Allogeneic islets combined with autologous peripheral blood stem cell transplantation in treatment of type 1 diabetes mellitus: a 3<b>-</b>year follow<b>-</b>up clinical study_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YAO Yutong , LAI Chunyou , FENG Tianhang , SHANG Jin , YANG Qinyan , YANG Maozhu , ZHANG Wen ,  HUANG Xiaolun

Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu 610072, P. R. China;

Corresponding author：

HUANG Xiaolun, Email: garrymd@163.com

Keywords：

islet transplantation; diabetes; stem cell

DOI：

10.7507/1007-9424.202207011

Video：

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Objective To evaluate the 3-year follow-up results of allogeneic islets combined with autologous peripheral blood stem cells (PBSC) transplantation in treatment of type 1 diabetes mellitus (T1MD). Methods The clinicopathologic data of recipients underwent allogeneic islet cells combined with (or without) PBSC transplantation in the Sichuan Provincial People’s Hospital from January 2017 to December 2019 were retrospectively analyzed. The allogeneic islet cells combined with (or without) PBSC were infused into the liver by percutaneous hepatic portal vein puncture. Then the modified Edmonton immunosuppressive regimen was used after the operation. The recipients were followed-up for 3 years, and the insulin usage, C-peptide, and glycosylated hemoglobin A1c (HbA1c) were analyzed. Results There were 5 recipients of allogeneic islet cell transplantation alone (named as alone group) and 5 recipients of allogeneic islet cell combined with PBSC transplantation (named as combined group). The gender, age, body mass index, preoperative insulin dosage, and HbA1c concentration of the recipients in the two groups were similar. ① The numbers of islets transplanted in the alone group and combined group were (50.60±2.51)×10⁴ islet equivalent quantity (IEQ) and (48.70±4.76)×10⁴ IEQ, respectively, and the number of PBSC transplanted in the combined group was (9.2±2.6)×10⁷. ② In the alone group and combined group, there were 3 cases and 3 cases of insulin withdrawal at the 12th month, as well as 2 cases and 3 cases of insulin withdrawal at the 36th month after operation, respectively. The postoperative insulin dosages of the two groups were decreased as compared with that before operation, and which of the combined group showed a lower trend as compared with the alone group within 12 months after operation. ③ The C-peptide level at the fasting in the alone group peaked at 24th month after operation and began to decline, and which at the fasting and postprandial 2 h peaked at 12th month after operation and began to decline, but that at postprandial 2 h began to increase slightly at 24th month in the combined group, and which showed a higher trend at 12th and 36th month after operation in the combined group as compared with the alone group. ④ Within 36 months after operation, the HbA1c concentrations of the two groups decreased at different times after operation as compared with those before operation, and basically maintained a normal and stable level at 6 months after operation, and the change trend of the two groups was basically similar. ⑤ There were no obvious immune rejection and adverse reactions in the two groups. Conclusion From the preliminary results of this study, PBSC has a certain protective effect on islet transplantation, which improves the clinical efficacy of allograft islet transplantation for 3 years, but the long-term efficacy still needs to be observed, and the mechanism still needs to be further explored.

Citation： YAO Yutong, LAI Chunyou, FENG Tianhang, SHANG Jin, YANG Qinyan, YANG Maozhu, ZHANG Wen, HUANG Xiaolun. Allogeneic islets combined with autologous peripheral blood stem cell transplantation in treatment of type 1 diabetes mellitus: a 3-year follow-up clinical study. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(9): 1189-1194. doi: 10.7507/1007-9424.202207011 Copy

1.	Polsky S, Ellis SL. Obesity, insulin resistance, and type 1 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes, 2015, 22(4): 277-282.
2.	Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med, 2000, 343(4): 230-238.
3.	Shapiro AM, Pokrywczynska M, Ricordi C. Clinical pancreatic islet transplantation. Nat Rev Endocrinol, 2017, 13(5): 268-277.
4.	Rickels MR, Robertson RP. Pancreatic islet transplantation in humans: recent progress and future directions. Endocr Rev, 2019, 40(2): 631-668.
5.	Rifai L, Saleh FA. Conventional and alternative mesenchymal stem cell therapies for the treatment of diabetes. Adv Exp Med Biol, 2021, 1312: 97-106.
6.	Cayabyab F, Nih LR, Yoshihara E. Advances in pancreatic islet transplantation sites for the treatment of diabetes. Front Endocrinol (Lausanne), 2021, 12: 732431. doi: 10.3389/fendo.2021.732431.
7.	黄孝伦. 胰岛移植治疗1型糖尿病的进展与挑战. 中华移植杂志(电子版), 2017, 11(3): 138-142.
8.	Brennan DC, Kopetskie HA, Sayre PH, et al. Long-term follow-up of the Edmonton protocol of islet transplantation in the United States. Am J Transplant, 2016, 16(2): 509-517.
9.	Nakamura T, Fujikura J, Anazawa T, et al. Long-term outcome of islet transplantation on insulin-dependent diabetes mellitus: an observational cohort study. J Diabetes Investig, 2020, 11(2): 363-372.
10.	Rifai L, Saleh FA. Conventional and alternative mesenchymal stem cell therapies for the treatment of diabetes. Adv Exp Med Biol, 2021, 1312: 97-106.
11.	Bellin MD, Kandaswamy R, Parkey J, et al. Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes. Am J Transplant, 2008, 8(11): 2463-2470.
12.	Du S, Li Y, Geng Z, et al. Engineering islets from stem cells: the optimal solution for the treatment of diabetes?. Front Immunol, 2022, 13: 869514. doi: 10.3389/fimmu.2022.869514.
13.	姚豫桐, 魏玲玲, 杨卯竹, 等. 同种异体胰岛移植治疗1型糖尿病10例及随访观察3年的临床研究. 中华器官移植杂志, 2016, 37(2): 90-94.
14.	黄孝伦, 姚豫桐, 罗兰云, 等. 同种胰岛细胞移植及采用改良Edmonton方案治疗1型糖尿病三例. 中华器官移植杂志, 2014, 35(3): 160-164.
15.	Mochida T, Ueno H, Tsubooka-Yamazoe N, et al. Insulin-deficient diabetic condition upregulates the insulin-secreting capacity of human induced pluripotent stem cell-derived pancreatic endocrine pro-genitor cells after implantation in mice. Diabetes, 2020, 69(4): 634-646.
16.	施静, 魏玲玲, 冯天航, 等. 胰岛与骨髓间充质干细胞联合移植治疗Sprague-Dawley大鼠1型糖尿病远期疗效比较. 中华糖尿病杂志, 2018, 10(3): 226-233.
17.	Aali E, Mirzamohammadi S, Ghaznavi H, et al. A comparative study of mesenchymal stem cell transplantation with its paracrine effect on control of hyperglycemia in type 1 diabetic rats. J Diabetes Metab Disord, 2014, 13(1): 76. doi: 10.1186/2251-6581-13-76.
18.	Wang Y, Wang JW, Li Y, et al. Bone marrow-derived mesenchymal stem cells improve rat islet graft revascularization by upregulating ISL1. Stem Cells, 2021, 39(8): 1033-1048.
19.	Wu X, Wang Y, Xu J, et al. MM-BMSCs induce naïve CD4⁺ T lymphocytes dysfunction through fibroblast activation protein α. Oncotarget, 2017, 8(32): 52614-52628.
20.	Cnop M, Toivonen S, Igoillo-Esteve M, et al. Endoplasmic reticulum stress and eIF2α phosphorylation: the Achilles heel of pancreatic β cells. Mol Metab, 2017, 6(9): 1024-1039.

1. Polsky S, Ellis SL. Obesity, insulin resistance, and type 1 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes, 2015, 22(4): 277-282.
2. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med, 2000, 343(4): 230-238.
3. Shapiro AM, Pokrywczynska M, Ricordi C. Clinical pancreatic islet transplantation. Nat Rev Endocrinol, 2017, 13(5): 268-277.
4. Rickels MR, Robertson RP. Pancreatic islet transplantation in humans: recent progress and future directions. Endocr Rev, 2019, 40(2): 631-668.
5. Rifai L, Saleh FA. Conventional and alternative mesenchymal stem cell therapies for the treatment of diabetes. Adv Exp Med Biol, 2021, 1312: 97-106.
6. Cayabyab F, Nih LR, Yoshihara E. Advances in pancreatic islet transplantation sites for the treatment of diabetes. Front Endocrinol (Lausanne), 2021, 12: 732431. doi: 10.3389/fendo.2021.732431.
7. 黄孝伦. 胰岛移植治疗1型糖尿病的进展与挑战. 中华移植杂志(电子版), 2017, 11(3): 138-142.
8. Brennan DC, Kopetskie HA, Sayre PH, et al. Long-term follow-up of the Edmonton protocol of islet transplantation in the United States. Am J Transplant, 2016, 16(2): 509-517.
9. Nakamura T, Fujikura J, Anazawa T, et al. Long-term outcome of islet transplantation on insulin-dependent diabetes mellitus: an observational cohort study. J Diabetes Investig, 2020, 11(2): 363-372.
10. Rifai L, Saleh FA. Conventional and alternative mesenchymal stem cell therapies for the treatment of diabetes. Adv Exp Med Biol, 2021, 1312: 97-106.
11. Bellin MD, Kandaswamy R, Parkey J, et al. Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes. Am J Transplant, 2008, 8(11): 2463-2470.
12. Du S, Li Y, Geng Z, et al. Engineering islets from stem cells: the optimal solution for the treatment of diabetes?. Front Immunol, 2022, 13: 869514. doi: 10.3389/fimmu.2022.869514.
13. 姚豫桐, 魏玲玲, 杨卯竹, 等. 同种异体胰岛移植治疗1型糖尿病10例及随访观察3年的临床研究. 中华器官移植杂志, 2016, 37(2): 90-94.
14. 黄孝伦, 姚豫桐, 罗兰云, 等. 同种胰岛细胞移植及采用改良Edmonton方案治疗1型糖尿病三例. 中华器官移植杂志, 2014, 35(3): 160-164.
15. Mochida T, Ueno H, Tsubooka-Yamazoe N, et al. Insulin-deficient diabetic condition upregulates the insulin-secreting capacity of human induced pluripotent stem cell-derived pancreatic endocrine pro-genitor cells after implantation in mice. Diabetes, 2020, 69(4): 634-646.
16. 施静, 魏玲玲, 冯天航, 等. 胰岛与骨髓间充质干细胞联合移植治疗Sprague-Dawley大鼠1型糖尿病远期疗效比较. 中华糖尿病杂志, 2018, 10(3): 226-233.
17. Aali E, Mirzamohammadi S, Ghaznavi H, et al. A comparative study of mesenchymal stem cell transplantation with its paracrine effect on control of hyperglycemia in type 1 diabetic rats. J Diabetes Metab Disord, 2014, 13(1): 76. doi: 10.1186/2251-6581-13-76.
18. Wang Y, Wang JW, Li Y, et al. Bone marrow-derived mesenchymal stem cells improve rat islet graft revascularization by upregulating ISL1. Stem Cells, 2021, 39(8): 1033-1048.
19. Wu X, Wang Y, Xu J, et al. MM-BMSCs induce naïve CD4⁺ T lymphocytes dysfunction through fibroblast activation protein α. Oncotarget, 2017, 8(32): 52614-52628.
20. Cnop M, Toivonen S, Igoillo-Esteve M, et al. Endoplasmic reticulum stress and eIF2α phosphorylation: the Achilles heel of pancreatic β cells. Mol Metab, 2017, 6(9): 1024-1039.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Allogeneic islets combined with autologous peripheral blood stem cell transplantation in treatment of type 1 diabetes mellitus: a 3-year follow-up clinical study

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