Objective
Our team has discovered that by turning on a switch, named the neuropeptide Y5 receptor (Y5R), in some immune cells in the pancreas, we can protect the cells that make insulin. This discovery could help prevent T1D by stopping beta-cells being attacked by the person’s immune system. Our key objective is to understand fully how this happens. To then show it works in human islets and then prove it can work at stopping T1D in animal models of T1D. We are a diverse team of experts with complementary skills that allow us to work efficiently and effectively towards our goal. To achieve our key objectives, we have laid out the following steps:
1. Establish a good understanding of how our approach works: We will carry out in-depth studies to understand how activating the switch in immune cells living in the islet protects beta-cells and stops the immune cells attacking the islet. By investigating the important effects involved we will gather information that will help us evaluate the medication's effectiveness in future clinical trials. We will also expand our research to human cell cultures, which will give us insights into how the medication can prevent immune cells from attacking the insulin-producing cells in people.
2. Demonstrate the potential of our treatment to prevent T1D: An important step in our research is to provide evidence that our medication can prevent or delay the onset of T1D using animal models. This will allow us to understand the key processes involved and compare our findings with those from our mouse and human cell studies.
Our interdisciplinary team's collective expertise will enable us to make significant progress in a timely manner, ultimately advancing the potential of our strategy as a novel approach for the prevention of T1D.
Background Rationale
Islets are small clusters of cells that produce hormones, including insulin. Alongside these hormone-producing cells, there is a small number of supporting immune cells. Among these immune cells, macrophages play a crucial role. They help maintain a healthy environment within the islet and contribute to various processes, such as the development of insulin-producing cells and managing inflammation.
In T1D, macrophages are key players in disease development. They are involved in attracting harmful immune cells into the islets, which leads to the destruction of insulin-producing cells and the development of diabetes. Studies in mice have shown that when these macrophages are removed, type 1 diabetes can be prevented. This suggests that by changing how the macrophage behave, we may be able to delay or prevent the onset of T1D.
We have identified a potential switch for modifying the activity of the macrophages’, a specific signalling protein on their surface, also called a receptor. By activating this switch our data shows we can protect insulin-producing cells in both mice and human islets. Importantly, we have also shown that activation of the switch can shift macrophages to an anti-inflammatory state, which is good for preserving insulin-producing cells, and the activation stops the migration of harmful immune cells into the islet in laboratory experiments.
These findings offer hope for the development of new strategies to prevent or delay the onset of T1D. By targeting the immune cells within the islet, particularly macrophages, using specific drugs, we may be able to disrupt the harmful immune responses that lead to the destruction of insulin-producing cells. While more research is needed to confirm these findings and explore their potential in clinical settings, they provide exciting possibilities for advancing T1D prevention and improving the lives of those at risk of or living with T1D.
Description of Project
Globally, there are 10.9 million people living with Type 1 Diabetes (T1D), a condition where the body's own immune system mistakenly destroys insulin-producing cells. Unfortunately, there are currently no treatments available to prevent T1D. However, there has been a recent breakthrough with the approval of teplizumab, an antibody that can delay the onset of T1D, which gives hope for prevention efforts.
In our research, we focus on a unique target for delaying or preventing T1D: a specialised immune cell called a macrophage. These cells are like security guards, constantly patrolling and protecting different parts of our body from harmful invaders. Some of these cells live within the islet and play a critical role in the initial immune response that leads to T1D. Importantly, when these resident cells are absent, diabetes does not develop in mice. This suggests that by changing how the immune cells that live in the islet behave, we may be able to delay or prevent T1D.
We have discovered these cells display a specific switch. In laboratory studies, we can activate this swich using a drug. This signal tells the cells to protect the insulin producing beat-cells, reducing harm and preventing attacks from the body’s defences. Our research team consists of experts with complementary skills and diverse backgrounds. Together, we aim to uncover the precise mechanisms by which activation of this switch protects insulin-producing cells in both mice and human cell models. Additionally, we will conduct experiments to demonstrate the effectiveness of this strategy in preventing the onset of T1D in animal models.
Our goal is to begin the development of a therapeutic product that can be tested in clinical trials. Through our research, we hope to contribute to the development of new strategies for delaying or preventing T1D, bringing us closer to a world where this autoimmune condition can be managed more effectively or even prevented altogether.
Anticipated Outcome
In our research, we are focusing on a specific group of immune cells called resident macrophages (MΦ) that are found living in the islet. These cells play a role in calling toxic immune cells to the pancreas at the start of T1D and can kill insulin-producing cells. We have discovered a specific switch on these resident cells. By activating this switch using a drug, we can change the behaviour of these immune cells. The drug promotes a state in the macrophages that is reparative and anti-inflammatory, meaning they help to reduce inflammation and support healing processes.
What's exciting is that when we use this drug, it not only protects the insulin-producing cells but also prevents toxic immune cells from entering the pancreas and causing further damage. This is important because immune cell infiltration into the pancreas is a key step in the development of T1D. Overall, our research has several expected outcomes. We anticipate developing a stratgey that can selectively activate the beneficial receptor displayed by macrophages. We also aim to gain a full understanding of how activating this switch modifies macrophage function and protects beta cells. Additionally, we will provide proof-of-concept evidence showing the preventive effects of our medication in animal models of T1D. This research is ground-breaking as it represents the first drug based strategy to modify macrophage function for the prevention of T1D.
Relevance to T1D
Globally, there are 10.9 million people living with Type 1 Diabetes (T1D), a condition where the body's own immune system mistakenly destroys insulin-producing cells (Beta-cells). Unfortunately, there are currently no treatments available to prevent T1D. However, there have been recent breakthroughs. For example, the recent approval of teplizumab, an anti-CD3 antibody which can delay T1D in some people [1], and the positive data emanating from the phase 2 trial of the Janus Kinase inhibitor Baricitinib [2] are a step towards prevention. Our application proposes to begin the development of a new medication that may reduce or prevent the immune system from attacking and destroying the beta-cells. It represents the first pharmacological strategy to modify the function of immune cells that live in the islet for the prevention of T1D. This contrasts with current strategies which all focus on switching off the function of these recruited cells and not the initiating signal. To do this they employ relatively broad-spectrum immune suppression which has significant drawbacks. It may be possible by targeting the Y5R in macrophages we can avoid this drawback.