Objective
Islet autoantibodies are used to predict type 1 diabetes (T1D) development and are currently the earliest indication that an attack on the beta cells has begun. Intervention therapies started after the appearance of islet autoantibodies can transiently delay the need for insulin, but no therapy to date has effectively prevented disease development. This is because the presence of islet autoantibodies themselves indicate that the immune response targeted by these therapies is already well underway. The objective of this proposal is to identify targets for earlier intervention, with a long term goal to achieve lasting prevention. Antibody production and changes in B cells are currently the earliest indicators of pending beta cell attack. In this project, we will identify key cells, signaling pathways, and triggers that promote islet antibody production, so that they can be targeted for earlier intervention. At the same time, understanding the events that precede antibody production will also foster the discovery of additional markers of T1D risk that can be used to improve identification individuals for therapy.
Background Rationale
In the United States, more than 15,000 children are diagnosed with type 1 diabetes (T1D) each year. Between 2001 and 2009, its prevalence in Americans under age 20 increased by 21%, and by 2050, the current prevalence estimate of 1-3 million T1D patients in the US is expected to triple. The economic burden for T1D-associated health care expenses is greater than $14 billion annually. A childhood diabetes diagnosis comes with the looming threat of cardiovascular disease, stroke, nephropathy, retinopathy, and other diabetes related complications; complications that can be delayed or avoided with strict adherence to intensive insulin regimens. Adherence to these regimens, however, is complicated by significant financial strain and high rates of stress, anxiety, and depression for families coping with T1D. The demands of these regimens are costly, complex, and difficult to maintain, and for some families, impossible to sustain. Therefore, in addition to providing life-changing health benefits, altering the onset and progression of T1D will inevitably provide significant economic, psychosocial, and public health benefits as well.
Teplizumab’s approval by the FDA to delay type 1 diabetes (T1D) onset marked the first therapy since the discovery of insulin to change the trajectory of disease. However, permanent delay and prevention of T1D remain elusive, and it is not effective in all individuals. We learned from teplizumab that targeting T cells earlier in T1D development, prior to the need to insulin, was more efficacious than doing so at onset, highlighting the importance of the timing of intervention. It is possible that by the time an individual with antibodies is treated with teplizumab, too much beta cell destruction has already occurred. In order to identify individuals at earlier timepoints for intervention, and to expand the options for intervention therapy, there is a critical need to understand what is happening to initiate the disease process in the first place.
Description of Project
In type 1 diabetes, immune cells that normally protect the body from infection and viruses mistakenly attack insulin-producing beta cells in the pancreas. The attack can last months to years, and it is not until most of the insulin-producing cells have been destroyed that symptoms develop (high blood sugars, frequent urination, weight loss), indicating the need for insulin. Antibodies are proteins found in the blood that signal that an attack is underway. They can be detected long before symptoms develop and long before the need to start insulin injections. In November 2022, the FDA approved the first ever treatment to slow the immune attack and delay the need to insulin injections in individuals who have multiple antibodies. However, the therapy does not work for everyone, and the length of delay is highly variable. One reason for this is that in some individuals, by the time antibodies are detected, too many beta cells have been destroyed, and intervention at that time is too little, too late. Though they appear before symptoms or the need for insulin, antibodies themselves indicate that immune cells have already started to attack beta cells. Longer delay and prevention may be possible with earlier intervention. Therefore, understanding the events that trigger the attack in the first place, and identifying individuals who are most at risk, is critical for improved outcomes with current therapies, and identification of new therapies for type 1 diabetes prevention.
Immune cells themselves, the signals they send to other cells, and the environments that condition them to attack, are all potential targets for intervention. This project will investigate each of those elements before and after antibodies appear in order to identify cells, signaling pathways, or other triggers to target for earlier intervention. During type 1 diabetes development, B cells make antibodies and contribute to disease by providing help to cells around them, encouraging them to attack. Changes in B cells are one of the first signs that an attack is about to start. We will uncover key targets in this process by asking first, what are the effects of the environment on B cell function before and after antibody production? Second, what are the signaling pathways needed to trigger responses in B cells? And finally, what other markers can be detected, before antibodies, to signal an attack is imminent? Systematically addressing each of these questions will uncover new targets for intervention and earlier markers of risk so that the right interventions can be given to the right people at the right time – and long before the need for insulin – in order to achieve lasting prevention.
Anticipated Outcome
The data obtained in these studies will answer key questions about the events that occur before islet autoantibody production. We expect to demonstrate that how B cells use energy (B cell metabolism) impact how they function. As a result, targeting metabolic pathways in B cells has the potential to change B cell function and prevent self-destructive responses. By answering the questions asked in this proposal, we anticipate identification of new targets for intervention and prevention therapy in type 1 diabetes, in addition to the identification of novel markers that can be detected in the blood and used to identify individuals at high risk for disease, even before antibodies can be detected in the blood.
Relevance to T1D
Since the discovery that type 1 diabetes (T1D) was immune-mediated, we have been attempting to modulate the immune system to change the trajectory of disease. While teplizumab’s approval has changed the landscape of type 1 diabetes care, it has not yet been shown to prevent disease, provide lasting remission, or to help individuals already diagnosed with T1D achieve insulin independence. Understanding the events that occur during the first triggers of T1D development is critical for identifying alternative targets for therapy and for identifying individuals prior to significant beta cell destruction.