Grant: Operating Grant

Insulin-dependent or type 1 diabetes mellitus (T1D) results from immune dysregulation (autoimmunity) leading to destruction of the insulin-producing cells of the pancreas (beta cells) by beta cell-killer white blood cells. Susceptibility to T1D is genetically determined, but the underlying mechanisms are poorly understood. Our studies to date have explored mechanisms underlying the genetic risk to T1D afforded by 3 different genes, and have discovered that all 3 affect the development and function of a type of white blood cells whose job is to protect us against autoimmune disease ('suppressor white blood cells'). Particularly significant with regards to human T1D are our studies of the mouse 'Interleukin 2' gene. Like its mouse counterpart, the human Interleukin 2 gene is associated with human T1D. We have shown that the variants of this gene that afford T1D risk in mice do so because they work slightly less than normal (i.e. make less interleukin 2 protein). Since the 'suppressor white blood cells' require interleukin 2 to function, mice that make less interleukin 2 than normal have 'suppressor' cells that don't work very well; this is the reason why this gene is associated with T1D. This prompted us to investigate a related gene that is also associated with human T1D: 'Interleukin 2 receptor alpha'. This gene codes for a protein on the surface of the 'suppressor' cells that allows them to capture 'Interleukin 2' from the blood. We hypothesize that the variants of this gene that are associated with T1D are those that make less 'Interleukin 2 receptor alpha' protein. The objective of this grant is to investigate if relatively small variations in the function of the genes coding for 'Interleukin 2' and 'Interleukin 2 receptor alpha' (alone and in combination) result in significant variations in the function of 'suppressor' cells leading to T1D. This work will help identify new therapeutic targets for T1D and other autoimmune diseases.