Objective
The objective of this work is to develop a new way to safely control the immune response to transplanted insulin‑producing cells. This project focuses on combining targeted therapies that are expected to have minimal side effects and may be safe for use even in people without long‑standing type 1 diabetes.
Background Rationale
Current methods to prevent immune rejection of transplanted insulin‑producing cells carry substantial risks. One approach uses multiple drugs commonly prescribed after solid organ transplantation, but these medications suppress the immune system broadly, increasing the risk of infections and cancer. Another strategy uses gene editing to make transplanted cells less visible to the immune system; however, this also prevents the immune system from detecting infected or abnormal cells.
We have been studying an alternative approach that re‑educates the immune system using its natural regulatory mechanisms, specifically regulatory T cells. Our previous work in skin and islet transplant models showed that regulatory T cell therapy alone was not sufficient to achieve long‑term immune tolerance. We therefore explored combinations with antibodies that block key immune‑activating pathways and discovered strong synergistic effects. The goal of the current project is to apply these findings to islet transplantation and determine whether this approach can safely and effectively control immune responses to potentially curative cell therapies.
Description of Project
Type 1 diabetes occurs when the immune system destroys the insulin‑producing cells of the pancreas. Transplanting insulin‑producing cells made from stem cells offers a promising way to restore insulin production, but these transplanted cells are often attacked and rejected by the immune system. Current methods to prevent rejection rely on long‑term immune‑suppressing drugs, which can cause serious side effects, or on genetically modifying the cells to hide them from the immune system, which may not provide complete or lasting protection.
We propose a new and complementary strategy that aims to teach the immune system to tolerate transplanted insulin‑producing cells rather than broadly suppressing immunity. This approach uses a specialized type of immune cell called regulatory T cells, which are engineered to specifically recognize donor tissue. In previous work, we showed that these engineered regulatory T cells can slow transplant rejection, but on their own they are not sufficient to provide long‑term protection. Importantly, our recent findings show that combining these cells with short‑term, non‑toxic immune‑modulating antibodies dramatically improves transplant survival in animal models.
The goal of this project is to test whether this combination therapy can promote long‑lasting immune tolerance to transplanted pancreatic islet cells or stem cell‑derived insulin‑producing cells. First, we will evaluate this strategy in mouse models of diabetes and transplantation to determine how well it protects transplanted cells and restores normal blood sugar control. We will also study how the immune system responds to treatment. Next, we will test this approach using human immune cells and advanced mouse models that carry human immune systems.
Together, these studies aim to develop a safer and more durable way to protect transplanted insulin‑producing cells without the need for lifelong immune suppression, bringing us closer to a long‑term treatment—and potentially a functional cure—for type 1 diabetes.
Anticipated Outcome
We aim to identify at least one strategy that can induce immune tolerance to transplanted islets. A key component of this work will be understanding how these tolerance‑inducing approaches function and how robust they are, including whether tolerance can be disrupted by immune challenges such as infection. We will perform parallel studies in mouse models and with human immune cells to generate proof‑of‑concept data while also defining the strengths and limitations of each strategy.
Relevance to T1D
Islet transplantation has the potential to provide a functional cure for type 1 diabetes, but its widespread use is limited by the availability of donor organs and the need for lifelong immunosuppression. Insulin‑producing cells derived from pluripotent stem cells offer a promising alternative, and recent clinical trials have demonstrated remarkable progress. However, for both donor‑derived and stem cell‑derived insulin‑producing cells, immune rejection remains a major barrier. As a result, this therapy is currently limited to individuals with advanced disease.
To fully realize the potential of islet replacement therapy as a functional cure for type 1 diabetes, safer and more effective methods to control immune responses are urgently needed. If successful, this project will deliver a new strategy that combines a targeted cell therapy with antibody‑based immune modulation. Because this approach is expected to carry lower risks than current treatments, it could ultimately be applied more broadly to people at different stages of type 1 diabetes and advanced toward clinical testing.