Cyclosporin A for Immunosuppression: Observations in Rat Heart, Pancreas, and Islet Allograft Models and in Human Renal and Pancreas Transplantation

Abstract

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.

Transplantation of Purified Islet Cells in Diabetic Rats: III. Immunosuppressive Effect of Cyclosporin

“…This notion is now further documented by the finding that all recipients of pure p-cell allografts remained normalized under cyclosporin treatment. The earlier reported inability of cyclosporin to suppress the rejection of islet and pancreatic allografts (12,13) may thus be primarily caused by the presence of too many nonendocrine elements in the donor tissue. The degree of contamination by nonendocrine elements also determined the rapidity and the extent of the rejection process in the period after discontinuation of the cyclosporin treatment.…”

Evaluation of Factors to Decrease Bioavailability of Cyclosporin A in Rats with Gentamicin-Induced Acute Renal Failure

“…Cyclosporin A (CsA) is a strong immunosuppressant, which is effective in the prevention of rejection after solid organ transplantation and graft-versus-host disease after allogenic bone marrow transplantation, 1,2) and has been increasingly used for the treatment of auto-immune disease such as nephrosis, aplastic anemia or psoriasis.…”

Long-term effects of cyclosporin A on cultured mouse pancreatic islets

“…Despite its liver and kidney toxicity cyclosporinA (CsA) has rapidly become the immunosuppressive agent most commonly used in clinical transplantation [1] including pancreatic transplantation [2]. CsA has also become an interesting therapeutical alternative for immune suppression therapy in Type 1 diabetes, since there is evidence that an autoimmune process directed at the insulin-producing fl cells may play a role in the development of this disease [3].…”