PREVENTION OF AUTOIMMUNE DESTRUCTION OF SYNGENEIC ISLET GRAFTS IN SPONTANEOUSLY DIABETIC NONOBESE DIABETIC MICE BY A COMBINATION OF A VITAMIN-D-3 ANALOG AND CYCLOSPORINE

Background. Type 1 diabetes is characterized by the presence of an aut oimmune memory, responsible for the destruction of even syngeneic isle t grafts. This recurrence of autoimmunity is partly responsible for th e need of extensive immunosuppression in pancreas and islet transplant ation in type 1 diabetic patients. The aim of the study was to evaluat e the capacity of a 20-epi-analog of vitamin D-3,, KH1060, both alone and in combination with cyclosporine (CsA) to prevent diabetes recurre nce 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 combina tion of both drugs from the day before transplantation until recurrenc e or 60 days after transplantation. Results. Vehicle-treated mice show ed a recurrence of diabetes in 100% of cases (n=17) within 4 weeks. Tr eatment with high doses of CsA (15 mg/kg/day) or KH1060 (1 mu g/kg/2 d ays) significantly prolonged islet survival (60 days and 50 days, resp ectively, versus 9.5 days in controls; P<0.001 and P<0.0001), Mice tre ated with subtherapeutical doses of both drugs combined (KH1060 0.5 mu g/kg/2 days + CsA 7.5 mg/kg/day) had significant prolongation of graf t survival (48 days; P<0.001) and more importantly, four of five mice that were still normoglycemic 60 days after transplantation showed no recurrence after discontinuation of all treatment. Histology of the gr afts of control and combination-treated mice demonstrated that graft i nfiltration and islet destruction were less severe in grafts of combin ation-treated mice. Cytokine mRNA analysis in the grafts 6 days after transplantation revealed a clear suppression of interleukin-ll and T h elper 1 cytokines and higher levels of interleukin-4 in combination-tr eated mice. Conclusions. KH1060, an analog of 1,25(OH)(2)D-3, delays a utoimmune disease recurrence after syngeneic islet transplantation in NOD mice, both alone and especially in combination with CsA, possibly restoring tolerance to beta cells in 30% of cases.