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The aim of this study was to determine whether diabetes could be ameliorated in totally pancreatectomized baboons by heterotopic intraperitoneal autotransplantation of the tail of the pancreas with the duct unligated. Twenty-five baboons were made diabetic by total pancreatectomy. Six untreated pancreatectomized animals survived a median of 5 days with mean (+/- SE) plasma glucose levels of 18 +/- 1.37 mmol/L and mean (+/- SE) potassium (K) values of 0.36 +/- 0.02% before death. Successful autotransplantation of the tail of the pancreas rendered pancreatectomized baboons consistently normoglycemic. Intravenous glucose tolerance tests performed 6 weeks after transplantation in 12 autograft recipients showed glucose intolerance in 12 of 14 recipients, and K values were significantly reduced to 1.03 +/- 0.015% (P less than 0.05). The K value of 40 normal baboons was 2.18 +/- 0.15. Histologic examination of successfully transplanted autografts of 12 animals at 6 weeks showed islets with intact beta and alpha cells, atrophy of the exocrine pancreas, graft fibrosis, and a cellular infiltration of the mononuclear type. The addition of a distal arteriovenous fistula to the graft did not reduce the incidence of graft vessel thrombosis, and all five animals died of hemorrhagic pancreatitis and venous thrombosis within 24 hours of transplantation.

In this study the efficacy of the new immunosuppressive agent, cyclosporin A (CYA), was examined in a model of segmental, intraperitoneal pancreatic allotransplantation with free duct drainage in totally pancreatectomized, outbred Chacma baboons. CYA, in doses of 25 to 50 mg/kg/day administered to recipients of heterotopic segmental (tail) allografts, produced a slight but significant prolongation of graft survival. CYA (25 to 85 mg/kg/day), administered orally after pancreatic transplantation gave daily serum trough levels of CYA that ranged from 300 to 600 ng/ml. Mean serum trough levels on the first postoperative day in recipients of 50 mg/kg/day were 121.1 +/- 61.6 ng/ml. There was a wide variation in daily serum trough levels exhibited between primates on the same daily oral dose, and there was no correlation between absolute serum trough levels of CYA and rejection. It is postulated that adequate serum CYA levels were not achieved by the oral administration of the drug to ensure allograft survival beyond 60 days in pancreatectomized recipients. Adverse effects occurred frequently and included anorexia, diarrhea, and tremors and were in direct proportion to the quantity of CYA required to prolong graft survival. Free duct drainage into the abdominal cavity frequently resulted in pancreatic ascites, which necessitated paracentesis, indicating that this method of duct drainage has limited clinical application. Although heterotopic autotransplantation or allotransplantation of the tail of the pancreas in the baboon was capable of maintaining normoglycemia in pancreatectomized baboons, glucose intolerance, reduced K values, and hypoinsulinemia were consistent findings during glucose tolerance tests, suggesting that an insufficient islet cell mass had been transplanted.

The present study was undertaken to evaluate the effectiveness of cyclosporine (CS) alone, total lymphoid irradiation (TLI) alone, and CS in combination with total body irradiation (TBI) in suppressing segmental pancreatic allograft rejection in totally pancreatectomized outbred chacma baboons. The administration of CS 25 mg/kg/day and 50 mg/kg/day resulted in mean graft survival of 21.5 days and 24.5 days, respectively. CS 85 mg/kg/day resulted in median graft survival of 9 days. There was a wide daily fluctuation of CS serum trough levels exhibited between primates receiving the same oral dose. TBI in excess of 300 rads resulted in irreversible bone marrow suppression. Modest results were achieved in recipients of TBI-76 rads (38 X 2 rads), with median graft survival of 21 days, results not different from recipients treated with CS. TLI recipients of 600 rads (150 X 4 rads) resulted in median pancreatic graft survival of 16 days. TBI together with oral CS administration exhibited no synergistic or additive effect and a single peroperative donor-specific blood transfusion did not enhance pancreatic allograft survival in this model. However, of 10 primates receiving TBI 100 rads (50 X 2 rads) and CS 25 mg/kg/day administered orally indefinitely, four remained normoglycemic for more than 60 days. TBI 100 rads (50 X 2 rads) together with oral and parenteral CS resulted in necrotizing enterocolitis in four of six recipients. Some immunosuppressive regimens gave modest graft survival, none resulted in indefinite graft survival, and there was considerable toxicity with many of the regimens. Although CS administration alone or in combination with irradiation resulted in modest pancreatic allograft survival in this model, the place of CS combined with TBI or TLI or other chemical immunosuppressive agents remains to be defined.