Objective
The objective of this project is to characterize immune cells, and β-cell specific T cells that drive β-cell elimination, within the pancreatic lymph nodes and other tissues from normal, auto-antibody positive, and T1D donors. Further, we aim to measure the responses of β-cell specific T cells upon exposure to target β-cells.
Background Rationale
In some people, the immune system will attack and eliminate insulin producing cells in the pancreas, also known as β-cells. In time, this leads to diabetes, or a loss of insulin production and high levels of blood glucose, which can have devastating consequences for those affected. Type 1 Diabetes (T1D) occurs when otherwise healthy individuals, the majority of which are children, have an unknown pre-disposition that drives the immune system to attack β-cells in an autoimmune response. Unfortunately, T1D onset is difficult to detect, as it often develops over years’ time and diabetes symptoms only arise when almost all β-cells are eliminated. Understanding the immune system’s role in this process, and how it changes over time throughout T1D development, is critical to targeting therapies to immune cells that drive the elimination of β-cells. Recent evidence suggests that memory T cells in the pancreatic lymph nodes (pLN) are immune cells that facilitate β-cell attack and directly eliminate β-cells. However, human pLN samples are extremely difficult to obtain. As a researcher within the Human Pancreas Analysis Program, I have access to pLN and other tissues from normal and T1D donors. Importantly, I also have access to tissues from auto-antibody positive (AAb+) donors, who do not have clinical T1D but may have immune cells that are beginning to attack β-cells. I have developed a series of assays to not only survey the immune system in these samples but also identify specific memory T cells that recognize β-cell specific proteins, which are likely the cells driving autoimmunity. Novel insights into the immune system’s recognition and elimination of β-cells throughout diabetes onset may facilitate therapeutic T1D interventions targeting the immune system.
Description of Project
In some people, the immune system will attack and eliminate insulin producing cells in the pancreas, also known as β-cells. In time, this leads to diabetes, or a loss of insulin production and high levels of blood glucose, which can have devastating consequences for those affected. Type 1 Diabetes (T1D) occurs when otherwise healthy individuals, the majority of which are children, have an unknown pre-disposition that drives the immune system to attack β-cells in an autoimmune response. Unfortunately, T1D onset is difficult to detect, as it often develops over years’ time and diabetes symptoms only arise when almost all β-cells are eliminated. Understanding the immune system’s role in this process, and how it changes over time throughout T1D development, is critical to targeting therapies to stop immune cells that drive the elimination of β-cells. Recent evidence suggests that memory T cells in the pancreatic lymph nodes (pLN) are immune cells that facilitate β-cell attack and directly eliminate β-cells. However, human pLN samples are extremely difficult to obtain. As a researcher within the Human Pancreas Analysis Program, I have access to pLN and other tissues from normal and T1D donors. Importantly, I also have access to tissues from auto-antibody positive (AAb+) donors, who do not have clinical T1D but may have immune cells that are beginning to attack β-cells. It is predicted that pLN T cells from AAb+ and T1D donors will be more activated, and β-cell targeting T cells will have more cytotoxic-like characteristics than the general T cell population. I have developed a series of assays to not only survey the immune system in these samples but also identify specific memory T cells that recognize β-cell specific proteins, which are likely the cells driving autoimmunity. Activated T cells are more frequent in the pLN of AAb+ and T1D donors compared to normal donors. Further, I have developed a novel cell culture technique that incubates pLN T cells with β-cells from the same donor, thus putting potential autoimmune T cells in direct contact with their β-cell target. With AAb+ donor tissues, I have observed T cells multiplying during incubation with β-cells, implying T cells are recognizing target β-cells. Future work will focus on deeper profiling of the immune cell landscape and β-cell specific T cells in pLNs, as well as further developing the β-cell – immune cell co-incubation method as a novel way to directly study immune attack of β-cells. With these collection of methods, novel insights into the immune system’s recognition and elimination of β-cells throughout diabetes onset may facilitate therapeutic insights targeting the immune system during T1D development.
Anticipated Outcome
It is anticipated that pancreatic lymph node T cells will be more activated, and β-cell targeting T cells will have more cytotoxic-like characteristics than the general T cell population, in autoantibody positive and recent onset T1D donor pancreatic lymph nodes (pLN). Further, pLN T cells from autoantibody positive and T1D donors will have a more significant proliferative and cytotoxic response when co-incubated with β-cells derived from the same donor.
Relevance to T1D
Type 1 Diabetes (T1D) occurs when otherwise healthy individuals, the majority of which are children, have an unknown pre-disposition that drives the immune system to attack β-cells in an autoimmune response. Unfortunately, T1D onset is difficult to detect, as it often develops over years’ time and diabetes symptoms only arise when almost all β-cells are eliminated. Understanding the immune system’s role in this process, and how it changes over time throughout T1D development, is critical to targeting therapies to immune cells that drive the elimination of β-cells. Recent evidence suggests that memory T cells in the pancreatic lymph nodes (pLN) are immune cells that facilitate β-cell attack and directly eliminate β-cells. My project focuses on these T cells and other immune cells that drive autoimmunity to β-cells.