Experimental pancreatic allotransplantation in large animals. The role of donor kidney and cyclosporine in modifying rejection.

Experiments were carried out in outbred dogs and pigs to evaluate the relative immunogenicity of pancreatic islets and segmental pancreas grafts, and whether these could be ameliorated by transplanting a kidney simultaneously from the same donor animal. Various immunosuppressive regimens were also studied. Pancreatic islet allografts never normalized blood glucose in totally pancreatectomized recipients despite the use of cyclosporine (CsA) in high doses (40 mg/kg/day) and the simultaneous transplantation of a kidney from the same donor. These grafts which never "took" contrast sharply with the experience of pancreatic islet autografts prepared in the same way and inoculated into the spleen, which in all nine instances normalized blood glucose in pancreatectomized recipients. Segmental transplants were performed in swine with duct drainage into the jejunum. Totally pancreatectomized pigs died at 7.8 +/- 1.0 days. In recipients suppressed with low-dose azathioprine (Az) and prednisone (Pred) pancreas grafts alone were rejected in 12.9 +/- 10 days. Synchronous pancreas and kidney transplants treated similarly extended the mean survival of pancreatic grafts to 20 +/- 10 days--which, however, was not significant (P less than 0.1 greater than 0.05). Mean survival time of pancreatic grafts in recipients receiving CsA at 20 mg/kg/day and prednisone 1 mg/kg/day was 14 +/- 6.3 days. The combination of CsA 20 mg/kg/day, Az 2 mg/kg/day, and Pred 1 mg/kg/day prolonged the mean survival time to 39.8 +/- 22 days. These results allow us to conclude that: crude preparations of islet tissue invariably capable of normalizing blood sugar at day 4 when used as autografts failed to "take" despite the existence of alternative sources of antigen present in a well vascularized kidney from the same donor, and despite very high dosages of CsA; triple immunosuppressive therapy had synergistic effects on pancreatic allograft survival; and simultaneous transplantation of kidney and pancreas had little effect on survival times of the pancreas or the kidney.