A New Approach To Retraining Immunity In Patients With T1D
Years to decades before a person develops Type 1 diabetes (T1D), abnormal activation of the immune system can be detected in their blood. Despite this advanced warning, we are unable to stop the progression of disease. Ultimately, this failure results in over 15,000 American children each year developing T1D and becoming reliant on a lifetime of shots. In this proposal, we will use new clues from the healthy immune system to stop T1D.
The healthy immune system possesses safety mechanisms that prevent autoimmune diseases like T1D from happening. One such safety net is regulatory immune cells—these are cells that healthy individuals have in their immune system that prevent other cells from harming tissues, such as the insulin-producing beta cells of the pancreas. These regulatory cells can stop the immune response before it harms the body and causes autoimmune disease, but they are insufficient in patients with T1D. Targeting these cells for enhancement and activation will overcome this insufficiency and restore the body’s normal protective processes to prevent and reverse T1D.
We will capitalize on over 20 years of experience in the Moore lab in studies of immune regulation in T1D to advance this new approach for diabetes prevention and reversal. Using the NOD mouse model of diabetes, we have identified a previously unrecognized cell that prevents T1D from progressing, known as a CD8 Treg. We will now define how this cell carries out this critical task and how it can be activated by clinically-relevant therapies–including an IL-15 super-agonist, anti-CD3, or anti-CD45RB–so that we can repair its function in patients with T1D or at-risk for disease.
Overall, we will define a new pathway to disease prevention and reversal by defining the action of a newly identified regulatory cell in T1D. Through your support, we will reveal how these cells work to prevent T1D. These studies will advance our goal of bringing new treatments to patients with T1D by understanding the fundamental reasons that islet beta cells are destroyed by the immune system.
Update on 12-01-17
We would like to thank the Diabetes Research Connection and all of our supporters for lifting up our project on immune regulatory cells in Type 1 diabetes. As you are likely aware, the presence of autoantibodies is the first sign of Type 1 diabetes and are evident in nearly everyone with new onset Type 1 diabetes. It has not been known what controls the production of these antibodies, why they appear, or how to stop this part of the process. Our project has focused on a type of immune regulatory cell that we found to be deficient in T1D and which has the capacity to shut down this deleterious step. Throughout our project, we determined new ways to expand and enhance these cells and demonstrated that they could prevent diabetes in the animal model. In additional studies, we attempted to determine how they might protect islet transplants. Through these studies, we determined that these cells may work through previously unidentified interactions in order to carry out their protective program. We further confirmed that the antibody-producing B lymphocytes are the key barrier that prevents us from having successful islet transplants. By supporting our investigation of protective immune cells and their functions, you have helped us become better enabled to repair the immune system and restore normal immune function so that islet destruction is stopped. In the future, we look forward to expanding on these results to continue to develop new approaches to facilitate beta cell replacement.
Update on 4-14-17
We continue our study of immune regulatory cells for the prevention and reversal of T1D. By contributing to our understanding of protective immune cells and their functions, we will be better enabled to repair the immune system and restore normal immune function so that islet destruction is stopped. Over the last 4 months, we have addressed several approaches to help these cells reach their maximum activity; in this effort, we have also determined that the cells that destroy islets appear to resist the effects of these regulatory cells. Therefore, in the last phase of this initial project, we will look to enhance the effect of these novel immune regulatory cells by sensitizing other immune cells to their actions. Building on these results, we will continue our investigation to optimize our approach to alter the course of T1D.
Update on 11-8-16
Update on 9-1-16
We continue our study to determine how a new type of regulatory cell can prevent and reverse T1D. These cells are known to protect islets from destruction in both spontaneous diabetes and also following islet transplantation. Over the last 4 months, we have focused on understanding how these cells interact with their targets. We have determined that one of the molecules that was previously thought to be absolutely required for their function is not needed when they protect beta cells from destruction. We are currently preparing these findings for publication. These findings will help us to focus on the necessary and sufficient features that allow these cells to work to protect islets. Building on these results, we will continue our investigation to determine how these cells can be optimized to alter the course of T1D.