The focus of our research is type 1 diabetes, an autoimmune disease that causes the loss of insulin-producing cells in the pancreas. Type 1 diabetes cannot be prevented or cured. Our goal is to change this by exploring new strategies to shut-down the autoimmune attack on the pancreas and to protect the insulin-producing cells against immune killing.

Understanding deficiencies in immune regulation in type 1 diabetes

The immune system is a highly coordinated collection of different cell populations that is equiped with many effective tools to fight infection, help repair tissue damage and destroy cells that pose a risk of cancer. With the power to kill and clear any cell in the body comes the potential for self-harm. To prevent autoimmunity, an immune reaction against seemingly healthy cells and organs, the immune system has many layers of checks and balances. One of the key orchestrators in immune regulation is the regulatory T cell (Treg).

In type 1 diabetes, Tregs attempt to curtail the immune attack on the pancreas but ultimately fail. Strategies to increase their number or activity are being pursued in clinical trials and in many preclinical studies to develop an effective strategy to prevent or halt the autoimmunity that causes type 1 diabetes.

Our laboratory has been investigating the function and homeostasis of Tregs in type 1 diabetes for many years (Gerold et al 2011, Zheng et al 2013, Nowakowska and Kissler 2016). More recently, we have started asking if different populations of Tregs were involved in regulating pancreas autoimmunity (Schuster et al 2018). We have increased our focus on this area of research and are currently testing the hypothesis that several distinct populations of Tregs participate in immune regulation in type 1 diabetes. We aim to better understand the respective contribution of each of these populations and thereby uncover which exact mechanisms of immune regulation are deficient in disease. This could allow us to develop a more targeted strategy to restore Treg function in type 1 diabetes.

Identifying genome edits in insulin-producing beta cells that protect against autoimmune destruction

In a completely distinct approach, we have undertaken a search for gene modifications in beta cells, the target of autoimmunity in type 1 diabetes, that could prevent their destruction (Cai et al. 2020). We used an ingenious strategy to leverage the immune system's destructive power to select protective mutations out of a pool of more than 60,000 gene modifications. The result of this approach is a very short list of candidate genes. We have since validated several of these 'protective' genes. Remarkably, two of these genes had already been associated with human diabetes in large genetic studies, providing a high degree of confidence that targeting these genes in beta cells could have a meaningful protective effect against autoimmune killing.