Report of 3 cases of transplantation of GGTA1 gene knockout porcine islet cells into type Ⅰ diabetic macaques_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

XIE Yuxuan ¹ , TANG Hongmei ¹ , LI Xin ² , PAN Dengke ¹ ,  ZHOU Jia ³

1. Institute of Organ Transplantation, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu 610072, P. R. China;
2. University of Electronic Science and Technology of China School of Medicine, Chengdu 610054, P. R. China;
3. Institute of Laboratory Animal Sciences, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu 610212, P. R. China;

Corresponding author：

ZHOU Jia, Email: zhoujia5824@126.com

Keywords：

pig-monkey islet xenotransplantation; α-1, 3-galactosyltransferase; knockout; type Ⅰ diabetes

DOI：

10.7507/1007-9424.202104047

Video：

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Objective To explore the effect of transplanting neonatal porcine islet cells of pig via hepatic portal vein in type Ⅰ diabetic monkeys.Method In this study, three pig-monkey islet xenotransplantation experiments were carried out by using α-1, 3-galactosyltransferase (GGTA1) gene knockout neonatal pig islet cells.Results Three macaques were successfully transplanted with islet cells. After the operation, their vital signs were stable and no symptoms of venous embolism occurred. After transplantation, the blood glucose and the dosage of exogenous insulin were significantly reduced, and the specific porcine C-peptide could be detected. Three macaques developed symptoms of ketoacidosis, and one macaque developed wound infection. After symptomatic treatment, all of them survived for 16 weeks.Conclusion GGTA1 knockout neonatal porcine islet cells transplanted through hepatic portal vein is effective for the treatment of type Ⅰ diabetes.

Citation： XIE Yuxuan, TANG Hongmei, LI Xin, PAN Dengke, ZHOU Jia. Report of 3 cases of transplantation of GGTA1 gene knockout porcine islet cells into type Ⅰ diabetic macaques. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(5): 561-565. doi: 10.7507/1007-9424.202104047 Copy

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2.	Wang L, Gao P, Zhang M, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA, 2017, 317(24): 2515-2523.
3.	Wang J, Wang QH, Xia T, et al. Is islet transplantation ready for widespread use in diabetes? Chin Med J (Engl), 2011, 124(6): 935-938.
4.	张友尚. 胰岛素生产的回顾与展望. 食品与药品, 2008, 10(1): 1-3.
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8.	李汝红, 李鹏, 于海东, 等. 猪-猴异种细胞移植治疗非人类灵长类糖尿病的应用研究. 云南农业大学学报, 2013, 28(3): 317-321.
9.	Shin JS, Kim JM, Kim JS, et al. Long-term control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets. Am J Transplant, 2015, 15(11): 2837-2850.
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12.	Theriault BR, Thistlethwaite JR, Levisetti MG, et al. Induction, maintenance, and reversal of streptozotocin-induced insulin-dependent diabetes mellitus in the juvenile cynomolgus monkey (Macaca fascilularis). Transplantation, 1999, 68(3): 331-337.
13.	程树军, 黄韧, 杨守凯, 等. 恒河猴和食蟹猴血糖和胆固醇的比较. 中山大学学报论丛, 2001, (3): 11-14.
14.	岑罗旭, 何江娟, 万鹏夏. 兔抗人胸腺细胞免疫球蛋白治疗肝移植术后难治性排斥反应的护理. 护理与康复, 2017, 16(10): 1115-1116.
15.	Singh A, Ramachandran S, Graham ML, et al. Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. Nat Commun, 2019, 10(1): 3495.
16.	李文莉. 肾移植术后行经皮经肝胰岛细胞移植的围术期护理. 实用器官移植电子杂志, 2020, 8(6): 486-488.
17.	Sakata N, Yoshimatsu G, Tsuchiya H, et al. Animal models of diabetes mellitus for islet transplantation. Exp Diabetes Res, 2012, 2012: 256707.
18.	盛金艳, 孙晓敏. 糖尿病酮症酸中毒胰岛素治疗的护理研究进展. 外科研究与新技术, 2017, 6(1): 60-64.
19.	Qi M, Kinzer K, Danielson KK, et al. Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. Acta Diabetol, 2014, 51(5): 833-843.
20.	Clemente-Casares X, Tsai S, Huang C, et al. Antigen-specific therapeutic approaches in Type 1 diabetes. Cold Spring Harb Perspect Med, 2012, 2(2): a007773.
21.	Johnson PR, Jones KE. Pancreatic islet transplantation. Semin Pediatr Surg, 2012, 21(3): 272-280.
22.	McCall M, Shapiro AMJ. Update on islet transplantation. Cold Spring Harb Perspect Med, 2012, 2(7): a007823.
23.	Ryan EA, Lakey JR, Rajotte RV, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes, 2001, 50(4): 710-719.
24.	Zhu H, Yu L, He Y, et al. Nonhuman primate models of type 1 diabetes mellitus for islet transplantation. J Diabetes Res, 2014, 2014: 785948.
25.	Ellis CE, Korbutt GS. Justifying clinical trials for porcine islet xenotransplantation. Xenotransplantation, 2015, 22(5): 336-344.
26.	Schuurman HJ. Regulatory aspects of clinical xenotransplantation. Int J Surg, 2015, 23(Pt B): 312-321.

1. Robertson RP. Islet transplantation for type 1 diabetes, 2015: what have we learned from alloislet and autoislet successes? Diabetes Care, 2015, 38(6): 1030-1035.
2. Wang L, Gao P, Zhang M, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA, 2017, 317(24): 2515-2523.
3. Wang J, Wang QH, Xia T, et al. Is islet transplantation ready for widespread use in diabetes? Chin Med J (Engl), 2011, 124(6): 935-938.
4. 张友尚. 胰岛素生产的回顾与展望. 食品与药品, 2008, 10(1): 1-3.
5. Vadori M, Cozzi E. The immunological barriers to xenotransplantation. Tissue Antigens, 2015, 86(4): 239-253.
6. Cooper DK, Bottino R. Recent advances in understanding xenotransplantation: implications for the clinic. Expert Rev Clin Immunol, 2015, 11(12): 1379-1390.
7. Dufrane D, Gianello P. Pig islet for xenotransplantation in human: structural and physiological compatibility for human clinical application. Transplant Rev (Orlando), 2012, 26(3): 183-188.
8. 李汝红, 李鹏, 于海东, 等. 猪-猴异种细胞移植治疗非人类灵长类糖尿病的应用研究. 云南农业大学学报, 2013, 28(3): 317-321.
9. Shin JS, Kim JM, Kim JS, et al. Long-term control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets. Am J Transplant, 2015, 15(11): 2837-2850.
10. Bottino R, Wijkstrom M, van der Windt DJ, et al. Pig-to-monkey islet xenotransplantation using multi-transgenic pigs. Am J Transplant, 2014, 14(10): 2275-2287.
11. Graham ML, Mutch LA, Rieke EF, et al. Refining the high-dose streptozotocin-induced diabetic non-human primate model: an evaluation of risk factors and outcomes. Exp Biol Med (Maywood), 2011, 236(10): 1218-1230.
12. Theriault BR, Thistlethwaite JR, Levisetti MG, et al. Induction, maintenance, and reversal of streptozotocin-induced insulin-dependent diabetes mellitus in the juvenile cynomolgus monkey (Macaca fascilularis). Transplantation, 1999, 68(3): 331-337.
13. 程树军, 黄韧, 杨守凯, 等. 恒河猴和食蟹猴血糖和胆固醇的比较. 中山大学学报论丛, 2001, (3): 11-14.
14. 岑罗旭, 何江娟, 万鹏夏. 兔抗人胸腺细胞免疫球蛋白治疗肝移植术后难治性排斥反应的护理. 护理与康复, 2017, 16(10): 1115-1116.
15. Singh A, Ramachandran S, Graham ML, et al. Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. Nat Commun, 2019, 10(1): 3495.
16. 李文莉. 肾移植术后行经皮经肝胰岛细胞移植的围术期护理. 实用器官移植电子杂志, 2020, 8(6): 486-488.
17. Sakata N, Yoshimatsu G, Tsuchiya H, et al. Animal models of diabetes mellitus for islet transplantation. Exp Diabetes Res, 2012, 2012: 256707.
18. 盛金艳, 孙晓敏. 糖尿病酮症酸中毒胰岛素治疗的护理研究进展. 外科研究与新技术, 2017, 6(1): 60-64.
19. Qi M, Kinzer K, Danielson KK, et al. Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. Acta Diabetol, 2014, 51(5): 833-843.
20. Clemente-Casares X, Tsai S, Huang C, et al. Antigen-specific therapeutic approaches in Type 1 diabetes. Cold Spring Harb Perspect Med, 2012, 2(2): a007773.
21. Johnson PR, Jones KE. Pancreatic islet transplantation. Semin Pediatr Surg, 2012, 21(3): 272-280.
22. McCall M, Shapiro AMJ. Update on islet transplantation. Cold Spring Harb Perspect Med, 2012, 2(7): a007823.
23. Ryan EA, Lakey JR, Rajotte RV, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes, 2001, 50(4): 710-719.
24. Zhu H, Yu L, He Y, et al. Nonhuman primate models of type 1 diabetes mellitus for islet transplantation. J Diabetes Res, 2014, 2014: 785948.
25. Ellis CE, Korbutt GS. Justifying clinical trials for porcine islet xenotransplantation. Xenotransplantation, 2015, 22(5): 336-344.
26. Schuurman HJ. Regulatory aspects of clinical xenotransplantation. Int J Surg, 2015, 23(Pt B): 312-321.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Report of 3 cases of transplantation of GGTA1 gene knockout porcine islet cells into type Ⅰ diabetic macaques

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