Siegelman, Mark H., MD, PhD
Increasing potent and specific autoreactive Treg in human T1D using a novel T cell adhesion biomarker CD44act
General Research Subject: Type 1 Diabetes
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
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 (T1D; IDDM) is an autoimmune disease that results from white blood cells from the body's own immune system destroying the insulin producing beta cells of it's own pancreas. This process involves specialized white blood cells called "T cells" that enter the pancreas by traveling through the walls of small vessels within the pancreas. A second kind of T cell is called a "regulatory" T cell (Treg). Treg can intercede in the destructive actions of the damaging T cells and do so in most individuals not afflicted with T1D. When Treg are unable to provide this protection, a person can develop an autoimmune disease such as T1D. Our research seeks to focus on a small population of Treg which we hypothesize are particularly relevant to T1D and therefore hold substantial promise for T1D treatment and prevention. Using Treg to prevent or reverse disease has been difficult because 1) there are very few of them, 2) they are difficult to grow outside the body, and 3) we don't understand completely how they are different from the cells that cause disease. My research laboratory has shown that a small number of Treg expressing a form of a protein that we have designated CD44act are much better at controlling the damaging T cells than other Treg that do not make CD44act. This is true in both human autoimmune conditions and mouse models of autoimmune diseases, and we believe will apply to T1D as well. Our evidence suggests that this protein can be used to identify and purify the Treg most specific and most efficacious for treating T1D. Moreover, we believe that the molecule we are studying is pivotal in directing the cells bearing it to the sites where they are most needed, in the case of T1D to the islets containing the insulin-producing beta cells. The purpose of this research is to better characterize the role of these cells in T1D patients, to determine whether they have the hallmarks of those Treg most capable of treating an individual's own diabetes, and to expand them in culture in order to understand them better and to determine if they can be useful to provide individualized patient therapy.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
We are taking a new approach to identifying a very unique subpopulation of lymphocytes that are responsible for controlling the immune system in such a way as to prevent autoimmune (Type 1) diabetes. If we can correctly identify and isolate these cells, we may be able to understand how they control disease and utilize them in a way that has not previously been possible. Armed with more information about these cells and their targets, and the pathways that they use to enter the pancreas, we can devise strategies for enhancing their function in patients with or predisposed to T1D. Importantly, screening at-risk patients/family members for this population prior to any signs of disease may allow much earlier intervention and treatment. While these studies may not provide immediate benefit to you and other individuals already diagnosed with Type 1 diabetes, we hope that they will lead to methods of earlier diagnosis and to new therapies for preventing the progression of disease once it has commenced.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have had an interest in the basic mechanisms of autoimmunity and inflammation throughout my research career. Members of my family as well as friends have suffered from the complications of diabetes, including blindness at a young age. To be able to contribute to the body of knowledge that may ultimately aid in the control of this disease and its often devastating consequences gives my work a very personal meaning. It is my hope that understanding the mechanisms by which the immune system regulates or fails to regulate the autoimmune responses leading to beta cell destruction, we can impact diabetes as well as many other immunologically driven diseases.
In what direction do you see the future of diabetes research going?
I believe that understanding and manipulating immune regulation will lead to major advances in the control of autoimmune diabetes. I anticipate that as we gain more knowledge about basic mechanisms in immune regulation, we will be better able to design strategies for the prediction and the prevention of disease. Every step in the disease pathway is a potential site for intervention. As we learn ever more about individual steps, such as lymphocyte migration into the pancreas or activation of particular lymphocyte subsets, we can design new ways to control the cells involved in disease. It is becoming ever clearer that the system that we have been studying for many years at the basic science level has very great potential for translation to clinical settings. As an M.D. physician scientist, it is my most fervent desire to determine the clinical applicability of our findings to T1D, and bring our studies to the bedside as rapidly and responsibly as possible. I think that diabetes research will continue to move in the direction of understanding basic mechanisms, which in turn will lead to the application of new technologies such as ours for the design of appropriate and in our case individualized therapeutic modalities.
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