title: Prevention of autoimmune destruction of syngeneic islet grafts in spontaneously diabetic nonobese diabetic mice by a combination of a vitamin D3 analog and cyclosporine.
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 microg/kg/2 days) significantly prolonged islet survival (60 days and 50 days, respectively, versus 9.5 days in controls; P<0.001 and P<0.0001). Mice treated with subtherapeutical doses of both drugs combined (KH1060 0.5 microg/kg/2 days + CsA 7.5 mg/kg/day) had significant prolongation of graft 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 grafts of control and combination-treated mice demonstrated that graft infiltration and islet destruction were less severe in grafts of combination-treated mice. Cytokine mRNA analysis in the grafts 6 days after transplantation revealed a clear suppression of interleukin-12 and T helper 1 cytokines and higher levels of interleukin-4 in combination-treated mice.
  
  
  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 beta cells in 30% of cases.
authors.affiliation: Laboratory for Experimental Medicine and Endocrinology (LEGENDO), Gasthuisberg, Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Casteels
authors.forename: M
authors.initials: M
authors.lastname: Waer
authors.forename: J
authors.initials: J
authors.lastname: Laureys
authors.forename: D
authors.initials: D
authors.lastname: Valckx
authors.forename: J
authors.initials: J
authors.lastname: Depovere
authors.forename: R
authors.initials: R
authors.lastname: Bouillon
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002762:Cholecalciferol / Q000031:analogs & derivatives*; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000235:genetics* / Q000276:immunology / Q000601:surgery*; D004338:Drug Combinations; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology; D007328:Insulin / Q000032:analysis; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D055502:Secondary Prevention; D014185:Transplantation, Isogeneic
chemical_list: D004338:Drug Combinations; D007166:Immunosuppressive Agents; D007328:Insulin; C074279:KH 1060; D002762:Cholecalciferol; D016572:Cyclosporine; D002117:Calcitriol; D002118:Calcium