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.	王文涛, 严律南, 曾勇, 等. 大鼠肝移植模型的制作和胆道外引流方法的改进 [J]. 中国普外基础与临床杂志, 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，韩德恩. 不同品系大鼠之间原位肝移植的实验观察 [J]. 中华实验外科杂志, 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.	陆炯炯，杜隽铭, 　周学平, 等. 大鼠原位肝移植术后排斥反应病理动态变化 [J]. 上海交通大学学报(医学版), 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，张升宁，冉江华, 等. 受体来源未成熟树突状细胞诱导大鼠肝移植免疫低反应性的实验研究 [J]. 中国普外基础与临床杂志, 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.	魏晓平，李立. 他克莫司与环孢素A在器官移植中的应用比较 [J]. 中国普外基础与临床杂志, 2003; 10(4): 415-418.
27.	马秋野, 孙峰, 武步强, 等. 肝移植术后他克莫司血药浓度与尿α1微球蛋白及微量白蛋白的相关性研究 [J]. 中国普外基础与临床杂志, 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. 王文涛, 严律南, 曾勇, 等. 大鼠肝移植模型的制作和胆道外引流方法的改进 [J]. 中国普外基础与临床杂志, 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，韩德恩. 不同品系大鼠之间原位肝移植的实验观察 [J]. 中华实验外科杂志, 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. 陆炯炯，杜隽铭, 　周学平, 等. 大鼠原位肝移植术后排斥反应病理动态变化 [J]. 上海交通大学学报(医学版), 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，张升宁，冉江华, 等. 受体来源未成熟树突状细胞诱导大鼠肝移植免疫低反应性的实验研究 [J]. 中国普外基础与临床杂志, 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. 魏晓平，李立. 他克莫司与环孢素A在器官移植中的应用比较 [J]. 中国普外基础与临床杂志, 2003; 10(4): 415-418.
27. 马秋野, 孙峰, 武步强, 等. 肝移植术后他克莫司血药浓度与尿α1微球蛋白及微量白蛋白的相关性研究 [J]. 中国普外基础与临床杂志, 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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