Dynamically Observed Histopathologic Changes of Acute Rejection in Rat Orthotopic Liver Transplantation Model after Tacrolimus Discontinued _CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Zhu ,  LI Li , RAN Jianghua , ZHANG Shengning , LIU Jing , LIU Diansheng , LI Laibang , CHEN Juan.

Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Ganmei Hospital of Kunming Medical College and The First People’s Hospital of Kunming City, Kunming 650011, China;

Corresponding?author：

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

Keywords：

Rat; Animal model; Orthotopic liver transplantation; Acute rejection; Tacrolimus

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Objective To observe the dynamic histopathologic changes of acute rejection in rat orthotopic liver transplantation (OLT) model after tacrolimus discontinued and provide some prediction and evaluation data for clinical acute rejection after liver transplantation. Methods Kamada two-cuff technique was used to establish 60 rat OLT model， and male DA rats, male Lewis rats were used as donors and recipients respectively. Therapeutic amount of tacrolimus (0.05 mg/kg, twice per day, continued for 8 d, 1 d before operation and 7 d after operation, intragastric administrated) was administrated to recipients, then continuously half dose was decreased every day beginning from day 8 after operation and tacrolimus administration was stopped on day 13. Liver tissues were collected on day 7, 14, 21, and 28 after liver transplantation. Histopathologic changes and rejection activity index (RAI) of liver tissues were observed, survival time of recipients was calculated. Results Owing to protection effects of tacrolimus, liver tissues displayed no significant histopathologic changes of acute rejection in 7 d after OLT, while typical acute rejection histopathologic changes began to be observed on day 14 after OLT due to tacrolimus discontinuation. On day 14, 21, and 28, RAI were 3.7±0.9, 6.3±0.9, and 8.1±0.7 respectively. Survival time of recipients was (20.85±0.71) d with a median of 21 d. Conclusion Acute rejection could be induced in rat OLT model after tacrolimus discontinuation, and data collected from this model shows some extent of predictive value and assessment value for clinical liver acute rejection.

Citation： LI Zhu,LI Li,RAN Jianghua,ZHANG Shengning,LIU Jing,LIU Diansheng,LI Laibang,CHEN Juan.. Dynamically Observed Histopathologic Changes of Acute Rejection in Rat Orthotopic Liver Transplantation Model after Tacrolimus Discontinued . CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(12): 1253-1257. doi: Copy

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.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Dynamically Observed Histopathologic Changes of Acute Rejection in Rat Orthotopic Liver Transplantation Model after Tacrolimus Discontinued 

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