Cyclosporin A for immunosuppression: observations in rat heart, pancreas, and islet allograft models and in human renal and pancreas transplantation.

Cyclosporin A (CsA) is a unique immunosuppressive cyclic polypeptide that is currently being used, either alone or in combination with low-dose prednisone, to treat recipients of renal or pancreas allografts in clinical trials. CsA is very effective in preventing rejection of heart and renal allografts in rodents, but in nontoxic doses does not consistently prevent rejection of pancreas and islet allografts. Therefore, we tested low-dose CsA in various combinations with low-dose prednisone, azathioprine, or total lymphoid irradiation in rat heart, pancreas, and islet allograft models. Several combinations are synergistic and when administered continuously can indefinitely prevent rejection of heart allografts, but only delay rejection of pancreatic allografts, transplanted across a major histocompatibility barrier, CsA by itself prolonged the survival of islet allografts transplanted across a minor, but not a major, histocompatibility barrier. CsA and azathioprine had a synergistic effect in the minor histocompatibility barrier islet transplant model, but, in the nontoxic combinations tested, could not prevent rejection indefinitely. A randomized prospective trial comparing standard immunosuppressive therapy (ALG, prednisone, and azathioprine), with CsA and low-dose prednisone for clinical renal allotransplantation is ongoing at the University of Minnesota. Current actuarial 1-yr graft survival is 93% for CsA-treated patients (N = 48) and 81% for conventionally treated patients (N = 52). Patient survival is 98% for CsA and 100% for conventionally treated patients. A pilot trial of CsA in the clinical pancreas transplant program at the University of Minnesota is also underway. Since 1978, 46 pancreas transplants have been performed in 43 patients. Of 30 technically successful pancreatic allografts, 5 of 12 recipients treated with conventional immunosuppression and 6 of 18 recipients treated with CsA currently have functioning grafts and are insulin independent between 1 and 44 months after transplantation. The results of metabolic studies are similar in conventional and CsA-treated patients with functioning pancreas grafts. Since pancreas grafts may fail for reasons other than rejection, further observations are needed to ascertain the role of CsA in clinical pancreas transplantation.

Combined immunosuppressive therapy with cyclosporin A and azathioprine. A synergistic effect in three of four experimental models.

Cyclosporin A (Cy A) by itself is limited in its clinical application by its dose-related liver and kidney toxicity. Combining Cy A with prednisone allows lower doses of Cy A to be used, but the side effects of steroids are cumulative. Thus, we tested the effect of Cy A and various drug-dose combinations with azathioprine (AZA) in four different models. The one that gave the best results with the least toxicity was 1.25 mg of Cy A plus 15 mg of AZA for islet allotransplantation in rats across a minor histocompatibility barrier and for heterotopic heart allotransplantation in rats across a major histocompatibility barrier. In the latter, using the same strain of rats, no significant effect can be shown in rat pancreas allotransplantation. In canine renal allografts, only one dose combination (5 mg of Cy A plus 2.5 mg of AZA) was tested, but it was synergistic. Cy A may potentiate the myelosuppressive effect of AZA, and the dose may have to be adjusted to avoid this problem.

Prolongation of heterotopic cardiac allografts in rats by cyclosporin A.

Cyclosporin A (CsA), an investigational immunosuppressive drug, was tested for its ability to prevent rejection of heterotopic rat heart allografts transplanted across a major histocompatibility barrier (ACI to Lewis). The relative efficacy of CsA was compared to a combination of azathioprine and prednisolone. Various dose-schedule combinations of CsA as a single drug were evaluated in regard to duration of grafts beating, recipient mortality rate, and histology of long-term functioning grafts. A daily dose of CsA of 10 mg/kg prevented rejection, but was associated with a 40% recipient mortality rate from infection. CsA in 5 mg/kg/day doses resulted in long-term graft function (> 100 days), but histological examination of these grafts showed mild rejection. A dose-schedule of CsA in 10 mg/kg/day for 7 to 35 days followed by a reduction to 5 mg/kg/day prolonged the survival rate of all grafts to longer than 100 days; no rats died from this treatment and there was no evidence of rejection on graft histology. In contrast, a combination of 4 mg/kg/day azathioprine and 4 mg/kg/day prednisolone did not prolong graft survival rates. Azathioprine in 30 mg/kg and prednisolone in 12 mg/kg prolonged allograft survival (50 to 60 days), but was associated with significant recipient morbidity (> 25% weight loss) and histological evidence of acute and chronic rejection. A nontoxic dose of CsA is superior to a combination of azathioprine and prednisolone in preventing the rejection of heterotopic rat heart allografts. The therapeutic index of cyclosporin A in rats can be increased by using a tapering dose schedule, as opposed to a fixed dose schedule. CsA has good potential for clinical application to organ transplantation.

Cyclosporin A in renal transplantation: a prospective randomized trial.

Cyclosporin A combined with prednisone was compared with standard immunosuppressive therapy (antilymphoblast globulin, prednisone, and azathioprine) in a prospective randomized trial of 100 mismatched, living related donor and cadaveric renal transplants. The results demonstrated cyclosporin A plus prednisone to be an effective immunosuppressive regimen for renal transplantation. The actuarial graft survival at 1 year was 93% for patients treated with cyclosporin A and 81% for patients treated with conventional immunosuppression. Patient survival was 98% for the cyclosporin A group and 100% for the conventional group. Cyclosporin A-treated patients had fewer rejection episodes and fewer infections complications including a marked decrease in the incidence of posttransplant cytomegalovirus infection. The side effects of cyclosporin A were mild, but nephrotoxicity caused by cyclosporin A was frequent and significant. Nephrotoxicity was reversible and managed by decreasing the daily cyclosporin A dose. It is concluded that the combination of cyclosporin A plus prednisone provides an excellent alternate immunosuppressive regimen for renal transplants as compared with conventional therapy. The consequences of long-term administration of cyclosporin A are at present unknown.

Segmental pancreas transplantation from living related and cadaver donors: a clinical experience.

Between July 25, 1978, and January 25, 1981, 20 segmental pancreas transplants from 14 cadaver (cad) and six related (rel) donors were performed. All but two recipients had previously received renal allografts for treatment of end-sage diabetic nephropathy. The grafts were placed intraperitoneally-13 with open ducts, 4 with prolamine-injected ducts, and 3 with silicone rubber-injected ducts. At this writing six patients have functioning grafts (3 silicone, 3 open duct) at less than 1 (cad), 2 (cad), 3 (rel), 15 (cad), 20 (rel), and 31 (cad) months. Five open-duct grafts failed for technical reasons. Two prolamine-injected grafts lost function between 1 and 3 months; biopsy specimens showed severe fibrosis. The others lost function between 2 and 4 months. Three patients died 1 to 3 months after transplantation. Metabolic test results were normal or nearly normal in most recipients with functioning grafts. Splenectomy was required in one related donor; there were no other complications of donation. Technical problems and rejection are impediments to application of pancreas transplantation, but a sustained correction of the metabolic defect has been achieved in a few patients, and the effect on secondary complications are studied.

Hodgkin's disease in human renal transplantation.

After transplantation Hodgkin's disease developed in two recipients of related donor renal allografts. Only one case of Hodgkin's disease had previously been reported in this specific patient population and these two cases demonstrate the very atypical biologic behavior of Hodgkin's disease in the immunosuppressed renal transplant patient.

Technical aspects of segmental pancreatic grafting in rats.

Four techniques for segmental pancreatic transplantation were used sequentially in rats. The success rate and the incidence and type of technical complications that developed in each group of recipients were determined and attempts were made to improve the microsurgical technique. A strict comparison of the relative merits of the four different techniques was not made, but rather the development of an approach to an original technique that resulted in a high success is rate presented. The various modifications and details of this experience are documented. The various complications, each of which results in a typical postoperative pattern of weight and plasma glucose changes and each of which is preventable by the use of proper microsurgical techniques, are also analyzed.

Total or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis.

Total or near total pancreatectomy is the surest way to relieve the pain of chronic pancreatitis but is rarely applied because the metabolic consequences are so severe. For most patients drainage procedures are applicable, but pancreatectomy may be the only alternative for small duct disease or where procedures to improve duct drainage have failed. Preservation of endocrine function is a major problem in patients who require pancreatectomy. Experiments in pancreatectomized dogs have shown that intrasplenic or intraportal transplantation of unpurified pancreatic islet tissue dispersed by collagenase digestion can prevent diabetes. We have applied this technique to ten patients with chronic pancreatitis, small ducts, and intractable pain. The entire pancreas of > 95% of the pancrease was excised, minced, dispersed by collagenase digestion and infused into the portal vein < 2 1/2 hours after removal. Mean (+/- SD) rise in portal pressure was 17 +/- 8 cm of water. Liver function tests were altered minimally. All patients were relieved of pain. One patient died of a complication not related to the islet autotransplant; viable islets were identified in the liver at autopsy. Of the remaining nine patients, three have been insulin independent for 1, 9, and 38 months. One patient was insulin indpendent for 15 months and now takes 12 units of insulin daily. Three have nonketosis prone diabetes (tested by insulin withdrawal) and take 15--30 units of insulin per day. C-peptide studies in these patients show that functioning islets are present. Two patients are diabetic and require 35 and 60 units of insulin per day. In eight of nine patients tested serum insulin concentrations fell to undetectable levels during the interval between pancreatectomy and islet transplantation. Serum insulin levels during the first few hours after islet transplantation predicted success. In the insulin independent or in the patients with mild diabetes, insulin levels were persistently greater than or equal to 6 microU/ml. In the other two patients, the increase in insulin concentration was not sustained. Islet tissue preparation from a diseased pancreas is difficult. The surgeon and the patient must still be willing to accept diabetes for relief of pain when performing this operation. In some patients, however, islet autotransplantation can prevent or partially ameliorate diabetes after pancreatectomy, and preservation of endocrine function is worthwhile.