EVIDENCE THAT CYCLOSPORINE PREVENTS REJECTION AND RECURRENT DIABETES IN PANCREATIC TRANSPLANTS IN THE BB RAT

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Abstract
Cyclosporine prevents the development of diabetes in spontaneously diabetic BB rats and NOD mice. However, islet transplants have been shown to be subject to immunologic destruction in hosts treated with CsA and anti-CD4 antibody or those rendered tolerant to donor antigens. This study determines whether the minimum dose of CsA necessary to prevent rejection of pancreatic transplants will also prevent recurrent diabetes in pancreas transplants in BB rats. Lewis recipients promptly reject BN (n = 13, MST 9.2 .+-. 0.7 days) and Fisher (n = 6, MST = 11.3 .+-. 0.8 days ) pancreatic transplants. Treatment with CsA 5 mg/kg/day 00-50 days posttransplant and 2 mg/kg/day 51-100 days (low-dose CsA) produced indefinite survival of BN (n = 5) but not Fisher (n = 4) allografts. Fisher allografts were uniformly successful if maintained on 5 mg/kg/day (n = 4). Treatment with CsA 5 mg/kg/day for 14 days had no deleterious effect on glucose tolerance in Lewis isografts (control [K = 1.8 .+-. 0.24, n = 8] vs. CsA treated [K = 1.76 .+-. 0.20, n = 8, P = NS]). Low-dose CsA ensured permanent survival or MHC-compatible WF (n = 7, MST > 115 days) and MHC-incompatible BN (n = 9, MST > 117 days, P = NS) pancreatic transplants in spontaneously diabetic BB/Wor hosts. Three of 11 recipients surviving > 100 days enjoyed seemingly permanent acceptance of their allografts after discontinuation of CsA. Immunocompetence was demonstrated by rejection of their pancreas transplants when challenged with donor skin. Vascularized pancreatic allografts treated with CsA appear to be less vulnerable to recurrent diabetes than are islet transplants. Low-dose CsA protects vascularized pancreatic allografts in BB rats from both rejection and recurrent diabetes.