Grant: CIHR Fellowship

Diabetes is an autoimmune disease in which the immune system destroys insulin-producing cells in the pancreas. Insulin production can be restored by transplanting islets, which contain insulin-producing cells, either from deceased donors or made from stem cells. However, immunosuppressive drugs must be used to prevent rejection, and these leave patients vulnerable to cancer and infection. We are investigating ways to reduce the need for immunosuppressive drugs through cell therapy consisting of regulatory T cells (Tregs), a type of immune cell that suppresses unwanted immune responses. The overall aim of this project is to optimise the function of human Tregs so they will still function within the high-insulin environment of the pancreas. I am taking two approaches to achieve this aim. The first is to modify Tregs to function in the presence of high levels of insulin. Initially, I will use cell culture to understand the effect of insulin on Treg function and survival. Then, I will genetically engineer Tregs so that they respond to insulin by increasing growth and activity. To test the ability of these engineered Tregs to suppress immune responses in high-insulin environments, I will perform in vitro assays measuring suppression against immune cells in the presence of artificially added insulin or insulin from stem cell-derived pancreatic cells. I will also test the survival of these Tregs in mouse models. My second aim is to improve the function and metabolism of Tregs by optimising their cell culture medium. I will test their ability to proliferate and suppress immune responses in vitro after culture in medium with varying amounts of glucose and lactic acid. After optimisation of the cell culture medium, I will test these cells using a mouse model of transplant rejection. Together, this work will produce Tregs that are optimised to function in the insulin-rich pancreatic islets, and prevent immune rejection of pancreatic islet transplants.