Objective
Type 1 diabetes (T1D) is a serious condition in which the body’s immune system mistakenly destroys the insulin-producing cells in the pancreas. People with T1D must inject insulin every day and regularly monitor their blood sugar to stay healthy. Although this treatment helps manage the disease, it is not a cure. Over time, many individuals still develop serious complications, including vision problems, kidney failure, nerve damage, and heart disease. A promising, curative, alternative to insulin therapy is islet transplantation, where insulin-producing cells from a donor are transplanted into a person with T1D to restore natural insulin production. This therapy is already approved for clinical use and has helped some patients become insulin-independent. However, widespread use is limited by two major challenges: the need for lifelong immune-suppressing drugs to prevent rejection of the donor islets, and a shortage of suitable donor tissue. This project seeks to address both challenges. The first goal is to develop a safer way to retrain the immune system to accept donor cells without the need for harmful drugs. The second goal is to determine whether lab-grown insulin-producing cells derived from stem cells can be shielded from immune attack and provide a reliable, renewable source of transplantable tissue. To help the immune system accept donor cells from a completely different individual, we will use a technique called mixed hematopoietic chimerism. This approach involves transplanting blood-forming, hematopoietic stem cells (HSCs) from a donor to a recipient. When successful, this causes the immune system to “learn” that donor tissues are not a threat, allowing it to tolerate transplanted cells like islets without the need for lifelong immunosuppression. While this method has shown great promise in some clinical settings, it currently requires patients to receive toxic conditioning treatments, such as high-dose chemotherapy or radiation, to make space for the donor HSCs. These treatments carry serious risks and are not acceptable for people who do not have cancer, such as most individuals with T1D. Here, I will develop and test a safer alternative that uses targeted antibodies and drugs, rather than radiation or chemotherapy, to prepare the recipient for transplant. These drugs aim to gently open space in the bone marrow, allowing donor HSCs to implant and create a stable mixed immune system. The hope is that this non-toxic conditioning approach will allow for long-lasting immune tolerance, support successful islet transplantation, and lead to durable diabetes reversal in animal models. The second part of the project addresses the shortage of donor islets by investigating the use of lab-grown insulin-producing cells made from pluripotent stem cells. These “β-like” cells, which function similarly to the body’s natural insulin-producing β cells, are currently being tested in clinical trials and could eventually offer an unlimited supply of transplantable tissue. However, it is still unknown whether the immune system will accept these lab-made cells, especially when they come from unrelated donors. Using newly developed genetically engineered mouse embryonic stem cell lines that glow when insulin is produced, I will test whether mixed chimerism enables long-term acceptance and function of these cells in diabetic mice. I will also examine whether this strategy works in autoimmune diabetes (T1D) and will explore how the immune system is reprogrammed to tolerate these cells and reverse autoimmunity. In summary, this project aims to make islet transplantation a safer and more widely available option for people living with T1D. By eliminating the need for toxic immune-conditioning and exploring the use of stem cell-derived insulin-producing cells, this work has the potential to transform the way we treat T1D and bring us closer to a lasting, functional cure.
Background Rationale
Type 1 diabetes (T1D) occurs when the immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. Without insulin, the body cannot regulate blood sugar, requiring people with T1D to rely on multiple daily insulin injections or pumps and constant blood glucose monitoring. While these tools have significantly improved quality of life, they are not a cure. People with T1D still face a lifelong disease burden and remain at risk for serious complications. These challenges highlight the urgent need for effective, curative treatments. Islet transplantation is one curative approach, where insulin-producing cells from a donor are implanted into a person with T1D to restore natural insulin production. This strategy has already enabled some individuals to live without daily insulin injections. However, its use is limited by two major problems. First, the immune system sees donor cells as foreign and attacks them. To prevent this, patients must take immune-suppressing drugs for the rest of their lives, which come with serious risks like infections and organ damage. Second, there aren’t enough organ donors to meet the needs of everyone with T1D. This project directly addresses both obstacles. The first goal is to safely and durably retrain the immune system to accept donor cells without the need for chronic immune-suppressing drugs. To do this, I will use an approach called mixed hematopoietic chimerism, where a person receives blood-forming, hematopoietic stem cells (HSCs) from a donor. If successful, the recipient’s immune system becomes a mix of their own cells and the donor’s. This “re-educates” the immune system to accept the donor’s tissues, including insulin-producing islets, as if they were their own, and can also correct the underlying autoimmunity. This technique has worked in some patients receiving kidney transplants, helping them avoid rejection without long-term use of immune-suppressing drugs. However, this method currently requires patients to undergo intense preparation involving radiation or chemotherapy to make room for the donor cells. These treatments are harsh and carry serious side effects, especially in patients who do not have cancer. For people with T1D, these risks often outweigh the benefits. Thus, we aim to develop and test a gentler, safer method for achieving mixed chimerism using targeted antibodies and medications instead of radiation or chemotherapy. If successful, this could make immune tolerance more widely available and enable safer, longer-lasting islet transplantation. The second challenge, the shortage of donor tissue, is actively being addressed through stem cell research. Researchers have developed methods to create insulin-producing cells in the lab from human pluripotent stem cells. These stem cells can develop into nearly any cell type in the body and offer a potentially unlimited supply of insulin-producing “β-like” cells for transplantation. Early clinical trials have shown that these cells can help control blood sugar levels in people with T1D. However, it’s still unclear whether the immune system will tolerate these lab-made cells, especially when they come from unrelated donors. To answer that question, we will test whether mixed hematopoietic chimerism can protect stem cell-derived insulin-producing cells from immune rejection in non-diabetic and diabetic mice. Importantly, we will also explore whether this approach works in T1D and evaluate how the immune system becomes tolerant to these lab-grown cells. Here, we aim to deliver practical, scalable solutions to two of the biggest roadblocks standing between people with T1D and a functional cure. By combining immune tolerance induction with regenerative stem cell-based therapies, this work has the potential to revolutionize T1D treatment and move the field closer to a world without T1D.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease in which the immune system mistakenly attacks and destroys the insulin-producing cells in the pancreas. Current treatments for T1D include insulin injections and constant blood sugar monitoring. However, these treatments do not provide a cure, and the risk of long-term diabetes complications remains. An alternative approach to insulin therapy is islet transplantation, where insulin-producing cells from a donor are transferred into a person with T1D. This method is FDA-approved and has shown success, but two major challenges limit its widespread use: the risk of immune rejection of the donor cells and the limited availability of suitable donor tissue. To overcome these obstacles, this research focuses on a strategy called mixed hematopoietic chimerism, which can train the immune system to permanently accept donor tissues without the need for lifelong immunosuppressive drugs. This approach involves transplanting donor blood-forming stem cells (hematopoietic stem cells) into the recipient. If successful, the recipient's immune system learns to accept donor-matched tissues, including islets, which could enable lasting diabetes reversal. However, the procedures used to prepare patients for this type of transplant currently involve high doses of radiation or chemotherapy, which carry serious side effects and limit the approach’s use in non-cancer conditions like T1D. In aim 1, I will develop a safer way to make mixed chimerism possible. Instead of radiation or chemotherapy, this new method uses antibodies and targeted drugs to prepare the recipient to accept the donor stem cells. This radiation- and chemotherapy-free regimen will be tested for its ability to support stable chimerism, reverse diabetes, and promote long-term acceptance of transplanted islets. If successful, this would represent a major step forward in making this approach for immune tolerance induction safer and more broadly applicable. Even if the immune system can be re-educated to accept donor cells, the limited supply of donor islets remains a significant hurdle. A promising solution to this problem is to generate insulin-producing cells from human pluripotent stem cells in the lab. These stem cell–derived β-like cells are already being tested in early clinical trials and may eventually provide an unlimited source of transplantable tissue. However, it is still unknown whether these lab-grown cells will be accepted by the immune system without rejection, especially when derived from unrelated donors. In aim 2, I will investigate whether mixed chimerism can also promote tolerance to stem cell–derived β-like cells. Using a new set of genetically engineered mouse embryonic stem cell lines that glow when insulin is produced, this study will test whether mixed chimerism allows diabetic mice to accept and benefit from transplanted β-like cells, even when they come from completely mismatched donors. It will also explore whether this approach can work in the setting of autoimmune diabetes and investigate how the immune system becomes tolerant to these lab-grown cells. Together, this project aims to make islet transplantation a safer, more widely available therapy for people with T1D. By eliminating toxic conditioning and addressing the shortage of donor tissue through stem cell technologies, this work has the potential to transform cell-based therapies and move closer to a functional cure for T1D.
Anticipated Outcome
Here, we aim to lay the groundwork for a new kind of treatment for type 1 diabetes (T1D): one that goes beyond managing symptoms and instead promotes long-term immune tolerance to transplanted insulin-producing cells. If successful, the work will bring us significantly closer to a functional cure for T1D using safe, scalable, and lasting cell-based therapies. The first major anticipated outcome is the development of a radiation- and chemotherapy-free approach to immune tolerance. Currently, reprogramming the immune system to accept donor tissues, via a strategy called mixed hematopoietic chimerism, requires intense conditioning with toxic drugs or radiation. These treatments are too dangerous for most people with T1D. We wish to test an alternative, safer, clinically relevant protocol that uses targeted antibodies and medications to prepare the body for donor hematopoietic stem cells, without the harsh side effects. Early studies suggest that this gentler approach can still achieve strong, durable immune tolerance. If validated, this would open the door to making immune tolerance available to people with T1D, organ transplant recipients, and patients receiving other types of cell therapy. The second major anticipated outcome is to demonstrate that the immune system, once retrained through mixed chimerism, can accept stem cell-derived insulin-producing cells from unrelated donors. This is a critical step forward that could help solve the long-standing problem of limited donor islets. Lab-grown beta-like cells, made from pluripotent stem cells, have the potential to provide a renewable, unlimited source of transplantable insulin-producing tissue. However, unless we can protect these cells from rejection, their use will be limited. Our study will test whether the immune tolerance created through mixed chimerism can extend to these stem cell-derived tissues and allow them to function long-term in diabetic recipients. In practical terms, this means that a person with T1D could one day receive two kinds of stem cell-based transplants: one to retrain their immune system, and another to restore insulin production. The need for toxic immune-suppressing drugs would be eliminated, and the problem of donor scarcity could be overcome through advances in stem cell manufacturing. This would represent a fundamental shift in how we treat T1D, from managing blood sugar with insulin injections to re-establishing the body’s natural insulin production in a lasting, immune-protected way. Beyond the direct clinical implications, this work will also yield valuable insights into the immune mechanisms that underlie tolerance and rejection. By studying how the immune system responds to donor stem cells, both blood-forming and insulin-producing, we can better understand how to fine-tune this process for different patients and conditions. These insights will help guide future therapies not only for T1D, but for a range of autoimmune diseases and transplant applications. In summary, this project is expected to deliver two critical breakthroughs: (1) a safe, translatable protocol for inducing immune tolerance without toxic conditioning, and (2) a demonstration that lab-grown insulin-producing cells can survive and function in tolerant recipients, even in the presence of autoimmunity. Together, these advances have the potential to transform cell-based therapies for T1D, making them safer, more accessible, and more effective for the people who need them most.
Relevance to T1D
Type 1 diabetes (T1D) is a lifelong autoimmune disease in which the immune system mistakenly destroys the body’s insulin-producing cells in the pancreas. Without insulin, the body cannot regulate blood sugar levels, leading to serious health problems. While insulin therapy has revolutionized diabetes care, it is not a cure. People with T1D must constantly monitor their blood sugar, give themselves insulin, and live with the risk of long-term complications like kidney failure, vision loss, nerve damage, and heart disease. One of the most promising approaches to curing T1D is to replace the lost insulin-producing cells through islet or beta cell transplantation. This strategy can restore natural insulin production and eliminate the need for insulin injections. In fact, islet transplantation is FDA-approved and has shown success in some patients. However, this approach faces two major barriers: (1) the transplanted cells need to be protected from rejection by the immune system, and (2) there is a severe shortage of donor islets. This project tackles both of these challenges head-on. First, it explores a new way to train the immune system to accept transplanted islets without lifelong immunosuppression. Most transplant patients must take powerful drugs to suppress their immune system, which come with serious side effects, including increased risk of infection, cancer, and organ damage. Our research uses a strategy called mixed hematopoietic chimerism, which involves transplanting blood-forming, hematopoietic stem cells (HSCs) from a donor. If successful, this retrains the recipient’s immune system to recognize the donor’s tissues, including transplanted insulin-producing cells, as “self.” This would eliminate the need for immune-suppressing drugs after islet transplantation for T1D. What makes our approach especially promising is that we are developing a non-toxic version of this transplant process. Traditional methods use high-dose radiation or chemotherapy to prepare the body for donor HSCs. These harsh treatments are too dangerous for most people with T1D. We are testing a safer alternative using targeted antibodies and clinically relevant drugs to prepare the body without radiation or chemotherapy. This would be a major step forward in making immune tolerance strategies safe and practical for broader use. Additionally, this project addresses the shortage of donor tissue by exploring the use of stem cell-derived insulin-producing cells created in the lab. These lab-grown “β-like” cells have shown promise in early clinical trials and may eventually provide an unlimited supply of transplantable cells. However, even these stem cell-derived cells are at risk of being attacked by the immune system, especially in people with autoimmune diseases like T1D. Our study will test whether mixed chimerism can also protect lab-grown beta cells from immune attack. If so, it would allow us to combine two powerful technologies: immune tolerance and stem cell-derived “β-like” cells. This combination could lead to a renewable, scalable, and immune-protected treatment for T1D, offering hope for a lasting cure. In summary, this work is highly relevant to the T1D community. It aims to solve two of the biggest hurdles in the field: immune rejection and lack of transplantable tissue. By developing a safe method to retrain the immune system and testing whether this method also works for stem cell-derived “β-like” cells, we hope to lay the foundation for a transformative treatment that restores natural insulin production, eliminates the need for immunosuppressive drugs, and moves us closer to a functional cure for T1D.