Grant: CIHR Fellowship

Type 1 diabetes (T1D) is an autoimmune disorder where auto-reactive T-cells selectively destroy the insulin-producing pancreatic beta-cells, leading to blood glucose dysregulation. Few compounds are available to delay the onset of T1D and there are no approved treatments that reverse T1D. Immunosuppressants, such as cyclosporin, can protect the beta-cells from autoimmune destruction but most are also toxic to beta-cells. Recently, a structurally similar molecule, voclosporin, has been approved for use in Lupus nephritis (an autoimmune kidney disease) and may also have value as a T1D therapeutic. Compared to tacrolimus, a common immunosuppressant used in transplant patients, voclosporin resulted in a lower incidence of new-onset diabetes after transplant and is less toxic to isolated human islets. This study aims to compare the effects of voclosporin, cyclosporin, and tacrolimus on the T1D incidence in NOD mice, a common model of auto-immune diabetes. NOD mice will be treated with different doses of voclosporin, cyclosporin, and tacrolimus, or a vehicle control that does not contain any drug. The incidence of T1D in each group will be measured, along with other important parameters such as body weight, plasma C-peptide levels (which indicate insulin secretion), and insulin autoantibody levels (which indicate autoimmune activity against beta-cells). In addition, a separate group of mice will be treated the same way but sacrificed at an earlier time when autoimmunity is present but not high blood glucose. Tissues collected from these mice will be used to analyse the differences in the immune cells present in the pancreatic islets, as well as changes in gene expression. Overall, the results of this study will provide insight into the mechanisms by which these important immunosuppressants act on physiology in the T1D context, and guide future preclinical and clinical development of T1D therapeutics.