Dooms, Hans , PhD
Inhibiting autoreactive memory T cells in type 1 diabetes
General Research Subject: Type 1 Diabetes
Focus: Immunology, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Diabetes Type: Type 1 diabetes
While significant advances in Type 1 diabetes (T1D) research have led to a better understanding of the autoimmune basis of the disease, improved methods for identifying at-risk individuals and novel clinical trials attempting to cure the disease, the ultimate goal to prevent and/or reverse T1D in humans remains elusive. Autoreactive T cells are considered the main culprits for destroying islet cells in the pancreas and are a premier target for T1D therapy. Islet-reactive T cells also represent a formidable problem for the successful restoration of insulin-producing cells through islet transplantation. Therefore, major efforts have been done trying to understand what causes these T cells to emerge and attack the islets. It is believed that a breakdown of immune tolerance mechanisms, which keep autoreactive T cells in check in healthy individuals, lies at the basis of autoimmune diseases such as T1D. Our recently published data suggest the existence of a novel pathway which regulates islet tolerance. We found that blocking the activity of the cytokine Interleukin-7 (IL-7) with antibodies against its receptor prevents and reverses diabetes in NOD mice.
In the current proposal we will further investigate how blocking IL-7 induces protective tolerance mechanisms in islet-specific memory T cells. Our studies may thus lead to a breakthrough in understanding the role of IL-7Ralphaƒnin the pathogenesis of diabetes and contribute to the design of therapeutic strategies using IL-7 targeting for improving the survival of transplanted islets and preserving existing islet cells.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
The goal of my project is to develop novel immunotherapies for type 1 diabetes. We recently found that blocking an immune system molecule, Interleukin-7 (IL-7), prevents and reverses type 1 diabetes in a mouse model. In a healthy immune system, IL-7 promotes the function of memory T cells that protect the body against microbes. In type 1 diabetes however, IL-7 supports the activities of "rogue" T cells that attack and destroy the insulin-producing cells in the pancreas. This ADA project will further investigate how IL-7 supports these autoreactive T cells and develop ways to more specifically target IL-7 acting on T cells attacking the pancreas. Blocking IL-7 is a novel approach to treating type 1 diabetes but challenges remain to translate this finding for use in the clinic. The key problem is to avoid a severe impact on the useful memory T cells of the immune system.
This project will increase our insight and understanding of the role of IL-7 in type 1 diabetes. This knowledge will be used to test therapeutic strategies of blocking IL-7 in combination with agents that direct this intervention towards the T cells that cause type 1 diabetes in mice. If successful, this immunotherapy may become a treatment for preventing and curing diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The project will test the feasibility of blocking IL-7, a molecule that contributes to the destruction of insulin-producing cells in the pancreas, for reversing type 1 diabetes. Although our data show this approach is effective in mouse models, the challenge is that this molecule is also critical for protecting the body against infectious diseases. A deeper understanding of the relationship between IL-7 and the cells destroying the insulin-producing cells in the pancreas may reveal improved methods to target this molecule with drugs while leaving the beneficial immune cells intact. Inhibiting the immune cells that attack the pancreas is a long-standing goal for the development of novel therapies that will cure type 1 diabetes. Such a method is highly sought after to either prevent further destruction of remaining islets or to allow successful introduction of new islets through transplantation or stem cells for example.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Diabetes is a disease on the rise with a major impact on many people's lives, including members of my family and friends. Type 1 diabetes is caused by T cells that mistakenly attack the insulin-producing cells in the pancreas. A number of years ago, I realized that my knowledge of memory T cells and the factors that are regulating them could shed more light on the immune processes that lead to type 1 diabetes. Applying insights gained from basic science to clinical problems is very rewarding and this award will enable me to continue my efforts evaluating the function of memory T cells specifically in models of type 1 diabetes.
In what direction do you see the future of diabetes research going?
There are two critical components for curing type 1 diabetes: 1) the autoimmune attack destroying the islets needs to be stopped and long-lasting tolerance achieved and 2) methods to increase insulin production or replace lost insulin-producing cells need to be developed. While both these goals are intensely being pursued, the future of diabetes research lies in developing approaches that are compatible and can successfully be combined. This will require increased communication and collaboration between scientists studying different aspects of the pathway to a cure.
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