Objective
The goal of this JDRF fellowship is to understand the communication between different cell types in the pancreas and the immune system, with the aim of finding ways to protect beta cells and reduce the autoimmune response in type 1 diabetes (T1D). The objective is to study factors secreted by islet cells and how they influence immune cell response.
Specific Aim 1: To determine how the hormones produced by cells in the pancreas influence the metabolism and function of immune cells. We believe that changes in the production of these hormones can affect the behaviour of immune cells and contribute to the development of T1D. By examining the effects of these hormones on immune cells, we can gain insights into their role in the disease.
Specific Aim 2: To understand how purines, which are molecules produced by dying cells in the pancreas, impact the metabolism and function of immune cells. Certain receptors on immune cells respond to purines, and we hypothesize that the purines produced by stressed or dying beta cells in response to stress have a significant effect on immune cell behaviour. By pharmacologically targeting intracellular pathways that make or breakdown purines, we can determine the influence of these molecules on immune cell function.
Specific Aim 3: To characterize how the release of building blocks of proteins, called amino acids (AAs), by the pancreatic islets affect immune response. AAs have been shown to influence immune cell metabolism. We believe AAs released by the islet cells play a role in fueling the autoimmune response in T1D and creating an environment that promotes inflammation.
Specific Aim 4: To characterize mitochondrial transport between beta cells and immune cells. Mitochondria, the energy factories of the cell, are essential in the modulation of immune cell function. Mitochondria can be released from a cell in situations of stress. We will determine whether and how mitochondria are transported between beta cells and immune cells, and how this influences immune cell metabolism and function during T1D.
Background Rationale
Type 1 diabetes (T1D) is an autoimmune disease where the immune system attacks and destroys insulin-producing cells in the pancreas. This leads to a loss of insulin production, high blood sugar levels, and an increased risk of complications. Children with T1D must constantly monitor their blood sugar levels and administer insulin. In T1D, immune cells within the pancreas, called macrophages and T cells, become overly active and cause inflammation. The remaining insulin-producing cells in individuals with T1D are not functioning properly and are under stress. These stressed cells communicate with nearby immune cells, releasing signals that can either promote inflammation or support the healing process. The exact impact of these signals on the immune cells and how they contribute to T1D is not yet fully understood.
Macrophages are immune cells responsible for clearing out waste and fighting infections. In T1D, inflammatory macrophages are thought to trigger autoimmunity. They increase their use of glucose while decreasing the activity of their mitochondria, an energy-producing organelle known as “the powerhouse of the cell”. The metabolic pathways used by macrophages in T1D are still not well known. T cells, another type of immune cell, also play a role in T1D. The metabolic pathways of T cells change when they are activated, and this affects their function. After the immune response, some T cells become memory cells, which have different metabolic profiles. Understanding how these metabolic pathways are regulated in T cells and how they are influenced by signals from the pancreas is important for developing therapies to minimize autoimmunity and promote tolerance.
Mitochondria, the cellular energy factories, can be transferred between different cells and cell types. This process of mitochondria transfer has been observed in various diseases and is associated with changes in the recipient cells, altering their metabolism. We believe that mitochondria released by live or dying cells within the pancreas could directly affect the local immune response in T1D.
We hypothesize that metabolic pathways in immune cells in the pancreas can be strongly influenced by the local environment within the islet and that a better understanding of these pathways may elucidate new therapeutic options to combat T1D.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease that occurs when the immune system attacks and destroys the beta cells in the pancreas. Beta cells are responsible for producing the hormone insulin, which regulates the levels of sugar in the blood. There is currently no cure for T1D. The immune system is responsible for protection of our bodies against infections and cancers. Immune cells are very sensitive to changes in the levels of sugar and other nutrients in the body, which changes in T1D.
In this proposal, we will study how immune cells and cells in the pancreas communicate. This will enable us to understand why the immune system ends up killing our own insulin-producing cells, leading to T1D. We propose that changes in the nutritional environment surrounding beta cells may increase the response by immune cells, inducing an exaggerated immune attack and loss of beta cells. So, we will study nutrients and other factors that are secreted by beta cells and how these factors are received and metabolized by immune cells. We will study factors released by healthy beta cells, beta cells in diabetes, as well as beta cells that have been through metabolic stress such as high and low levels of sugar, or stress induced by factors produced by immune cells that attack the beta cells. We will analyze how immune cells become activated after being exposed to these factors and try to turn off the pathways that are 'switched on' in immune cells in contact with stressed beta cells.
Our project aims to identify new ways to control and slow down the progression of T1D by focusing on the interaction between immune cells and beta cells in the pancreas. We hope to gain a better understanding of how changes in metabolism in immune cells may lead to the immune attack on beta cells in T1D, and design ways to alter these metabolic pathways in immune cells to prevent or slow T1D.
Anticipated Outcome
Our research aims to investigate how factors released by cells in the pancreas, including hormones, metabolites, and mitochondria, impact the metabolism and function of immune cells in the pancreas. Specifically, we are interested in understanding their effects on macrophages and T cells in type 1 diabetes (T1D). This knowledge will provide valuable insights into the changes that occur in immune cell metabolism in T1D and their contribution to the disease. Ultimately, given the proven efficacy of immunometabolic targets in other diseases, our findings could pave the way for new therapies targeting metabolic pathways in T1D.
Relevance to T1D
Type 1 diabetes (T1D) is an autoimmune disease that was once called juvenile diabetes because it is primarily diagnosed in children. It is a chronic condition, in which insulin-producing beta cells in pancreatic islets are destroyed by the immune system, leading to loss of insulin production and severely impacting blood glucose levels. Poorly controlled blood glucose can lead to serious complications later in life, including but not limited to damage to blood vessels, eyes, heart, and nerves. Children with T1D face a lifetime of monitoring blood sugar and administering insulin by injection or pump.
It is estimated that around 86,000 children worldwide develop T1D each year, and in Canada approximately 30,000 children are currently living with T1D. As imposing as these numbers may seem, there is currently no cure for diabetes. We aim to characterize how factors secreted by islet cells, including beta cells, influence the metabolism and function of immune cells, including macrophages and T cells, in health and diabetes. This research promises new insights into how islet immune cell metabolism may change in T1D and contribute to T1D and will move us closer to new therapies that target immune cell metabolism in T1D.
This work has high relevance to the goals of JDRF as it may lead to the discovery of new diagnostic approaches, therapies, and blood biomarkers for T1D, with the potential to improve the lives of thousands of children and families affected by T1D worldwide.