Objective
Currently, insulin is the only therapy for T1D. We’re working towards developing an intervention that acts early in the disease process to slow or halt the immune attack that causes T1D, before insulin injections are required. One problem with the immune therapies currently in development is that they will require ongoing, or potentially indefinite, use/administration. Hence, our objective is to develop an immune therapy that resets the immune system after a small number of treatments. More specifically, we will particularly focus on resetting the immune response by exhausting T cells that target the insulin secreting beta cells.
Our team will do this by pursuing three goals.
(i) Investigating exhausted T cells in preclinical models of diabetes, and in the islets and blood of people with T1D, we aim to identify a characteristic ‘signature’ for these cells in T1D. Once we have defined this ‘signature’ we will be able to measure the degree to which T cells are exhausted in samples from people, such as people in a clinical trial of an antigen-specfic therapy intended to prevent T1D by exhausting the relevant T cells . Our investigations will also lead to a deep understanding of the best way to achieve specific T-cell exhaustion.
(ii) A person’s immune system has 100s of millions of T cells. However, very, very few of them contribute to T1D-only the ones that ‘recognize’ and ‘attack’ the beta cells. Hence our challenge is to target just those T cells that destroy the insulin-producing beta cells. We can do this by identifying the exact targets that the disease-causing T cells ‘see’. We call these epitopes. We were the first to isolate and analyze human T cells from within the pancreatic islets of organ donors who had T1D. We will use this expertise to identity those epitopes that are most closely associated with T1D.
(iii) One of the unanticipated benefits of the Covid-19 pandemic has been the rapid development and clinical application of mRNA vaccines. For Covid-19, or any infection, the aim is to ‘prime’ the immune response to protect from a future infection. In autoimmune disease we want to ‘turn off’ an already existing immune response. Remarkably, current evidence suggests that making some changes to the composition of an mRNA vaccine can induce exhaustion, thereby ‘turning off’ T cells that recognize a particular antigen or epitope.
Hence, our goal is to combine our expertise in these three areas to bring forward an antigen specific therapy to prevent T1D by driving the T1D causing T cells to exhaustion.
Background Rationale
Nowadays we’re very good at manipulating the immune response. This is how vaccines that protect us from infectious diseases work. They ‘show’ the immune system bits of a virus or bacterium and ‘teach’ it that it should respond very aggressively if it ‘sees’ these components again; ie when the virus/bacterium invades the body in an attempt to cause an infection.
In an autoimmune disease, like T1D the immune system’s T cells mistakenly destroy the insulin-producing beta cells. Here we want to stop an existing, harmful, immune response. While the aims may seem to be opposing, the same principals used to develop vaccines against infectious diseases apply to developing a vaccine to prevent T1D: define the type of immune response we want to induce, find the appropriate targets and ‘show’ them to the immune system in a way the elicits the desired response.
We know that cancers and chronic viral infections escape immune attack by inactivating the immune system’s T cells. In these diseases, prolonged contact between the T cells and their targets causes the T cells to become ineffective. We describe these T cells as exhausted because they have been working hard to rid the body of the cancer or virus, but are unable to do so and then become functionally impaired. Here we ask: does T cell exhaustion play a role in T1D? And why don’t the T cells that cause T1D become exhausted? Would driving T1D-causing T cells to exhaustion prevent or delay the progression of the disease?
Here we develop a new approach to preventing T1D by driving beta-cell antigen specific T cells to exhaustion.
Description of Project
Cancers and chronic viral infections escape attack from the immune system by inactivating immune cells called T cells. In these diseases, chronic antigenic stimulation causes T cells to become functionally impaired and these are termed exhausted T cells. When T cells are exhausted, they are no longer able to mount an effective immune response, leading to a decrease in the body’s ability to fight off the infection, or cancer. T-cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear if and how T-cell exhaustion controls progression of T1D and whether this process can be harnessed to prevent diabetes.
Here our goal is to exhaust the T cells that ‘see’ the insulin-producing beta cells that cause T1D. We reason that, unlike in infections and cancer, T cell exhaustion will delay beta-cell destruction and the onset of T1D. We don’t want to exhaust all the T cells, just the ones that ‘see’ the insulin-producing beta cells. One way to do this is called antigen specific therapy. This is when the targets of the T cell response are themselves used in a type of vaccine. This dampens the T1D-causing immune response in a highly selective way. The great advantage of this approach is that it leaves the rest of the immune responses unaffected and fit to protect us from infections and cancers. To achieve this we need to know what exhausted T cells look like in the context of T1D, what the T cells ‘see’ and how to make a ‘vaccine’ that will exhaust just these T1D-causing T cells.
This project brings together a group of highly experienced scientists. Collectively they have expertise in: T1D, cancer and vaccine biology. The team’s goal is to provide proof of concept that impairing the function of T1D-causing T cells, by exhausting them, delays the progression of T1D either alone or in combination with other immune therapies. This idea will be tested in mouse models of T1D. We will define the characteristic signature of exhausted T cells in T1D. This will be used to determine if we have succeeded in exhausting T cells in future clinical trials. In addition, we will characterize an array of T1D associated protein fragments, called peptide epitopes, that are recognized by T cells for their relevance to the development of T1D. This insight will allow us to formulate a cocktail of peptide epitopes which will allow us to measure both the function and the number of T cells that recognize these epitopes. Finally, we will optimize formulations of mRNA vaccine to prevent, delay or reverse autoimmune diabetes in a mouse model of T1D. If successful, we anticipate that this proposal will produce a new treatment regimen that could be trialled in stage 2 or early stage 3 T1D.
Anticipated Outcome
This project will:
I. Define, for the first time, the features of exhausted T cells in the context of T1D.
II. Validate existing targets of the autoimmune T-cell responses in people with T1D, and identify new targets.
III. Develop a formulation that delivers the targets of T1D-causing T cells in a manner that drives them to exhaustion.
The significance of our collaborative project is that it will reveal important insights into how T cells in T1D do, or do not, become exhausted. It will further identify the targets of the autoimmune T-cell responses that are most relevant to the development of type 1 diabetes by studying T cells from the ‘scene of the crime’ the pancreatic islets of organ donors who suffered from T1D. We will apply the new advances in mRNA vaccine development to developing immune therapies that drive antigen specific T cells to exhaustion. This will focus on the antigens that are known to be relevant to the development of T1D. By working together, we will develop a cocktail of targets that can be delivered in an exhaustion-inducing way. In this manner we expect to broadly suppress the autoimmune response against beta cells. Our knowledge of the hallmarks of exhausted T cells in T1D will allow us to measure the degree to which we have succeeded in driving T1D-specific T cells to exhaustion. This ability will allow us to rapidly evaluate the efficacy of this new type of therapy in clinical trials.
Relevance to T1D
T1D remains unpreventable and incurable. Insulin therapy is still the only established treatment for Type 1 diabetes. However, the recent approval of teplizumab by the FDA is a landmark, being the first approved immune therapy that delays the onset of T1D. The approval of teplizumab has demonstrated the power and potential of T-cell targeting therapies for T1D. Inspired and encouraged by teplizumab we are working towards an antigen-specific therapy that is designed to induce exhaustion in the T cells that target the insulin-producing beta cells. We anticipate that this therapy will delay, or perhaps completely prevent the progression of T1D.