Study of the rejection mediated by antibodies on the transplantation model ofsensitized rat_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHAO Jiaojiao , ZHANG Shengning , MANG Yuanyi , GAO Yang ,  LI Li

Hepatobiliary Pancreaticovascular Surgery and Liver Transplantation Center, Calmete Hospital Affiliated to Kunming Medical University/The First Hospital of Kunming, Yunnan Provincial Organ Transplantation Clinical Medical Center, Kunming 650011, P. R. China;

Corresponding author：

LI Li, Email: ynkmlili62@hotmail.com

Keywords：

donor specific antibody; antibody-mediated rejection; liver transplantation; rat

DOI：

10.7507/1007-9424.202303007

Video：

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Objective To explore the pathological features of rejection reaction and whether it accord with antibody-mediated rejection (AMR) in the liver transplantation model of allo-sensitized rat. Methods Twelve male Lewis rats as the recipient, 250–290 g; 6 male Brown Norway (BN) rats as the donor, 250–280 g. Twelve Lewis recipient rats were randomly divided into 4 groups by random number method (n=3): Lewis control group (LC group, without any treatment), direct transplantation group (T group, livers from BN rats were directly transplanted into Lewis rats), sensitized group (S group, spleen lymphocytes from BN rats were injected into Lewis rats), and sensitized transplantation group (TS group, splenic lymphocytes from BN rats were injected into Lewis rats for 2 weeks before liver transplantation). On the 14th day after liver transplantation, 3–4 mL of recipient non-lethal blood was collected to detect serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), alkaline phosphatase (ALP) and creatinine (CRE) levels, and detect the expression of donor-specific alloantibody (DSA) and complement C4d in recipients. Hematoxylin-eosin (HE) staining and Masson staining were used to evaluate the morphological indexes of rat liver tissue, and CK-19, C4d and CD20 immunohistochemical staining methods were used to evaluate the degree of liver rejection and rejection activity index (RAI) score was performed. Results Compared with the T group, the serum AST, TB, and ALP levels, as well as the positive rates of DSA (IgG1, IgG2a, IgG2b, IgG2c) and C4d expression in Lewis rats in the TS group increased. Compared with the LC group, rats in the T group showed partial bile duct edema and lymphocyte infiltration, but no obvious damage of capillary structure was observed. Compared with the T group, a large number of lymphocytes or monocytes were infiltrated and capillaries were severely damaged in the anterior bile duct of rats in the TS group. The RAI and C4d scores of the TS group were higher than those of the T group. Conclusions More severe acute rejection and liver dysfunction occurred after liver transplantation in sensitized rats, and the acute rejection in sensitized rats was consistent with the characteristics of AMR. However, due to the small sample size in this study, further exploration of AMR model remains to be done.

Citation： ZHAO Jiaojiao, ZHANG Shengning, MANG Yuanyi, GAO Yang, LI Li. Study of the rejection mediated by antibodies on the transplantation model ofsensitized rat. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(6): 674-680. doi: 10.7507/1007-9424.202303007 Copy

1.	Vionnet J, Sempoux C, Pascual M, et al. Donor-specific antibodies in liver transplantation. Gastroenterol Hepatol, 2020, 43(1): 34-45.
2.	Taner T, Stegall MD, Heimbach JK. Antibody-mediated rejection in liver transplantation: current controversies and future directions. Liver Transpl, 2014, 20(5): 514-527.
3.	董辉, 丛文铭. 肝移植后抗体介导性排斥反应的进展. 中华器官移植杂志, 2014, 35(8): 509-511.
4.	Youn JC, Zhang X, Nishihara K, et al. Post-transplantation outcomes of sensitized patients receiving durable mechanical circulatory support. J Heart Lung Transplant, 2022, 41(3): 365-372.
5.	Lubetzky M, Hayde N, Broin PÓ, et al. Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor-specific antibody. Clin Transplant, 2019, 33(3): e13469.
6.	Madill-Thomsen KS, Böhmig GA, Bromberg J, et al. Donor-specific antibody is associated with increased expression of rejection transcripts in renal transplant biopsies classified as no rejection. J Am Soc Nephrol, 2021, 32(11): 2743-2758.
7.	Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant, 2011, 11(11): 2405-2413.
8.	Del Bello A, Congy-Jolivet N, Danjoux M, et al. De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients. Transpl Int, 2015, 28(12): 1371-1382.
9.	Maurice JB, Nwaogu A, Gouda M, et al. Acute antibody-mediated rejection in liver transplantation: impact and applicability of the Banff working group on liver allograft pathology 2016 criteria. Hum Pathol, 2022, 127: 67-77.
10.	Sakamoto S, Akamatsu N, Hasegawa K, et al. The efficacy of rituximab treatment for antibody-mediated rejection in liver transplantation: a retrospective Japanese nationwide study. Hepatol Res, 2021, 51(9): 990-999.
11.	Kamada N, Calne RY. Orthotopic liver transplantation in the rat: technique using cuff for portal vein anastomosis and biliary draninage. Transplantation, 1979, 28(1): 47-50.
12.	赵姣姣, 莽源祎, 李立, 等. 大鼠原位肝移植模型不同灌注方式和吻合方法的效果比较. 中国普外基础与临床杂志, 2023, 30(5): 549-553.
13.	Demetris AJ, Bellamy C, Hübscher SG, et al. 2016 comprehensive update of the Banff working group on liver allograft pathology: introduction of antibody-mediated rejection. Am J Transplant, 2016, 16(10): 2816-2835.
14.	陈栋, 魏来, 蒋继贫, 等. 肝移植后急性体液性排斥反应的诊断和治疗两例. 中华器官移植杂志, 2014, 35(8): 451-454.
15.	Lee M. Antibody-mediated rejection after liver transplant. Gastroenterol Clin North Am, 2017, 46(2): 297-309.
16.	Mang Y, Zhang S, Zhao J, et al. Characteristics of pre-sensitization-related acute antibody-mediated rejection in a rat model of orthotopic liver transplantation. Ann Transl Med, 2022, 10(19): 1066. doi: 10.21037/atm-22-4311.
17.	Petty M. Antibody-mediated rejection in solid organ transplant. AACN Adv Crit Care, 2016, 27(3): 316-323.
18.	Ono K, Ide K, Tanaka Y, et al. Molecular mismatch predicts T cell-mediated rejection and de novo donor-specific antibody formation after living donor liver transplantation. Liver Transpl, 2021, 27(11): 1592-1602.
19.	Astarcioglu I, Cursio R, Reynes M, et al. Increased risk of antibody-mediated rejection of reduced-size liver allografts. J Surg Res, 1999, 87(2): 258-262.
20.	Ueda H, Itoh S, Iwamoto Y, et al. Sensitization interval and administration method alter the effect of 15-deoxyspergualin on heart transplantation in sensitized recipient rats. Transpl Int, 1996, 9(6): 551-556.
21.	Stadlbauer TH, Faske R, Heidt MC, et al. Apoptotic cell death during accelerated rejection in sensitized rat recipients of cardiac allografts. Transplant Proc, 2009, 41(6): 2621-2624.

1. Vionnet J, Sempoux C, Pascual M, et al. Donor-specific antibodies in liver transplantation. Gastroenterol Hepatol, 2020, 43(1): 34-45.
2. Taner T, Stegall MD, Heimbach JK. Antibody-mediated rejection in liver transplantation: current controversies and future directions. Liver Transpl, 2014, 20(5): 514-527.
3. 董辉, 丛文铭. 肝移植后抗体介导性排斥反应的进展. 中华器官移植杂志, 2014, 35(8): 509-511.
4. Youn JC, Zhang X, Nishihara K, et al. Post-transplantation outcomes of sensitized patients receiving durable mechanical circulatory support. J Heart Lung Transplant, 2022, 41(3): 365-372.
5. Lubetzky M, Hayde N, Broin PÓ, et al. Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor-specific antibody. Clin Transplant, 2019, 33(3): e13469.
6. Madill-Thomsen KS, Böhmig GA, Bromberg J, et al. Donor-specific antibody is associated with increased expression of rejection transcripts in renal transplant biopsies classified as no rejection. J Am Soc Nephrol, 2021, 32(11): 2743-2758.
7. Stegall MD, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant, 2011, 11(11): 2405-2413.
8. Del Bello A, Congy-Jolivet N, Danjoux M, et al. De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients. Transpl Int, 2015, 28(12): 1371-1382.
9. Maurice JB, Nwaogu A, Gouda M, et al. Acute antibody-mediated rejection in liver transplantation: impact and applicability of the Banff working group on liver allograft pathology 2016 criteria. Hum Pathol, 2022, 127: 67-77.
10. Sakamoto S, Akamatsu N, Hasegawa K, et al. The efficacy of rituximab treatment for antibody-mediated rejection in liver transplantation: a retrospective Japanese nationwide study. Hepatol Res, 2021, 51(9): 990-999.
11. Kamada N, Calne RY. Orthotopic liver transplantation in the rat: technique using cuff for portal vein anastomosis and biliary draninage. Transplantation, 1979, 28(1): 47-50.
12. 赵姣姣, 莽源祎, 李立, 等. 大鼠原位肝移植模型不同灌注方式和吻合方法的效果比较. 中国普外基础与临床杂志, 2023, 30(5): 549-553.
13. Demetris AJ, Bellamy C, Hübscher SG, et al. 2016 comprehensive update of the Banff working group on liver allograft pathology: introduction of antibody-mediated rejection. Am J Transplant, 2016, 16(10): 2816-2835.
14. 陈栋, 魏来, 蒋继贫, 等. 肝移植后急性体液性排斥反应的诊断和治疗两例. 中华器官移植杂志, 2014, 35(8): 451-454.
15. Lee M. Antibody-mediated rejection after liver transplant. Gastroenterol Clin North Am, 2017, 46(2): 297-309.
16. Mang Y, Zhang S, Zhao J, et al. Characteristics of pre-sensitization-related acute antibody-mediated rejection in a rat model of orthotopic liver transplantation. Ann Transl Med, 2022, 10(19): 1066. doi: 10.21037/atm-22-4311.
17. Petty M. Antibody-mediated rejection in solid organ transplant. AACN Adv Crit Care, 2016, 27(3): 316-323.
18. Ono K, Ide K, Tanaka Y, et al. Molecular mismatch predicts T cell-mediated rejection and de novo donor-specific antibody formation after living donor liver transplantation. Liver Transpl, 2021, 27(11): 1592-1602.
19. Astarcioglu I, Cursio R, Reynes M, et al. Increased risk of antibody-mediated rejection of reduced-size liver allografts. J Surg Res, 1999, 87(2): 258-262.
20. Ueda H, Itoh S, Iwamoto Y, et al. Sensitization interval and administration method alter the effect of 15-deoxyspergualin on heart transplantation in sensitized recipient rats. Transpl Int, 1996, 9(6): 551-556.
21. Stadlbauer TH, Faske R, Heidt MC, et al. Apoptotic cell death during accelerated rejection in sensitized rat recipients of cardiac allografts. Transplant Proc, 2009, 41(6): 2621-2624.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Study of the rejection mediated by antibodies on the transplantation model ofsensitized rat

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