Markiewicz, Mary A., PhD
The role of NKG2D on CTL in Autoimmune Diabetes
General Research Subject: Type 1 Diabetes
Type of Grant: Junior Faculty
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
Diabetes Type: Type 1 diabetes
The proteins known as NKG2D ligands are proposed to play a key role in the development of Type 1 diabetes. Data generated with the best-described mouse model of the disease, the non-obese diabetic (NOD) mouse, suggest this is the result of expression of these proteins in the islets of the diabetic, but not normal, pancreas. Expression of NKG2D ligands can activate a population of immune cells known as cytotoxic T cells (CTLs), cells that are critical in the development of Type 1 diabetes. Preliminary studies suggest that NKG2D ligand expression in the pancreas of mice that do not spontaneously develop diabetes can induce the recruitment of CTLs. However, the islets are not destroyed and diabetes does not develop. This suggests that factors other than NKG2D ligand expression are involved in the development of disease. Therefore, the role of NKG2D on CTL function in mice with spontaneously developing diabetes will be determined using the NOD model. It will be determined whether NKG2D ligand expression in the pancreas of NOD mice plays a role in CTL invasion into the pancreas and diabetes development. Further, factors involved in inducing the expression of NKG2D ligands in the pancreas will be analyzed. With the completion of these studies, the role NKG2D ligands play in CTL-mediated destruction of the pancreas will be better understood. This has the potential to lead to the development of better therapies for Type 1 diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Type 1 diabetes is caused by the immune system attacking and destroying the ß-islet cells of the pancreas, cells responsible for the production of insulin. In this disease, T cells, critical components of the immune system responsible for the eradication of destructive microbes, react to the islet cells as if they were an invading pathogen. It is not clear what defects in normal immune function cause the T cells to have this inappropriate response against the body's normal tissue. The focus of our project is to determine the role of the protein called "NKG2D" in this process using a mouse model. This protein is expressed on the surface of a subset of T cells, cytotoxic T lymphocytes (CTL), cells that directly destroy islet cells during diabetes. Studies implicate NKG2D-mediated immunity in the development of type 1 diabetes in both patients and mouse models of the disease. However, how this protein is involved in T cell-mediated destruction of the islets is unclear. Determining this will allow for a better understanding of how Type 1 diabetes develops. This knowledge may lead to ways of predicting individuals who will develop diabetes and/or to developing better therapies for type 1 diabetes patients.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Although we know Type 1 diabetes is caused by the immune system attacking islet cells in the pancreas, we have little knowledge of the defects causing the immune system to attack self-tissue. The ultimate goal for the treatment of type 1 diabetes is to detect the disease early, halt immune destruction, and preserve islet cells so that insulin injections are no longer necessary. In order to reach this goal, we must thoroughly understand how the disease develops. The results of our studies will aid in this understanding.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Although the immunology community has uncovered much about the function of the immune system, still little is known about the causes of autoimmune diseases such as type 1 diabetes. This is hampering the ability of new treatments to be developed for these diseases. As the incidence of type 1 diabetes continues to increase, developing new therapies for this disease is particularly important. Treatment allowing patients to live more normal lives, without the dependence of insulin and constant blood sugar monitoring, would be invaluable. This is especially true given the young age that this disease often develops. This American Diabetes Association award will support my laboratory in our diabetes studies for the next three years, allowing us to get one small step closer to understanding how autoimmune diabetes develops. Upon successful completion of these studies, we hope our results will convince the National Institutes of Health to support our laboratory in future studies on the causes of type 1 diabetes.
In what direction do you see the future of diabetes research going?
I believe there will be two main lines of research in type 1 diabetes. The first will be to try to find a way to induce the regeneration of islet cells in patients so that they can begin making their own insulin again. The second will be to delineate the defects in the immune system allowing for the destruction of islet cells. Knowing the signals involved in initiating an immune attack on the pancreas will allow for the development of new therapies that inhibit these signals. The ultimate goal is for the results of both lines of research to then come together. Perhaps one day the standard of care for type 1 diabetes patients will be regeneration of islets followed by treatment that blocks destruction of these new islets by the immune system.
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