Combined liver and pancreatic islet transplantation in the rat.
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Biomedical subjects
Publications and source records attributed to H Reece-Smith.
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The effect on glucose metabolism of altering the site of the venous drainage of an isograft of isolated adult islets implanted beneath the renal capsule, from the systemic circulation to the portal circulation was determined in streptozotocin-induced diabetic rats. Reversal of diabetes was accomplished by the transplantation of 1000-1200 isolated islets beneath the left kidney capsule. The rate of fall of the glucose concentration (as expressed by the K value) was found to be significantly decreased in transplanted animals (1.7 +/- 0.5%/min; mean +/- SD) compared with normal animals (2.4 +/- 0.5%/min). Draining the left renal vein into the portal circulation restored the K value to that of normal animals (2.5 +/- 0.4%). However the fasting glucose concentration was significantly higher and the basal insulin levels lower in both normal and transplanted rats with a renoportal shunt.
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Cyclosporin A (Cy A) was evaluated in dogs to assess its effectiveness of prolonging survival of allogeneic pancreatic islet tissue transplanted to the spleens of totally pancreatectomized mongrel dogs. Thirty-seven dogs were made diabetic by total pancreatectomy. Ten untreated pancreatectomized animals survived a mean (+/-SE) of 6.3 +/- 0.9 days and died with mean (+/-SE) plasma glucose levels of 23.2 +/- 2.7 mmol/liter. Dispersed pancreatic fragments, prepared by collagenase digestion without separation of exocrine and endocrine components, were directly implanted into the splenic pulp of 27 pancreatectomized dogs. Twelve dogs given autotransplants became normoglycemic after 4.3 +/- 0.5 days and remained so until killed at 60 days post-transplant, although normal glucose tolerance tests were not achieved. Eight nonimmunosuppressed dogs given allogeneic pancreatic fragments did not become normoglycemic but survived for 13.0 +/- 2.1 days, the dogs dying with a terminal plasma glucose of 22.7 mmol/liter. An additional seven dogs given allogeneic transplants were given Cy A (oral solution), 25 mg/kg/day, for 14 days, and, although failing to become normoglycemic, survived for 28.1 +/- 5.4 days and died with terminal plasma glucose levels of 25.1 +/- 0.6 mmol/liter. Intrasplenic complications included subcapsular hematomas, intrasplenic necrosis and cavitation, capsular perforations, and arteriolar thrombosis. The failure to achieve normoglycemia with allogeneic dispersed pancreatic tissue in dogs treated with Cy A and the complications associated with the implantation of the tissue in the spleen do not suggest that this approach is worthy of clinical trial.
This study showed that a heterotopic autotransplant of the tail of the pancreas was capable of maintaining adequate glucoregulatory function in pancreatectomized dogs, glucose tolerance test curves, and K values not differing from normal dogs 4 months after transplantation. Hyperinsulinemia in the fasting state was observed in the absence of hypoglycemia in autograft and allograft recipients. Intraductal Ethibloc injection produced total replacement of the exocrine gland at 4 months by fibrosis but with the preservation of islets. Cyclosporin A (Cy A, oral drinking solution) in a dose of 25 mg/kg/day given to recipients of heterotopic segmental allografts produced a slight but significant prolongation of graft survival, but a dose of 40 mg/kg/day resulted in indefinite graft survival (greater than 100 days) in five of eight allograft recipients. During intravenous glucose tolerance tests (IVGTTs), fasting hyperinsulinemia and significantly impaired glucose degradation (K values) was observed in long-term surviving allograft recipients 4 months after transplantation. In four long-term surviving pancreatic allograft recipients initially given 40 mg/kg/day, the dose of Cy A was gradually reduced after 4 months to a maintenance dose of 5 mg/kg/day by 6 months. On a dose of 5 mg/kg/day, three dogs rejected their grafts between 18 and 28 days after this schedule had commenced. Successful reversal of the hyperglycemia in two of three dogs that rejected their grafts was achieved by i.v. methylprednisolone and increased doses of Cy A. These results indicate that Cy A alone could significantly prolong the survival of canine pancreatic segmental allografts, but initially higher doses were required than that found to be effective in prolonging renal allograft survival in the dog.
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In 138 mongrel dogs given renal transplants, 10 developed postoperative intussusceptions. The sites were jejunojejunal (seven), ileo-ileal (two) and ileocolic (one). In 30 puppies given intrasplenic autografts of dispersed pancreatic fragments after total pancreatectomy, five developed jejunojejunal intussusceptions. Presenting signs included vomiting, failure to eat, periodic attacks of pain, straining with the passage of bloodstained mucous, dehydration, weight loss, abdominal wall rigidity and an abdominal mass. The majority of dogs presented within the first seven days following transplantation, occasionally as late as the third week. Early operative intervention was essential to save the dogs and at laparotomy eight of nine intussusceptions were successfully reduced manually; one small bowel resection was performed for irreducibility. Recurrence was not observed in this series but reoperation in the puppies was invariably fatal. Factors contributing to the development of intussusception in the puppies included round worm infestation, recent dietary change following weaning, malabsorption and diarrhoea due to pancreatic insufficiency following pancreatectomy and respiratory infections suggesting an infective origin for the intussusceptions.
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Transplants of isolated allogeneic pancreatic islets behave as if extremely immunogenic but vascularized segmental pancreatic allografts do not evoke such a rapid rejection of islet tissue. We have transplanted rat pancreatic islets as a vascularized graft by implanting isolated islets under the renal capsule of a syngeneic diabetic rat and, after successful reversal of diabetes, a composite graft of kidney and islets was transplanted into an allogeneic diabetic host. Cyclosporin A was used to suppress rejection of the allografts in doses that have previously been shown to completely suppress rejection of renal allografts and delay rejection of vascularized segmental pancreatic allografts. This strategy produced indefinite survival of the allogeneic isolated pancreatic islets.
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Of 292 patients, excision of the tumour with replacement by stomach or jejunum was carried out in 216 in whom the lesion was considered operable on both technical and general grounds, intubation was performed in 45 and the remaining 31 were managed without operation. Of the 216 in whom resection was performed, only 20 per cent were free from local spread, lymph node involvement or secondary deposits at the time of operation. Hospital mortality was 18 per cent and did not significantly differ between one 5-year period and another. Survival at 1 year was 54 per cent, at 2 years 25 per cent and at 5 years 14 per cent. The average length of survival following intubation was 2.6 months and following non-operative management 2.8 months. The poor average survival of between 3.5 and 5 months obtained in those patients with secondary deposits at the time of resection suggests that resection is of questionable value in this group. There was a marked difference in survival following Roux loop procedures compared with upper partial gastrectomy for tumours of the lower third and cardia in patients without lymph node involvement or secondary deposits, strongly suggesting that upper partial gastrectomy, although a rather simpler and quicker operation, is not the operation of choice in these patients. On 31 December 1976, after a minimum follow-up of 1 year, there were only 22 patients still alive of the original 292 (7.5 per cent).