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AEB-071 has minimal impact on onset of autoimmune diabetes in NOD mice

Merani, S.
Edgar, R. L.
Emamaullee, J.
Thiesen, A.
Shapiro, A M. J.
Published in Autoimmunity. 2009, vol. 42, no. 3, p. 242-248
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.
Keywords Age FactorsAnimalsAutoantibodies/blood/immunologyCyclosporine/administration & dosage/pharmacokinetics/therapeutic useDiabetes Mellitus, Type 1/pathology/*prevention & controlFemaleGlutamate Decarboxylase/immunologyInsulin/metabolismMaleMiceMice, Inbred BALB CMice, Inbred NODPancreas/metabolism/pathologyProtein Kinase C/*antagonists & inhibitorsProtein Kinase Inhibitors/administration & dosage/pharmacokinetics/pharmacology/*therapeutic useRatsRats, Inbred BB
PMID: 19301207
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Research group Transplantation et hépatologie (905)
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MERANI, S. et al. AEB-071 has minimal impact on onset of autoimmune diabetes in NOD mice. In: Autoimmunity, 2009, vol. 42, n° 3, p. 242-248. doi: 10.1080/08916930802587950 https://archive-ouverte.unige.ch/unige:19961

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Deposited on : 2012-04-23

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