Objective
Type 1 diabetes is an autoimmune disease in which the insulin-secreting cells within the pancreas are destroyed by a person's own immune system. The current standard of care for this disease, insulin replacement, is cumbersome and the life expectancy of type 1 diabetes patients is still reduced compared with healthy individuals. In addition, the incidence of type 1 diabetes is increasing for unknown reasons. Therefore, novel prevention strategies are urgently needed. A clinical grade NKG2D blocking antibody exists and is currently being tested for efficacy in some autoimmune conditions. The overall goal of this research is to determine if such an antibody has the potential to be part of a clinical strategy to inhibit or delay type 1 diabetes in at-risk or newly diagnosed individuals.
Background Rationale
The part of the immune system that attacks the pancreas in type 1 diabetes are called T cells. Understanding what makes these cells respond to the pancreas is critical to developing better strategies for disease treatment. One protein believed to be involved in this process is called "NKG2D", and a clinical grade pharmaceutical that blocks NKG2D is being tested to treat some autoimmune conditions. However, this treatment is not being tested in individuals at-risk for type 1 diabetes, as the importance of NKG2D to diabetes is unclear owing to conflicting results in mouse studies performed to date. Therefore, we developed novel mouse models to determine the role of NKG2D signaling.
Description of Project
Type 1 diabetes is an autoimmune disease in which the insulin-secreting cells within the pancreas are destroyed by a person's own immune system. The current standard of care for this disease, insulin replacement, is cumbersome and the life expectancy of type 1 diabetes patients is still reduced compared with healthy individuals. In addition, the incidence of type 1 diabetes is increasing for unknown reasons. Therefore, novel prevention strategies are urgently needed. The part of the immune system that attacks the pancreas in type 1 diabetes are called T cells. Understanding what makes these cells respond to the pancreas is critical to developing better strategies for disease treatment. One protein believed to be involved in this process is called "NKG2D", and a clinical grade pharmaceutical that blocks NKG2D is being tested to treat some autoimmune conditions. However, this treatment is not being tested in individuals at-risk for type 1 diabetes, as the importance of NKG2D to diabetes is unclear owing to conflicting results in mouse studies performed to date. Therefore, we developed novel mouse models to determine the role of NKG2D signaling, including mice that contain no microbes, as we have found this is important to isolate the pancreas-specific role of NKG2D. From the results of our studies with these models, we propose that NKG2D plays an important role in the ability of the T cells to "see" the islets in the pancreas as something it should destroy. To test this, we propose two Specific Aims: In Aim 1, we will (1) confirm the importance of NKG2D in allowing T cells to "see" islets as foreign in mice, (2) determine if there is a similar effect in human T cells; (3) determine if the proteins that interact with NKG2D are expressed within human tissue in individuals with type 1 diabetes; (4) determine how microbes affect the importance of NKG2D in allowing T cells to "see" islets as foreign. In Aim 2, we will confirm that NKG2D does not act within the pancreas to enhance islet cell destruction and diabetes. The results of these studies will allow us to determine if NKG2D signaling blockade has the potential to be part of a clinical strategy to inhibit or delay type 1 diabetes in at-risk or newly diagnosed individuals.The results of these studies will allow us to determine if therapy that targets NKG2D has the potential to be part of a clinical strategy to inhibit or delay type 1 diabetes in at-risk or newly diagnosed individuals.
Anticipated Outcome
The results of these studies will allow us to determine if therapy that targets NKG2D has the potential to be part of a clinical strategy to inhibit or delay type 1 diabetes in at-risk or newly diagnosed individuals.
Relevance to T1D
Understanding what makes T cells attack the islets in the pancreas is critical to developing better strategies for disease treatment. One protein believed to be involved in this process is called "NKG2D", and a clinical grade pharmaceutical that blocks NKG2D is being tested to treat some autoimmune conditions. However, this treatment is not being tested in individuals at-risk for type 1 diabetes, as the importance of NKG2D to diabetes is unclear owing to conflicting results in mouse studies performed to date. We propose that NKG2D plays an important role in the ability of the T cells to "see" the islets as something it should destroy. The results of these studies will allow us to determine if NKG2D blockade has the potential to be part of a clinical strategy to inhibit or delay type 1 diabetes in at-risk or newly diagnosed individuals.