The Role of NKG2D-Ligand Interaction in Autoimmune Diabetes
Abstract
The studies in this proposal address the 2018 Peer Reviewed Medical Research Program Topic Area ?Diabetes.? Type 1 diabetes is a disease in which the insulin-producing beta cells in pancreatic islets are destroyed by a person?s own immune system. Approximately 1.25 million Americans, including 200,000 youths, are currently living with type 1 diabetes. For unknown reasons, the incidence of type 1 diabetes is increasing, with a 21% increase between 2001 and 2009 in the prevalence of the disease in youths under age 21. According to the Standards of Medical Fitness, diagnosis with type 1 diabetes precludes an individual from serving in the military, and management of this disease with insulin replacement requires constant diligence on the part of patients. In addition, the annual healthcare expenditure per year in the U.S. associated with management of this disease is estimated at $14 billion. Even with this spending, the life expectancy of patients with type 1 diabetes is still reduced by about 10 years compared with healthy individuals. Rather than treatment of diabetes, halting the progression of beta cell destruction prior to overt disease would provide a higher quality of life for people suffering from type 1 diabetes. Patients in early stages of the type 1 diabetes still have functioning beta islet cells. Development of a clinical intervention that retains beta cells at this stage would be ideal. The main drivers of type 1 diabetes are T cells. These cells must escape the many mechanisms that control the killing of islets by these cells in healthy individuals. Understanding these mechanisms, and how defects in them allow for autoimmunity, is critical to developing better strategies to inhibit the disease. One pathway implicated in the process involves a protein termed Natural Killer Group 2 Member D (NKG2D). Our preliminary data demonstrate for the first time that there is an unexpected protective role for NKG2D within the pancreas during autoimmune diabetes development. This is a paradigm shift from the current thinking in the field that NKG2D signaling solely enhances autoimmune T cell responses. This protection correlates with reduced numbers of ?killer? T cells within the pancreas. Therefore, we think that NKG2D on T cells protects against type 1 diabetes development by altering these T cells to stop them from destroying islet cells. We propose here to (1) test this idea using mouse models and (2) perform studies with human T cells to determine whether the results we obtain in these animal studies translate to type 1 diabetes patients. Defining how NKG2D within the pancreas inhibits diabetes development is a significant research endeavor. Once this is determined, manipulation of NKG2D in the pancreas could potentially be used to slow or inhibit type 1 diabetes development in humans. Further, by determining how NKG2D inhibits diabetes, we could uncover additional novel therapeutic targets impacted by NKG2D.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910047XX0
Entities
People
- Mary A Markiewicz
Organizations
- United States Army
- University of Kansas Medical Center