In vivo effect of FK506 on human pancreatic islets

The purpose of this study was to evaluate the in vivo effect of FK506 on human pancreatic islets. Twenty-five nude mice were made diabetic by one intravenous injection of streptozotocin. Approximately 600 islets were administered in the renal subcapsular space 3-5 days following streptozotocin administration. One week after transplantation, the mice were divided in four groups. In group 1, the animals received 1 injection of 0.5 ml of diluent i.p. daily for one week. In groups 2, 3, and 4 the treatments were daily i.p. injection of 0.3, 1, and 3 mg/kg FK506, respectively. After treatment, the functional integrity of the transplanted human islets was tested by measuring the plasma glucose and human C-peptide response to intraperitoneal glucose injection in groups 1 and 4. IPGTT alone was assessed in groups 2 and 3. The results indicate that i.p. administration of FK506 for one week at a dose 0.3 mg/kg/day did not result in any significant alteration of glucose disappearance and C-peptide response to IPGTT. Higher doses of FK506 produced a significant delay in glucose disappearance in groups 3 and 4, and a significant inhibition of glucose-mediated C-peptide response in group 4. © 1991 by Williams and Wilkins

Pancreatic islet transplantation after upper abdominal exeriteration and liver replacement

Nine patients who became diabetic after upper-abdominal exenteration and liver transplantation were given pancreatic islet-cell grafts obtained from the liver donor (eight cases), a third-party donor (one), or both (four). Two patients were diabetic when they died of infections after 48 and 109 days, as was a third patient who died of tumour recurrence after 178 days. The other 6 are alive 101-186 days postoperatively, and five are insulin-free or on insulin only during night-time parenteral alimentation. C-peptide increased 1·7 to 3·3 fold in response to intravenous glucose in these five patients who have had glycosylated haemoglobin in the high normal range. However, the kinetics of the C-peptide responses to intravenous glucose in all eight patients tested revealed an absent first-phase release and a delayed peak response consistent with transplantation and/or engraftment of a suboptimal islet cell mass. The longest survivor, who requires neither parenteral alimentation nor insulin, is the first unequivocal example of successful clinical islet-cell transplantation. © 1990

Human islet isolation and allotransplantation in 22 consecutive cases

This report provides our initial experience in islet isolation and intrahepatic allotransplantation in 21 patients. In group 1, 10 patients underwent combined liver-islet allotransplantation following upper-abdominal exenteration for cancer. In group 2, 4 patients received a combined liver-islet allograft for cirrhosis and diabetes. One patient had plasma C-peptide >3 pM and was therefore excluded from analysis. In group 3, 7 patients received 8 combined cadaveric kidney-islet grafts (one retransplant) for end-stage renal disease secondary to type 1 diabetes mellitus. The islets were separated by a modification of the automated method for human islet isolation and the preparations were infused into the portal vein. Immunosuppression was with FK506 (group 1) plus steroids (groups 2 and 3). Six patients in group 1 did not require insulin treatment for 5 to > 16 months. In groups 2 and 3 none of the patients became insulin-independent, although decreased insulin requirement and stabilization of diabetes were observed. Our results indicate that rejection is still a major factor limiting the clinical application of islet transplantation in patients with type 1 diabetes mellitus, although other factors such as steroid treatment may contribute to deteriorate islet engraftment and/or function. © 1992 by Williams and Wilkins

Effect of FK 506 on spontaneous diabetes in BB rats

From days 30-120 after birth, 59 BB rats were treated with water (n = 20) or FK 506 in intragastric doses of 1 mg·kg-1·day-1 (n = 19) or 2 mg·kg-1·day-1 (n = 20). Diabetes developed in 75, 15, and 0% of the 3 groups, respectively. Animals protected from diabetes by FK 506 had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, and normal pancreatic insulin content. Forty-five to 75 days after stopping FK 506, ∼75% of the rats that were diabetes free at 120 days remained so

Detection of intrahepatic human islets following combined liver-islet allotransplantation

This article describes the localization of intact insulin-containing intrahepatic islets after combined liver-islet allotransplantation. The patient was a 36-year-old woman who underwent upper abdominal exenteration for neuroendocrine carcinoma; 289,000 islets were transplanted via portal vein infusion immediately after complete revascularization of the liver. Immunosuppression was with low-dose FK-506. OKT3 and steroids were used to treat one rejection episode 2 weeks after transplantation, but the patient subsequently developed multiple infections and died 109 days after transplantation. At autopsy, the transplanted liver did not show any sign of rejection and well-preserved islets were present in portal triads sampled from the anterior inferior edge of the right lobe. Immunohistochemical labeling confirmed the presence of insulin-containing cells. This finding indicated that human islets can survive after intrahepatic allotransplantation, despite positive cross-match with no HLA antigen match, suggesting that upper abdominal exenteration and liver transplantation may constitute a protective factor for the survival of allogeneic human islets. © 1992 Raven Press, Ltd., New York

Outcome of human islet isolation and allotransplantation in 20 consecutive cases.

This report provides our initial experience on islet isolation and intrahepatic allotransplantation in 20 patients. In Group 1, 10 patients underwent combined liver-islet allotransplantation following upper-abdominal exenteration for cancer. One patient underwent pancreatic islet allograft after near total pancreatectomy for chronic pancreatitis. In Group 2, 3 Type I diabetic patients received a combined liver-islet allograft for cirrhosis and diabetes. In Group 3, 7 Type I diabetic patients received 8 combined cadaveric kidney-islet grafts (one retransplant) for end stage renal disease. The islets were separated by a modification of the automated method for human islet isolation and the preparations were infused into the portal vein. Immunosuppression was with FK-506 (Group 1) plus steroids (Groups 2 and 3). Six patients in Group 1 did not require insulin treatment for 5 to >16 mo. In Groups 2 and 3 none of the patients became insulin-independent, although ongoing C-peptide secretion, decreased insulin requirement and stabilization of diabetes were observed. Our results indicate that islet transplantation is most effective in pancreatectomy induced diabetes. However, rejection is still a major factor limiting the clinical application of islet transplantation in patients with Type I diabetes mellitus. Other factors such as steroid treatment may contribute to deteriorate islet engraftment and/or function