Objective
The goal of this project is to better understand how new immune-based treatments for type 1 diabetes (T1D) work and why they help some people more than others. T1D happens when the immune system mistakenly attacks insulin-producing cells in the pancreas. New therapies, like teplizumab, can delay or slow the disease by changing how the immune system behaves. But we still don’t fully understand how each treatment works at the cellular level, or how to tell which people will benefit the most.
To solve this, we are building two advanced research platforms that allow us to test these treatments using real human immune cells in the lab. One system uses special mice that carry human immune cells, and the other uses lab-grown “organoids” made from human lymph node tissue. With these tools, we will study how four promising therapies effect key immune cells involved in T1D.
By linking immune responses to features like how fast a person’s disease is progressing, we hope to identify which treatments work best for different people. This work will help pave the way for more personalized and effective therapies to stop T1D before it causes lasting damage.
Background Rationale
Type 1 diabetes (T1D) develops when the immune system mistakenly attacks insulin-producing cells in the pancreas. New immune-targeting therapies are showing promise to delay or alter the course of disease. Teplizumab, an antibody that affects T cell activity, is now approved to delay disease onset in at-risk individuals, and other drugs like abatacept, IL-2 muteins, and deucravacitinib are being tested in clinical trials. These therapies work in different ways, but all aim to reset the immune system and prevent further damage.
A key challenge is that not all patients respond equally to these treatments, and we don’t fully understand why. In part, this is because current clinical trials are run independently, with different treatment schedules, patient selection criteria, outcome measures, and sampling protocols. This makes it difficult to compare how different therapies work. Additionally, most studies of clinical trial responses rely on small blood samples that limit our ability to examine immune responses in detail.
To address these gaps, our project will use two human-based laboratory models to test multiple therapies side by side under identical conditions. By directly comparing how each treatment affects key immune cells, we aim to uncover the mechanisms behind treatment response and resistance, paving the way for more personalized and effective strategies to stop T1D.
Description of Project
In recent years, researchers have made major progress in developing immune-based treatments that aim to prevent or slow progression of T1D by rebalancing the immune system. For example, the FDA recently approved teplizumab, a therapy that delays the onset of T1D in people at risk, and other immune-targeted therapies have also shown promise. However, we still don’t fully understand how each therapy works at the cellular level, why some people benefit more than others, or how to best combine different drugs for maximum impact. This lack of knowledge makes it difficult to match the right treatment to the right person or to develop new combination therapies that could work better to treat disease.
Our project aims to address this gap. We are developing two powerful research platforms that use human immune cells to study how different immune therapies work:
1. A model in which immune cells from people with T1D or healthy individuals are transferred into mice that allow the human cells to grow and function.
2. A lab-grown “organoid” system made from human lymphoid tissue (e.g., tonsils), which recreates a realistic environment where immune cells interact.
Using these systems, we can test how different treatments including teplizumab, abatacept, IL-2-based therapies, abatacept, and Tyk2 inhibitors (a new class of drugs that inhibit immune system signaling) effect key immune cell types involved in T1D, such as regulatory T cells, autoreactive T cells, and B cells. We can also examine at how other immune cells like dendritic cells or monocytes respond. This will help us build a detailed map of how each therapy alters the immune system.
In the second part of our study, we will use cutting-edge gene editing tools (called CRISPR) to investigate which genes control how T cells respond to treatment. By turning off specific genes in immune cells, we can identify which pathways are critical for the success of therapies like teplizumab. We will then test these findings in our mouse model using cells from people with T1D to see how these genes influence treatment response in a living system.
The knowledge gained from this research will help identify the most important immune pathways targeted by current therapies, helping uncover why people respond differently, and guiding the development of more personalized, effective treatments for T1D. Ultimately, this work could help transform the way we approach immune therapy, moving from one-size-fits-all to precision strategies tailored to each person’s immune profile.
Anticipated Outcome
This project will create new tools to better understand how immune-based treatments for type 1 diabetes (T1D) work in the human immune system. By studying multiple therapies side-by-side in standardized laboratory models using human immune cells, we aim to uncover how each drug affects the key cells involved in T1D. From this work we expect to identify the specific immune pathways activated or suppressed by each treatment and learn how these effects differ between individuals. By including samples from T1D patients with fast or slow disease progression, we also hope to discover biological markers that may help explain why some people respond better than others.
By identifying pathways activated by different therapies, this work will also highlight potential combinations of therapies that could be more effective together than alone. The powerful lab platforms developed through this project will continue to support future testing of new drugs and treatment strategies. Ultimately, the knowledge gained from this research will bring us closer to personalized medicine in T1D, where treatments are matched to each person’s unique immune profile to stop the disease before permanent damage occurs.
Relevance to T1D
This project is focused on improving how we treat and care for people with or at risk of developing type 1 diabetes (T1D). Right now, even the most promising therapies—like teplizumab, which can delay the disease in people at high risk—don’t work for everyone. Doctors have no way to predict who will respond to a given treatment, or how to choose the right therapy for each individual.
Our research aims to change that by identifying the specific ways different immune therapies affect the cells that drive T1D. By testing multiple treatments side by side in advanced lab models that use real human immune cells, we can uncover the mechanisms behind treatment success—and failure. We’ll also compare responses in people with faster or slower disease progression to begin building tools that match therapies to patient profiles.
Ultimately, this work could help doctors make more informed decisions about when and how to use immune therapies. It could lead to better outcomes for people newly diagnosed with T1D and those identified as high-risk, by guiding the selection of the most effective, personalized treatment plans—before irreversible damage to insulin-producing cells occurs.