PREVENTION OF AUTOIMMUNE DESTRUCTION OF SYNGENEIC ISLET GRAFTS IN SPONTANEOUSLY DIABETIC NONOBESE DIABETIC MICE BY A COMBINATION OF AVITAMIN D3 ANALOG AND CYCLOSPORINE1

Abstract

Background. Type 1 diabetes is characterized by the presence of an autoimmune memory, responsible for the destruction of even syngeneic islet grafts. This recurrence of autoimmunity is partly responsible for the need of extensive immunosuppression in pancreas and islet transplantation in type 1 diabetic patients. The aim of the study was to evaluate the capacity of a 20-epi-analog of vitamin D₃, KH1060, both alone and in combination with cyclosporine (CsA) to prevent diabetes recurrence in syngeneic islet grafts in nonobese diabetic (NOD) mice. Methods. Spontaneously diabetic NOD mice grafted with syngeneic islets(n=500) under the kidney capsule were treated with KH1060, CsA, or a combination of both drugs from the day before transplantation until recurrence or 60 days after transplantation. Results. Vehicle-treated mice showed a recurrence of diabetes in 100% of cases (n=17) within 4 weeks. Treatment with high doses of CsA (15 mg/kg/day) or KH1060 (1 μg/kg/2 days) significantly prolonged islet survival (60 days and 50 days, respectively, versus 9.5 days in controls;PPP. Conclusions. KH1060, an analog of 1,25(OH)₂D₃, delays autoimmune disease recurrence after syngeneic islet transplantation in NOD mice, both alone and especially in combination with CsA, possibly restoring tolerance to β cells in 30% of cases.