**6. Overcome the issue of donor shortage**

#### **6.1 Clinical porcine islet xenotransplantation**

In 1994, transplantation of porcine islet-like cell clusters (ICCs) was implanted into 10 insulin-dependent diabetic kidney transplant patients (**Table 1**) [13]. Among the 10 patients, 8 patients received ICCs into the portal vein and the other two patients received ICCs under the kidney capsule. Four patients who received ICCs into portal vein secreted porcine C-peptide for 200 to 400 days. A biopsy was conducted on one patient who received ICCs under kidney capsule, and ICCs with positive insulin and glucagon stains were detected. On the other hand, insulin reduction was not achieved.

In 2000, two cases of encapsulated neonatal porcine islet transplantation were reported (**Table 1**) [14]. The first patient was a 41-year-old male who had type 1 diabetes for 18 years and required 50 units insulin per day. He received total of 13,000,000 IEQ encapsulated porcine islets. The second patient was a 39-year-old female who had type 1 diabetes for 24 years. She required 49 units of insulin per day. She received kidney transplantation two years before this islet transplantation; therefore. She took maintenance immunosuppression with cyclosporine, azothiaprine, and prednisone. She received 930,000 IEQ-encapsulated porcine islets. Both patients experienced a significant reduction in frequency of severe hypoglycemic reactions. Porcine C-peptide had been detected over 14 months, and improved HbA1c and 8–40% reduction of insulin were confirmed until 27 months post-transplantation.

More than 9 years after transplantation, the first patient was followed. Oral glucose tolerance test revealed positive porcine insulin. Laparoscopic biopsy demonstrated that the alginate capsule included insulin and glucagon-positive cells [42].

In 2005, twelve adolescent diabetic patients received neonatal porcine islet combined with porcine Sertoli cell transplantation using a subcutaneous device. Eleven patients received second transplantation and 4 patients received third transplantation. At 4 years, half of the patients achieved reduction of insulin doses. Notably, two patients achieved insulin independence [43]. The same group reported long-term follow-up study outcomes of 21 type 1 diabetic patients [44]. The median time posttransplantation was 5.7 years. More than half of the patients reduced insulin doses by more than 30% compared with pre-transplantation. Before transplantation 14 patients had chronic complications of diabetes including neuropathy (n = 5) evidenced by abnormal speed of nervous conduction, non-proliferative diabetic retinopathy (n = 5), and microalbuminuria (n = 8). At the follow-up, only two patients had chronic complications. No patients had neuropathy, 1 patient had retinopathy and 2 patients had microalbuminuria.

In 2011, Wang et al. reported that 22 patients received neonatal porcine islets in the hepatic artery [45]. The first 14 patients were treated with cyclosporine, mycophenolate mofetil (MMF), and prednisolone, the following 2 patients were treated with cyclosporine and MMF, and the next 6 patients were treated with OKT. The first 14 patients required less insulin and improved HbA1c after transplantation. In the 2 subsequent patients did not have any metabolic change and porcine C-peptide was negative. The last 6 patients reduced insulin requirements, and HbA1c was normalized 3 months after the transplantation.

In 2011, Matsumoto et al. reported that 14 patients in received encapsulated neonatal porcine islets in the abdominal cavity without immunosuppressive drugs in New Zealand [46]. Patients received 5000 (n = 4), 10,000 (n = 4), 15,000 (n = 4), and 20,000 (n = 2) IEQ/kg islets. There were no apparent differences among the groups. Patients experienced reduction of unaware hypoglycemia and minimal change in HbA1c and insulin doses one year after transplantation. In 2016, the same group reported 8 patients who received encapsulated neonatal porcine islets in the abdominal cavity without immunosuppressive drug in Argentina [47]. Four patients received 10,000 IEQ/kg and the other 4 patients received 20,000 IEQ/kg. All patients improved HbA1c, and high dose group demonstrated a significant reduction in the number of unaware hypoglycemia. They also demonstrated no zoonosis after 5–7 years of islet xenotransplantation [48]. Recently, they reported 21 patients' opinions who received encapsulated neonatal porcine islet transplantation after approximately 10 years [49]. Importantly, no patients suffered zoonosis, and no patients suffered cancer. Compared with pre-transplantation, the majority of patients still improved glycemic control, diabetic management, and reduced severe hypoglycemic events and hyperglycemia required hospitalization even after 10 years of transplantation. All patients considered this treatment adequate and majority of patients wanted to recommend this treatment to the other patients and desired to receive booster transplantation.

#### **6.2 Stem cell-derived beta cell transplantation in clinic**

In 2021, stem cell-derived pancreatic endoderm cell transplantation was reported (**Table 1**) [20]. Stem cell-derived pancreatic endoderm cells within the device were transplanted into 17 type 1 diabetic patients. Since the device has no immune protective property, the patients received immunosuppressive drugs. The induction immunosuppression was anti-thymocyte globulin up to 6 mg/kg iv over 5 days, TNF alpha blocking etanercept 50 mg iv pre-implant followed 25 mg subcutaneous x 3 doses

*Allogeneic Islet Transplantation and Future DOI: http://dx.doi.org/10.5772/intechopen.111812*

after transplant. Maintenance immunosuppression was tacrolimus (target 10–12 ng/ mL for the first 3 months; 7-9 ng/mL there-after) and mycophenolate mofetil up to 2 g per day as tolerated.

Primary efficacy endpoint was C-peptide measurements. A total of 6/17 subjects (35.3%) demonstrated stimulated C-peptide at varying time points. Adverse events were related to side effects of immunosuppressive drugs (33.7%) followed by surgical procedures (27.9%).
