title: AEB-071 has minimal impact on onset of autoimmune diabetes in NOD mice.
abstract: Protein kinase C (PKC) is an important signaling enzyme in the activation and regulation of T lymphocytes. T-cell-mediated destruction of beta-cells is a characteristic feature of autoimmune (Type 1) diabetes. Here we explore the ability of PKC inhibition, using the PKC inhibitor AEB-071 (AEB), to reduce disease in two animal models of spontaneous autoimmune diabetes (non-obese diabetic (NOD) mouse and biobreeding rat (BB)). NOD mice were treated with AEB for 4 weeks, starting at either 4 weeks of age (prior to the development of insulitis) or at 8 weeks of age, once insulitis is present. Animals treated with AEB during the effector phase of the disease (treatment onset at 8 weeks of age), showed a 2-week delay in diabetes onset (p < 0.05). In these animals, the extent of insulitis was lower than in vehicle-treated controls; however, neither serum autoimmune anti-GAD65 antibody levels nor pancreatic insulin content were different between experimental groups. Overall, inhibition of PKC can mildly reduce lymphocytic infiltrate of pancreatic islets and modestly delay onset of autoimmune diabetes in NOD mice. AEB, a T-cell-targeted immunosuppressive strategy, is only sufficient as a monothereapy to modestly delay onset of autoimmune disease in the NOD mouse.
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Merani
authors.forename: R L
authors.initials: RL
authors.lastname: Edgar
authors.forename: C
authors.initials: C
authors.lastname: Toso
authors.forename: J
authors.initials: J
authors.lastname: Emamaullee
authors.forename: A
authors.initials: A
authors.lastname: Thiesen
authors.forename: A M J
authors.initials: AM
authors.lastname: Shapiro
mesh_terms: D000367:Age Factors; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011913:Rats, Inbred BB
chemical_list: D001323:Autoantibodies; D007328:Insulin; D047428:Protein Kinase Inhibitors; D016572:Cyclosporine; D011493:Protein Kinase C; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2