫司停藥或者用藥不規(guī)律所致急性排斥反應(yīng)的預(yù)測和評估提供理論依據(jù)。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(shù)前1 d和術(shù)后7 d內(nèi)飼喂治療劑量的他克莫司，之后半量遞減至停藥。分別于術(shù)后7、14、21及28 d處死部分受體大鼠，獲取肝組織標(biāo)本，觀察受體大鼠肝臟大體和鏡下的動態(tài)病理學(xué)改變，并進行排斥活動指數(shù)評分，同時觀察受體大鼠的術(shù)后生存時間。結(jié)果 受體大鼠術(shù)后7 d內(nèi)由于受他克莫司的保護，肝臟未出現(xiàn)典型的急性排斥反應(yīng)表現(xiàn)，至術(shù)后14 d由于他克莫司的減量及撤出，迅速發(fā)生肝臟的急性排斥反應(yīng)，術(shù)后14、21及28 d排斥活動指數(shù)評分分別為（3.7±0.9）分、（6.3±0.9）分和（8.1±0.7）分。受體術(shù)后生存時間為（20.85±0.71） d，中位生存期為21 d。結(jié)論 通過圍手術(shù)期短期飼喂治療劑量他克莫司并逐漸減量至撤藥誘發(fā)肝移植大鼠急性排斥反應(yīng)模型術(shù)后的急性排斥反應(yīng),動態(tài)觀察該實驗條件下排斥反應(yīng)發(fā)生的時限和嚴(yán)重程度，對臨床肝移植術(shù)后類似情況下所發(fā)生的急性排斥反應(yīng)具有一定的預(yù)測價值和嚴(yán)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(fā)大鼠肝移植急性排斥反應(yīng)的病理學(xué)觀察與分析. 中國普外基礎(chǔ)與臨床雜志, 2010, 17(12): 1253-1257. doi: 復(fù)制

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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(yán)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(chǔ)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(xué)平, 等. 大鼠原位肝移植術(shù)后排斥反應(yīng)病理動態(tài)變化 [J]. 上海交通大學(xué)學(xué)報(醫(yī)學(xué)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(dǎo)大鼠肝移植免疫低反應(yīng)性的實驗研究 [J]. 中國普外基礎(chǔ)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(huán)孢素A在器官移植中的應(yīng)用比較 [J]. 中國普外基礎(chǔ)與臨床雜志, 2003; 10(4): 415-418.
27. 馬秋野, 孫峰, 武步強, 等. 肝移植術(shù)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(guān)性研究 [J]. 中國普外基礎(chǔ)與臨床雜志, 2006; 13(3): 334-335.
  1. 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. 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. 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. 4. 王文濤, 嚴(yán)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(chǔ)與臨床雜志, 2002； 9(3): 161-163.
  5. 5. Spiegel HU, Palmes D. Surgical techniques of orthotopic rat liver transplantation [J]. J Invest Surg, 1998; 11(2): 83-96.
  6. 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. 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. 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. 9. Furness PN. The BANFF classification: a pan-European study [J]. Transplant Proc, 2002; 34(6): 2485.
  10. 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. 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. 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. 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. 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. 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. 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. 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. 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. 19. 陸炯炯， 杜雋銘, 　周學(xué)平, 等. 大鼠原位肝移植術(shù)后排斥反應(yīng)病理動態(tài)變化 [J]. 上海交通大學(xué)學(xué)報(醫(yī)學(xué)版), 2007; 27（4）： 475-477.
  20. 20. Neuberger J, Adams DH. What is the significance of acute liver allograft rejection? [J]. J Hepatol, 1998; 29(1): 143-150.
  21. 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. 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. 23. 李立， 張升寧， 冉江華, 等. 受體來源未成熟樹突狀細胞誘導(dǎo)大鼠肝移植免疫低反應(yīng)性的實驗研究 [J]. 中國普外基礎(chǔ)與臨床雜志, 2009; 16(1): 32-38.
  24. 24. Wavamunno MD, Chapman JR. Individualization of immunosuppression: concepts and rationale [J]. Curr Opin Organ Transplant, 2008; 13(6): 604-608.
  25. 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. 26. 魏曉平， 李立. 他克莫司與環(huán)孢素A在器官移植中的應(yīng)用比較 [J]. 中國普外基礎(chǔ)與臨床雜志, 2003; 10(4): 415-418.
  27. 27. 馬秋野, 孫峰, 武步強, 等. 肝移植術(shù)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(guān)性研究 [J]. 中國普外基礎(chǔ)與臨床雜志, 2006; 13(3): 334-335.