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Original

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

, , , , &
Pages 242-248 | Received 21 Sep 2008, Accepted 29 Oct 2008, Published online: 07 Jul 2009
 

Abstract

Protein kinase C (PKC) is an important signaling enzyme in the activation and regulation of T lymphocytes. T-cell-mediated destruction of β-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.

Acknowledgements

The authors would like to thank Drs Jurgen Wagner and Walter Schuler for their thoughtful contribution to experimental design and interpretation of data, and Dr John Elliott for providing GAD65 for our assay of anti-GAD65 antibody.

Funding for this project was provided by charitable donations from the Roberts family, the Diabetes Research Institute Foundation of Canada, and the Victor family.

A. M. J. S. is a scholar supported through the Alberta Heritage Foundation for Medical Research (AHFMR). S. M. is a recipient of the AHFMR MD/PhD Studentship, the CIHR Walter & Jessie Boyd and Charles Scriver MD/PhD Studentship, and Lionel E. McLeod Award. C. T. is supported by the Swiss National Science Foundation, a FS Chia award and the AHFMR. J. A. E. is supported by fellowships from the American Society of Transplantation, Juvenile Diabetes Research Foundation, AHFMR, and Rhind Foundation.

Declaration of interest: S. M., R. L. E., C. T., J. E., A. T., and A. M. J. S. have no duality of interest to declare.

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