Wagner, Jr., David H, PhD
CD40 As A Biomarker in Type 1 Diabetes
General Research Subject: Type 1 Diabetes
Type of Grant: Career Development
Project Start Date: January 1, 2008
Project End Date: December 31, 2012
Funded by the Estate of Thomas R. Lee
T cells that attack the pancreatic islets lead to destruction of insulin production and then hyperglycemia. This is a hallmark of type 1 diabetes (T1D). Controlling these harmful T cells is essential to controlling the disease. We identified a biomarker for the damaging T cells in T1D, CD40. In this grant we wish to further study CD40 and how it affects T cells. CD40 is a protein expressed on many cells, and occurs as 5 different protein forms. We discovered that a difference in how the CD40 protein is expressed occurs on T cells from diabetic subjects compared to non-diabetic subjects. We also discovered that treating T cells from diabetic mice (and humans) with anti-CD40 has very different outcomes than treating the identical T cells from non-diabetic subjects. This suggests that CD40 may be a useful biomarker in T1D. We wish to explore the differences in CD40 on T cells from T1D and control subjects. We propose to understand how CD40 causes T cells in T1D to be damaging while not having that effect in non-autoimmune subjects. These studies will lead to better understanding of CD40 in type 1 diabetes and lead to better therapeutic agents to control only the harmful T cells in the disease while not causing harm to the overall immune system.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
One of the major concerns for T1D is identifying cellular markers associated with the disease. We have identified a unique T cell subset that is radically expanded in number in T1D compared to normal control subjects. This is true both in the mouse model for T1D and importantly in human T1D patients. This T cell subset further distinguishes type 1 and type 2 diabetes. We identified the biomarker, CD40, as describing this unique T cell subset. In T1D subjects, mouse and human, CD40+ T cells are drastically expanded in number. We found that the levels of CD40 itself are drastically increased in CD40+ T cells from T1D compared to non-autoimmune controls. In the mouse T1D model, significantly expanded levels of CD40+ T cells are predictive for diabetes onset. We hypothesize that the same will prove true for human patients. We also found that the signals to CD40+ T cells in T1D are drastically different than those to the identical T cell subset from non-autoimmune controls. In this grant we will explore the CD40 receptor on T cells from T1D compared to non-autoimmune controls. Another interesting finding is that the CD40 receptor configuration is markedly different in diabetogenic T cells versus non-diabetogenic T cells. CD40 occurs as 5 different isoforms and those isoforms determine the CD40 receptor configuration. Induced changes, which we can measure, in the CD40 receptor configuration are predictive of whether those T cells will cause diabetes. We will determine how different types of stimulation affect the CD40 receptor relative to diabetogenicity. Are there conditions that will render diabetogenic T cells no longer diabetogenic? Such understanding will lead to treatments or even prevention of T1D. We will define the different configurations of the CD40 receptor on diabetogenic versus non-diabetogenic T cells and how the different combinations of CD40 affect T cell signaling. This project will aid in early detection of T1D by examining CD40 and the different CD40 receptor configurations as determined by the CD40 isoforms. Through our model it is very likely that we can predict T1D prior to hyperglycemia onset. By studying how to affect the CD40 receptor, to make it a friendlier version, we can design potential therapy to prevent T1D onset.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Because of this grant, e.g. identifying CD40 as a biomarker in type 1 diabetes, we may well be able to diagnose type 1 diabetes before hyperglycemia. This is good for early detection. By better understanding the T cells that cause diabetes, attack pancreatic islets and attack islet transplants, and potentially cause many of the associated complications; we can design directed therapies to silence the damaging T cells. By focusing solely on the rogue T cell subset, we will not damage the immune system, but will be able to detect and silence the T cells that are attacking self-tissues. Many of the current therapies to control auto-aggressive T cells cause immuno-suppression. This strategy of altering autoaggressive T cells can prevent diabetes onset, and drastically improve islet transplant survival. Furthermore, many of the T cell derived complications can be prevented. This directly impacts individuals already suffering for T1D.
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 major disease affecting millions of people. Treatments have improved matters but 'cure' must still be sought. My interest in diabetes began because of the interesting science. I was involved in the discovery of a unique T cell subset, that turned out to be directly involved in diabetes. With careful work, my group made the connection between CD40+ T cells and type 1 diabetes. This research has excited me and I feel confident that these studies will make a major impact on type 1 diabetes. We are pursuing what will prove to be a predictor allowing detection prior to hyperglycemia onset in type 1 diabetes. Once hyperglycemia occurs, the current diagnostic standard, it is too late for the pancreatic islets, which have been destroyed by the immune system. In addition we are studying ways to control only the 'rogue' T cells that are attacking the pancreatic islets. Thus we can develop therapies to prevent the onset and control the disease after it occurs. This award plays a major role in developing these studies. Without the support of the American Diabetes Association we would not be able to conduct the new approaches on this important research. The proposed studies that this award supports will allow us to understand the CD40 receptor on Th40 cells, the identified rogue T cells in type 1 diabetes. We will better be able to control the CD40 receptor and perhaps prevent its ability to convert normal T cells to auto-aggressive T cells.
In what direction do you see the future of diabetes research going?
Diabetes research is advancing in many exciting areas including treatments and prevention. Genetic studies have proven very enlightening and basic immunology, understanding why the immune system attacks normal tissue, the pancreatic islets, is providing many new important insights. Diabetes research will continue to unravel these complex mysteries of the human body. We are gaining tremendous understanding about controlling auto-immunity and at the same time preserving normal immune functions.
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