Piganelli, Jon. B., PhD
Redox modulation of LAG-3 for inhibition of diabetogenic TH1 cell activation
General Research Subject: Type 1 Diabetes
Focus: Immunology, Other, Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
Diabetes Type: Type 1 diabetes
Chronic inflammation is a major culprit for promoting autoimmune diseases, such as type 1 diabetes. In an effort to decrease overall inflammation, antioxidant delivery has shown great promise in mouse models. Not only does antioxidant treatment alleviate inflammation from the innate and adaptive arms of the immune response, which are both involved in type 1 diabetes, but it also delays the onset of disease significantly. However, the mechanism behind the reduction of inflammation in adaptive immune cells is unknown. The adaptive immune response is made up of T cells and B cells. T cells are the primary lymphocytes that mediate beta cell destruction, manifesting into loss of insulin secretion and diabetes onset. One molecule expressed on T cells immediately upon an immune response is LAG-3, or Lymphocyte Activation Gene-3. LAG-3 inhibits T cell activation, and therefore, enhancing LAG-3 expression may be a possible way of restraining T cells that would otherwise attack the pancreas. Pro-oxidants control an enzyme that negatively regulates LAG-3 expression. Therefore, antioxidant treatment may theoretically prevent the enzyme's activity by decreasing pro-oxidants, which are necessary for enzyme function, and thus, increase LAG-3 expression. By targeting a specific T cell molecule as well as its regulatory enzyme, antioxidant treatment may 'kill two birds with one stone', leading to diminished autoimmune responses against the beta cells and prevention of type 1 diabetes onset.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The funding for this basic science grant allows us to better understand how the free radicals activate the immune system, and how we can utilize methods that block these free radicals to control the abnormal immune response. Our group previously demonstrated that redox modulation using a manganese metalloporphyrin catalytic antioxidant (MnP) can dissipate ROS, dampen pro-inflammatory cytokine synthesis, impair T cell function and prevent transfer of diabetes. However, the mechanism by which MnP promotes this inhibition is unknown. We believe that affecting the activation of T cells alter, autoreactive CD4 T cells in such a way that they are not capable of responding to self-antigens, like beta cells. Furthermore, this reduced activation may also afford us an ability to monitor the activation of the T cells in the blood of those individuals that have a genetic susceptibility to type 1 diabetes. This blood test may serve as an early T cell-specific biomarker for type 1 diabetes onset. This work will be instrumental in contributing to our understanding of how to block the progression of diabetes and also to track progression before disease onset and to monitor the effectiveness of new treatments.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
We are hopeful that the work will lead us to a better understanding of how we can block the activation of self-reactive T cells against the recognition of self-antigen. In conjunction with our previously ADA funded work we have a better understanding of why the immune system recognizes these self-proteins, we can now combine our approach to temper the self-reactive immune response to these self antigens. Furthermore, if we have a better understanding as to why the immune system becomes activated against particular antigens we can begin to design therapies in conjunction with other strategies that we are developing to derive protocols that will incorporate the elimination of the rogue T cells without globally making individuals immunodeficient. These strategies are becoming a more realistic goal, to combine with our previous efforts to initiate effective therapies for protection against type 1 diabetes onset, and more sensitive methods to detect the progression of the disease prior to disease onset.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is a devastating disease that affects all of us. Those individuals that do not have the disease know someone who struggles with it and those with it know their struggle and fear the long-term affects of the complications. The complications associated with the disease took their toll on my mother, by ravaging her body until in the end she finally succumbed. Studying Type 1 diabetes, which affects primarily children, leaves me with an even stronger sense of urgency to understand the disease. I truly believe and began my career in the field because I think I can help to find a cure for this disease. When you decide to study a chronic disease like T1D, you have to dedicate your life to it, and all you can hope for is that through your work and the ability to teach and train others it will all come together to find a cure for this disease. This award obviously helps me to continue my work toward understanding the disease process and also to train the next group of young scientists to continue the efforts. I always joke with the people in my lab, telling them we are in unique job situation. We work to put ourselves out of work. I hope that I have to change jobs sooner than later. In what direction do you see the future of diabetes research going? I see the direction for T1D moving toward understanding and controlling aberrant immune function. In conjunction with our ability to now predict with reasonable confidence those individuals who will progress to disease we can utilize our knowledge gained from regulation of immune function to designed strategies that will lead to prophylactic treatment individuals predisposed to diabetes onset. Also detailed analysis of environmental factors would be critical for understanding triggers that lead to the initiation of T1D. Although these types of studies do not appear to be in the applied channel of research the knowledge gained from them is critical for the implementation of therapeutic design.
In what direction do you see the future of diabetes research going?
At present we are making great strides in further understanding how uncontrolled inflammation leads to damage in both type 1 and 2 diabetes. It is now apparent that most major pathological conditions have an inflammatory component associated with them and therefore our understanding of why this occurs and how we can alter it to protect against further damage is now becoming a new line of research. We now better understand through our work and the work of others how these inflammatory mediated signals activate the immune system, which leads to beta cell destruction. In type 2 diabetes it is now known that low grade chronic inflammation contributes significantly to insulin resistance and high blood glucose. Knowing now how critical it is for us to control the inflammatory response has lead to new lines of investigation that in the future should help not only for the design of new therapeutics but also for the design of new strategies for the prophylactic treatment of individuals with susceptibility to type 1 diabetes progression.
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