Objective
The objective of this project is to develop an assay that will allow clinicians to routinely measure T-cell responses that both cause and work to protect people from developing T1D. Our goal is to measure both the ‘good’ and the ‘bad’ T cell responses at the same time. This long-sought goal has been particularly challenging because the T cells that respond to parts of the insulin producing beta cells are very rare in the blood. Despite this, we and other researchers have developed assays to measure these responses in the past. Unfortunately, none of the previous assays have been suitable for routinely assessing T cell responses in the clinic. This is because all of the earlier assays require large volumes of blood (>25mL), highly skilled scientists to perform the assay and highly skilled scientists to analyse the results.
Our goal here is further develop our assay. We aim to further optimise the assay so that is requires even less blood (~4.0-8.0mL). We are also working on the mix of T-cell targets that we use with the goal of making the assay better at distinguishing between people with and without T1D. Ongoing work will focus on producing a stable and reliable assay which can be used in a busy clinical setting. We are very excited about the potential for this assay to help clinicians develop and monitor new immune therapies for T1D. For this reason, our goal is to develop this assay commercially so that it will become widely available to the T1D community as quickly as possible.
Background Rationale
Type 1 diabetes (T1D) develops when the immune system’s T cells destroy the insulin-producing cells found in the pancreas. A major focus of current research is on finding ways to attenuate the immune response that causes T1D with the goal of preventing or reversing the condition. These efforts have been frustrated by our inability to routinely measure the activity of the T cells that respond to insulin producing beta cells. While we have known for decades that it is the immune system’s T cells that are responsible for destroying the insulin-producing cells we have not been able to routinely measure the activity of these cells. Instead, clinicians and researchers have had to measure changes that occur ‘downstream’ such as changes in glucose metabolism, or beta-cell mass (via C-peptide). Currently, the only component of the immune responses that clinician can routinely measure is antibodies that recognize components of the insulin-producing cells. Measuring islet autoantibodies can identify individuals who may have an otherwise undetected autoimmune response against their beta cells, but it gives no insight into the nature of the T-cell response and gives only a very vague indication as to when/if a person may develop T1D. For these reasons there has been for many years, an urgent need for an assay that can measure the number and function of human T cells that respond to components of the insulin-producing beta cells.
Researchers, including us, have developed methods to measure beta-cell antigen specific T cells. These innovative assays have been useful research tools, but none of them have been suitable for routine monitoring in the clinic. These ‘research’ assays all require large volumes of blood and are very complex to set up and analyse. This prompted us to look for simpler ways to measure human T cell responses against beta cells. We’re very excited by the progress we’ve made towards this goal and now seek support to move this assay forward towards the clinic by developing it commercially.
Description of Project
Type 1 diabetes (T1D) develops when the immune system’s T cells destroy the insulin producing cells found in the pancreas. We have known for decades that it is the immune system’s T cells that are responsible for destroying the insulin-producing cells. However, we have not been able to routinely measure this unwanted, T-cell mediated, immune response in a clinical setting. Currently, the only component of the immune responses that clinician can routinely measure is antibodies that recognize components of the insulin producing cells. Measuring islet autoantibodies can identify individuals who may have an otherwise undetected autoimmune response against their beta cells, but it gives no insight into the nature of the T-cell response and gives only a very vague indication as to when/if a person may develop T1D.
The goal of this application is to commercially develop an assay that will allow clinicians to routinely measure T1D-causing T-cell responses. This long-sought goal has been particularly challenging because the T1D-causing T cells are very scarce in the peripheral blood. We have taken advantage of new technologies that allow us to measure immune responses by very few immune cells. We and other researchers have developed assays to measure these responses in the past, but none of the previous assays were suitable for routine measurements in a clinical setting because they all require: large volumes of blood, highly skilled scientists to perform the assay and highly skilled scientists to analyze the results. This assay will be a powerful tool for monitoring changes in the T1D-promoting T-cell responses.
We foresee the assay being a valuable tool in clinical trials of experimental immune therapies intended to prevent, or reverse T1D. It will also allow improvements in the diagnosis of T1D, particularly predicting when a person who has autoantibodies, will develop T1D and require insulin injections. Furthermore, it will help clinicians with patients that have other forms of diabetes by allowing them to determine whether or not these people have beta-cell autoimmunity. This insight will indicate if the person has T1D or another form of diabetes, such as MODY (Monogenic Diabetes of the Young) or type 2 diabetes.
Anticipated Outcome
Upon completion of this project we will have developed a simple whole blood assay that is capable of measuring T1D T-cell responses. During the course of this project we will optimize this assay. Specifically, we will define a set of targets that are recognized by T1D-promoting T cells. We will formulate a pool of these targets which will allow us to reduce the volume of blood required to do the assay. The assay will allow clinicians, for the first time, to measure T1D responses at the same time. The assay is very simple to set up, requires a small volume of blood and samples for analysis can easily be frozen and shipped for analysis. The assay will greatly improve the efficiency of clinical trials of immune therapies intended to prevent or reverse T1D.
This assay will be a valuable tool in clinical trials that are testing experimental therapies for preventing or reversing T1D. The assay will allow more accurate characterisation of the participant’s T-cell response against their beta cells at the start of the trial and measurement of the impact of the therapy on beta-cell specific T-cell responses during, or at the conclusion of the treatment period. This will greatly reduce the time required to run trials and the number of participants that need to be recruited.
Our assay will support the preclinical diagnosis of T1D which currently relies solely on the measurement of beta-cell antigen specific autoantibodies. The assay will allow endocrinologists to more accurately predict when a person will progress to stage 3 T1D. This will allow the identification of individuals who are most likely to benefit from immune therapies.
The assay we are developing will be a powerful research tool. It will allow researchers to rapidly evaluate beta-cell specific T-cell responses in research participants and to monitor changes in beta-cell specific T-cell function over time.
Relevance to T1D
This project is directly relevant to, and focuses entirely on, type 1 diabetes. This type of whole blood assay was recently developed for diagnosing coeliac disease, an immune disease triggered by immune responses to components of bread flour. We are the first to develop and apply this approach to type 1 diabetes. Our assay will meet a long-unmet need in T1D, specifically allowing clinicians to monitor changes in the T-cell responses against components of the insulin-producing cells. This will be an important contribution to developing safe and effective immune-based therapies to prevent and reverse T1D.