Wagner, David H., PhD
Th40 cell levels and type 1 diabetes risk
General Research Subject: Type 1 Diabetes
Type of Grant: Translational Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Diabetes Type: Type 1 diabetes
Predicting diabetes onset and early differentiation between type 1 and type 2 diabetes has proven difficult. Genetic markers have been identified which are helpful but additional information is required. We discovered a unique T cell subset occurring in all individuals, but that is drastically expanded in number in T1D subjects. In T1D these cells respond to human islets and other diabetes associated antigens. They produce proteins that create and drive inflammation in the pancreas.
We now have discovered that these cells, called Th40 cells, are greatly expanded in some diagnosed pre-diabetic subjects but not in others. When Th40 cells are greatly expanded, Th40hi, the cells respond to human islets but in prediabetic subjects who are Th40lo, the cells do not. We will explore if Th40 cell levels are predictive of diabetes onset; when subjects become Th40hi how long is the time frame to diabetes; and when do Th40 cells begin to respond to human islets. We will explore how Th40 cells develop to create inflammation and how they are influenced by other cells called Tregs that help to prevent diabetes onset. We are creating a database to compare Th40 cell levels and pathogenesis to other defined diabetes markers. In addition we will relate Th40 cell levels to disease prognosis. Finally we will transfer human Th40 cells from pre-diabetic and diabetic subjects to mice specifically designed to accept human lymphocytes. We will treat these mice to control Th40 and monitor effect on disease.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
We are examining pre-diabetic patients and new onset diabetic patients then comparing them to long term diabetic patients. We defined a unique T cell subset, called Th40 cells, that have proven to cause type 1 diabetes in mouse studies. In human patients we discovered that these T cells are greatly increased in number when compare to non autoimmune subjects. We discovered that these T cells differentiate Type 1 and Type 2 diabetes. We also discovered that these cells specifically attack pancreatic islet beta cells leading to loss of insulin production. We are proposing to study when these T cells begin to cause the problems that will lead to diabetes onset, which will be done in patients that are diagnosed "pre-diabetic". This project will explore how these T cells become problematic and when this occurs. The ultimate goal is to 1) identify the highest "at risk" subjects 2) control these T cells specifically, and thus control/prevent further damage that leads to worsening disease.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
By understanding the cells that attack the body during autoimmune disease, in this case Th40 cells, we can better control them. We are looking at ways to understand who is at greatest risk for diabetes development in an attempt to stop diabetes development. For those who have diabetes, we are identifying the cells that propel the disease and determining how to control them to prevent further damage. There is data that islet beta cells can regenerate, if the inflammation is controlled. We are working to promote islet regeneration by controlling the specific inflammation inducing T cells. Therefore this research project benefits not only "pre-diabetic" subjects but new onset and long term diabetic subjects as well.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As an immunologist, my research area has become focused in diabetes, specifically type 1 diabetes. My first ever grant was a diabetes grant. I have since become committed to seeing this work through and not stopping until diabetes is cured. This award allows my lab to continue to operate and to extend our work in human subjects. It is important to define diabetogenic processes in mice to try to understand the nuances of the immune reaction in diabetes. It is critically important to determine if/how those studies translate to human studies.
In what direction do you see the future of diabetes research going?
A central focus of diabetes research of course is to restore insulin production. There are several potential options for this. However, and this is equally important, it is critical to control the autoimmune component of diabetes. The autoimmunity of T1D directly impacts insulin production, but loss of insulin has no impact on the autoimmunity. Even if insulin is restored, if the autoimmunity is not controlled the disease will continue to progress. This is why islet transplants have failed. Also many of the complications, including vascular problems can be attributed to the autoimmunity. Therefore not controlling autoimmunity will allow further complications. It also is likely that T1D is a more broad category of diseases than currently thought. This means that each diabetic subject may have unique features to their disease. We need to understand all the facets of this disease and how to provide better care for each individual.
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