Objective
Our research has shown that targeting the protein ABHD11 can suppress overactive immune responses in T1D. Given that ABHD11 plays a key role in how T-cells generate energy, we believe it may be a promising target for new immunosuppressive therapies. We aim to build on this finding through the following research objectives:
Objective 1: Understanding How ABHD11 Inhibitors Affect Immune Cells in People With and Without Type 1 Diabetes
We aim to understand how altering ABHD11 activity, changes the behaviour of immune cells in adults with T1D compared to those without T1D. To do this, we will collect blood samples from several groups of people:
• Those recently diagnosed with T1D (within the last year),
• Those with intermediate-duration T1D (1–3 years since diagnosis),
• Those with long-standing T1D (over 3 years),
• Age- and sex-matched individuals who do not have T1D.
From these samples, we will isolate different types of immune cells including T-cells, B-cells, and natural killer (NK) cells, all of which contribute to damaging the insulin-producing cells. These cells will be exposed to different inflammatory mediators, mimicking how they would behave to cause T1D, in the presence or absence of new ABHD11-blocking drugs in the lab.
We will then assess a wide range of immune cell responses, including:
• Changes in the immune cells ability to promote inflammatory and anti-inflammatory responses and how they do this,
• Shifts in energy use and metabolism, using advanced technologies to analyse the fuels and proteins the immune cells rely on,
• Differences in immune cell response based on personal characteristics, such as:
- Age,
- Sex,
- Body Mass Index (BMI),
- C-peptide levels (which reflect remaining insulin production),
- HLA genotype (a genetic marker of immune risk),
- Duration of T1D.
This approach allows us to identify whether certain subgroups of people respond more strongly or more safely to ABHD11 inhibitors. The ultimate goal of this objective is to determine whether this treatment could be universally used for all people living with T1D or whether it should be preferentially tailored to specific groups living with T1D (personalised therapy).
Objective 2: Testing ABHD11 Inhibitors in Mouse Models to Evaluate Their Potential as a Treatment for T1D
To understand how ABHD11 inhibitors behave in living systems, we will test our newly developed, safer ABHD11-blocking drugs in mouse models of T1D that closely mimic human T1D. This will allow us to get vital information (as outlined below) prior to testing these drugs in humans in the future.
These experiments will help us:
• Evaluate how effectively the drug slows or prevents diabetes, by measuring blood glucose levels, insulin production, and the date of T1D diagnosis,
• Examine the immune response in detail in tissues we can’t access in living humans, including whether treated mice show reduced immune cell activation and inflammation in the pancreas,
• Monitor for side effects or unintended immune responses, ensuring the treatment remains targeted and safe.
By comparing different ABHD11 inhibitors, in both human cell experiments and mice, we will identify the most promising candidate(s) for future clinical studies. This includes selecting drugs that show strong anti-inflammatory effects, minimal toxicity, and good stability in the body. Together, these studies will give us a comprehensive view of how ABHD11-targeting therapies work from detailed effects in individual human cells to outcomes in the whole-body system of a living animal, providing strong evidence to move this forward into human clinical trials/studies.
Background Rationale
T1D is a lifelong autoimmune condition that affects millions of people around the world, and is caused when the immune system destroys the insulin-producing cells in the pancreas. While insulin is used to treat people with T1D, it is not a cure. Thus, there is a critical need for new therapies that can slow or stop the autoimmune attack itself.
In recent years, scientists have discovered that the energy needs of immune cells, particularly T-cells, play a key role in how the T-cells (an immune cell) behave during an immune response. When T-cells detect something harmful, such as a virus, they become inflammatory and need large amounts of energy to clear the virus. During this immune response, the T-cells change how they process nutrients like sugars, fats, and proteins in order to support their ability to protect the individual from the virus. This process is known as metabolic reprogramming.
In autoimmune diseases like T1D, T-cells undergo this metabolic shift even though they are responding to the body’s own healthy tissues. This change in T-cell metabolism promotes the damaging inflammation that leads to the T-cells destroying the insulin-making beta-cells. Therefore, one potential strategy to prevent T1D is to block or alter the way these cells utilize nutrients.
ABHD11 is found inside the mitochondria, known as the “energy powerhouse”, of cells and helps control a key part of energy production called the TCA cycle. Our earlier studies found that in inflammatory T-cells, ABHD11 activity increases; however, when we used a drug to stop ABHD11 activity, the T-cells became less inflammatory. Even more exciting, when we tested this approach in mice that normally develop accelerated T1D, those treated with the drug to stop ABHD11 activity developed T1D much more slowly or not at all.
These early findings suggest that ABHD11 may be an important potential therapeutic target to reduce the immune system’s attack on the pancreas in T1D. However, the drugs we used in these experiments were not safe enough to use in humans. Now, we are developing new, safer drugs that still stop ABHD11 activity but do not contain toxic chemical groups that could be used in the future directly in humans.
Our current proposal aims to fully understand confirm these new drugs work and whether they could be used as a potential treatment for people with T1D.
Our project is focused on exploring this in two ways:
1. Studying how human immune cells respond to blocking ABHD11 activity, comparing immune cell responses in people with and without T1D to find out who might benefit most from this type of treatment.
2. Testing the most promising drugs in animal models of T1D, to make sure the drugs are effective and safe before considering their use in clinical trials in humans.
By better understanding how ABHD11 controls immune cell behaviour and how we can safely interrupt that process by stopping ABHD11 activity, we hope to uncover a new, targeted way to treat T1D.
Description of Project
Type 1 Diabetes (T1D) is caused by immune cells known as T-cells, which usually protect the body against infections, mistakenly damaging and destroying the insulin-producing beta cells in the pancreas. During a normal immune response to infection, T-cells undergo tightly controlled metabolic shifts, altering how the T-cells process nutrients like sugars and proteins to support their activity. In autoimmune conditions like T1D, these metabolic changes become dysregulated, leading T-cells to cause harm instead of protection. Therefore, targeting these altered metabolic pathways therapeutically, to prevent the T-cells from damaging the insulin-producing beta cells, may provide a novel therapeutic strategy for treating T1D.
We have identified a protein called alpha/beta hydrolase domain-containing 11 (ABHD11) that plays a role in regulating metabolism in T-cells as a potential therapeutic target to prevent T1D. ABHD11 is involved in a key step of energy production within T-cells and may contribute to whether these T-cells become damaging to the insulin-producing beta cells. Interestingly, T-cells from individuals living with rheumatoid arthritis (another autoimmune disease) in remission (i.e. those with no clinical signs or symptoms) show lower levels of ABHD11 compared to those with active inflammatory disease (where clinical signs/symptoms are present). This suggests that ABHD11 may contribute to the disease-driving activity of T-cells, although its role is not yet fully understood.
We propose that targeting ABHD11 could modulate energy production in T-cells, potentially leading to anti-inflammatory effects, preventing T-cell-targeted destruction of the insulin producing cells. Encouragingly, our early experiments show that blocking ABHD11 (using a drug called an inhibitor) in T-cells from people living with T1D reduces harmful inflammation. In addition, treating mice that develop accelerated T1D with a similar ABHD11 inhibitor delays diabetes development. Both of these results point to ABHD11 as a promising novel therapeutic target in T1D.
The drugs used in our preliminary studies to stop ABHD11 activity contain a chemical group that is toxic and unsuitable for development into treatments for human use. The aim of this project is to identify and evaluate new, safer compounds that target ABHD11 without including this harmful group. We will investigate the broader impact of these candidate drugs in the context of T1D. This will involve studying immune cells (such as T-cells) from individuals living with T1D to assess how stopping ABHD11 activity influences their responses (i.e. inflammatory vs anti-inflammatory). We will include adults recently diagnosed (within 1 year) with T1D, those diagnosed with T1D 1-3 years ago, and those with established T1D (over 3 years post-diagnosis). Study participants will be age- and sex-matched with people who do not have T1D to compare how stopping ABHD11 changes the immune responses between those with and without T1D. Using advanced techniques, we will analyse changes in immune cell metabolism and protein expression that shape immune cell behaviour. Furthermore, we will also consider how different factors like age, sex, genetics, BMI, insulin production, and how long someone has had T1D affect the response to ABHD11 inhibition. This will help us understand which people might benefit most from this potential treatment. Finally, we will test the most promising drugs in a mouse model of T1D to evaluate their potential clinical relevance at delaying/preventing the development of T1D.
Overall, this research aims to determine which ABHD11 inhibitors work the best at controlling the inflammatory immune cells and whether inhibiting ABHD11 could be a new treatment for T1D.
Anticipated Outcome
This proposal aims to explore a new and innovative way to treat type 1 diabetes (T1D) by specifically targeting how the immune system uses energy to prevent the immune cells destroying the insulin-producing cells.
Our research focuses on a protein called ABHD11, which plays a role in how immune cells, particularly T-cells produce energy when they are responding to potential threats. T-cells are usually responsible for defending the body against viruses and bacteria, but in T1D, they mistakenly attack the healthy insulin-making cells in the pancreas. We have discovered that ABHD11 helps control energy production in T-cells and that when ABHD11 activity is stopped, the T-cells become less inflammatory. Based on our early findings, we believe that safely targeting ABHD11 may be a promising strategy to reduce or even prevent the immune attack that causes T1D. Over the course of this proposal, we aim to achieve the following key outcomes:
1. Development and Testing of Safer ABHD11-Blocking Drugs
In our earlier work, we used a drug that successfully blocked ABHD11, but it contained a chemical group that is too toxic for human use. In this project, we are testing new and safer versions of that drug—compounds that retain their ability to stop ABHD11 activity, but are better suited for potential clinical use.
We expect to:
• Identify one or more drug candidates that are effective at reducing immune activity,
• Show that these drugs can reduce inflammation and detrimental T-cell activity, while also evaluating how other immune cells may be altered,
• Demonstrate that the drugs are safe and stable enough to move toward clinical trials in the future.
2. Better Understanding of How ABHD11 Affects the Immune System in T1D
One of the first goals is to see how stopping ABHD11 activity impacts different types of immune cells from people with and without T1D. We will examine immune cells from adults who have been recently diagnosed with T1D (within 1 year of diagnosis), and those who have lived with T1D for many years, alongside people living without T1D, and study how their immune cells respond to these new, safer ABHD11-targeting drugs.
We anticipate that:
• Immune cells from people with T1D will respond differently than those from individuals living without T1D.
• The degree of response to the drugs may vary depending on factors like age, sex, how long someone has had diabetes, and how much insulin they still produce.
• These results will help identify who may benefit the most from this type of therapy.
3. Testing the Drugs in a mouse model of T1D
To evaluate how well the most promising drugs work in a living system, we will test them in a well-established mouse model of T1D. These mice naturally develop T1D, making them ideal for studying potential treatments that could stop or delay T1D development.
We hope to find that:
• Treatment with ABHD11-targeting drugs delays or prevents the onset of diabetes in these mice,
• The immune system becomes less aggressive, with fewer inflammatory immune cells attacking the pancreas,
• There are no major side effects, showing that the treatment could be safe for further testing in humans.
In Summary, if successful, this project could provide the foundation for a new way to treat T1D. This approach in the future could:
• Slow or stop disease progression, allowing people with T1D to maintain some of their own insulin production,
• Potentially offer a personalised treatment option, should a subgroup of people be identified as being responsive to the drugs, so that anyone who does respond favourably could receive the treatment.
Relevance to T1D
T1D occurs when the immune system mistakenly attacks the insulin producing beta cells in the pancreas, leading to insufficient insulin production and the need for insulin injections. Despite improvements in insulin delivery and blood sugar monitoring, insulin therapy remains a daily challenge for millions and does not stop the immune attack on the pancreas. Therefore, scientists are urgently seeking new therapies that can slow or halt the autoimmune response. Understanding how the immune system becomes harmful in T1D is critical to developing these therapies.
This proposal explores a promising new strategy: targeting the metabolic processes, that is, how immune cells produce and use energy, which support their harmful activity.
Why focus on immune cell metabolism?
T-cells are key defenders against infections and cancer, but in T1D, some become autoreactive and mistakenly attack the body’s insulin producing cells. When activated, these T-cells shift their metabolism, increasing how they process sugars and nutrients in our diet to fuel the attack.
This metabolic shift, normally tightly controlled, becomes dysregulated in autoimmune diseases like T1D, driving T-cell harm. Targeting the metabolic proteins that power autoreactive T-cells may reduce their damage without suppressing the entire immune system, offering a more precise and safer treatment for T1D.
The role of ABHD11 in T1D
ABHD11 is a protein involved in controlling a key step in cellular energy production within the mitochondria. Our early research shows ABHD11 activity increases in inflammatory T-cells, and that blocking it in human T-cells reduces inflammation. In mouse models of T1D, inhibiting ABHD11 delays disease onset, suggesting it plays a key role in driving the harmful immune response.
What makes ABHD11 especially promising is that it represents a new, previously untargeted approach to T1D therapy. Unlike general immune suppression, targeting ABHD11 could selectively cut off energy to harmful T-cells while sparing healthy immune function.
How this project addresses key challenges in T1D treatment
Although teplizumab, developed in the US, is a major advancement in delaying T1D, current treatments still do not directly address the root immune dysfunction. Our project seeks to fill this gap by
• Developing safer, more effective drugs that inhibit ABHD11 without harmful side effects
• Studying how these drugs affect immune cells from people with T1D across different disease stages and backgrounds
• Testing these compounds in animal models to confirm they can safely delay or prevent T1D
This work will yield critical insights into how immune metabolism contributes to T1D and assess whether targeting ABHD11 could be a viable treatment to prevent or delay the disease.
Potential impact on people living with T1D
If successful, this research could create a new class of treatments that halt or slow the autoimmune attack. This could
• Help people retain their own insulin production longer, reducing reliance on insulin therapy and lowering the risk of serious complications
• Enable more personalized treatments based on factors like age, sex, genetics, and disease stage, ensuring therapy reaches those most likely to benefit
Conclusion
This project addresses a central problem in T1D, the faulty immune response that destroys insulin producing cells. By focusing on ABHD11, a new target that controls immune cell energy use, this work could lead to breakthrough treatments that stop or delay T1D development, offering real hope to millions affected by the disease worldwide.