Objective
Overall, this proposal’s objective is to map the immune response of human PBMCs to various clinically relevant islet sources and how these responses impact the islet’s ability to survive and function after they are transplanted. If successful, we can reduce the risks of transplantation, increase the likelihood of single donor insulin independence, establish long-term durable graft function, and broaden the spectrum of T1D patients who will be eligible to receive a more personalized curative β-cell replacement therapy.
Background Rationale
At present, there is no cure for type 1 diabetes (T1D). While automated insulin delivery has enabled more individuals to reach glycemic targets, a residual risk for hypoglycemia and diabetic ketoacidosis persists, and it falls short of a functional cure. Although hugely exciting, diabetes prevention with immunotherapy will not address the needs of the millions with established T1D. Durable insulin independence as a functional cure remains elusive after more than a century of dependence on lifelong self-administered insulin therapy and glucose monitoring. Islet transplant has shown that insulin independence can be achieved. However, this therapeutic benefit is often transient, with <50% of recipients remaining insulin-independent beyond 5 years. Although graft survival rates have improved due to more refined immune suppression strategies, islet procurement, and surgical procedures, there remains significant heterogeneity in the therapeutic outcomes for islet transplant recipients. While the alloimmune response has been assumed to drive rejection in many cases, the interactions between islet grafts and the host immune system are not fully characterized, particularly concerning successful islet transplants. Additionally, recurrent autoimmunity despite immunosuppression has been clearly demonstrated in some cases of islet transplant failure but the prevalence of subclinical autoimmunity is unknown. Finally, islet grafts’ stress and metabolic state likely contribute to long-term survival. Overall, the mechanisms determining why some patients maintain graft function for over 20 years while others do not remain unclear. These considerations highlight the need to 1) expand our understanding of mechanisms contributing to the long-term survival of islets, 2) utilize clinically relevant animal models to optimize β-cell engraftment in the presence of a human immune system, and 3) develop predictive and individual tools to enhance β-cell replacement therapies. Through these innovations, cellular replacement therapies could become a more practical, accessible, and promising ‘functional cure’ for a wider range of individuals living with diabetes. Herein, we seek to map how islets best survive and function after they are transplanted. If successful, we can reduce the risks of transplantation, increase the likelihood of single donor insulin independence, establish long-term durable graft function, and broaden the spectrum of T1D patients who will be eligible to receive personalized curative β-cell replacement therapies.
Description of Project
Islet transplantation (iTx) is a treatment that can help people with type 1 diabetes (T1D) better control their blood sugar, avoid dangerously low blood sugar levels, and improve their overall quality of life. It also protects against some of the long-term complications that T1D can cause, such as damage to blood vessels. However, the therapy is not perfect. When insulin-producing islets are transplanted, many of them die shortly after the transplant due to immune cells causing inflammation. This leads to a significant loss of insulin-producing cells. Over time, the body’s immune system can attack the transplanted insulin-producing cells, leading to graft destruction. The reasons why some people’s transplants work for longer periods than others are still unclear. To avoid graft destruction, researchers need to understand more about what helps insulin-producing cells survive long-term and how to improve the chances of success.
In this project, we intend to learn more about how the immune system affects islet transplants derived from various cell sources. Our goal is to understand why some people’s immune systems accept the transplant while others attack it. By studying how different immune systems react to transplanted islets, we hope to develop better personalized medical strategies to improve graft survival.
Aim 1: Study host immune cells that attack insulin-producing cells
We will characterize human immune cells in the lab and their responses to various islet sources, such as porcine-derived, stem cell-derived, and human-derived, which may lead to a predictive tool to determine the most efficacious personalized cell therapy. We will use immune cells from healthy individuals, those with T1D, and those with T1D following an islet transplant. This will enable us to identify which immune cells are present before and after the transplant, particularly those associated with graft rejection.
Aim 2: Use a humanized mouse model to predict graft failure
We’ll also use a novel humanized mouse model, where the mice are reprogrammed to have a human-like immune system, and then transplanted with islets from these different islet sources. We’ll study 1) how the immune system of each patient group (non-diabetic, T1D, and T1D transplant recipients) reacts before the transplant, 2) how the insulin-producing cells respond to stress, and 3) how the immune system behaves after the transplant to see how different types of islets survive. This research will help us predict graft failure before it happens and build a biobank of islets for future studies.
The long-term goal of this project is to predict which type of islet—human, stem cell-derived, or pig—will work best for each patient. This could lead to a new diagnostic test that helps healthcare professionals choose the best cell therapy treatment based on each person’s immune system response.
Anticipated Outcome
Overall, this project aims to study how the immune systems of different people—those without diabetes, those with type 1 diabetes, those with type 1 diabetes who received an islet transplant—react to different sources of insulin-producing beta cells. By understanding these immune system reactions, we hope to create a test that can predict which type of beta cells (human islets, stem cell-derived islets, or pig islets) would work best for each individual based on their immune response.
Relevance to T1D
Type 1 diabetes has long been recognized as having an autoimmune basis. It is clear that both genetic and environmental factors underlie the risk of T1D and the progression of autoimmune destruction of beta cells, which is mediated by cellular and humoral immune pathways prior to clinical presentation. This is well described and provides an opportunity for immune interventions (e.g., teplizumab) to prevent the onset of T1D or extend the honeymoon period. Many new questions have emerged, however. The presence of residual C-peptide in longstanding T1D, along with the heterogeneity in the degree of insulitis and beta cell loss in islets from the same individual, suggests more complex mechanisms. While T1D can develop at any age, it is evident that beta cell loss is much more rapid in younger children. Thus, despite the major contribution of HLA to the genetic risk of T1D, understanding the heterogeneity in immune mechanisms and how these responses determine the success of cell therapies (islet transplantation-iTx) appears to be a key area that requires urgent study. Despite marked progress in the field of clinical iTx, the inability of this procedure to predictably deliver durable and sustained insulin independence clearly demonstrates the necessity of further refinements. While the successful engraftment of transplanted islets is an important challenge in the peri-transplant period, the gradual attrition of insulin independence rates over the longer term highlights the need to better understand both auto- and allo-immune mediated attack on transplanted islets and how they contribute to the long-term decline in functional beta cell mass, resulting ultimately in islet graft failure with recurrence of brittle diabetes and risk for severe hypoglycemia. The mechanisms that determine why some patients maintain graft function while others do not are unclear. These considerations highlight the need to 1) expand our understanding of mechanisms contributing to the long-term survival of islets, 2) utilize clinically relevant animal models to optimize β-cell engraftment in the presence of a human immune system, and 3) develop predictive and individual tools to enhance β-cell replacement therapies. Through these innovations, cellular replacement therapies could become a more practical, accessible, and promising ‘functional cure’ for a wider range of individuals living with diabetes. Herein, we seek to map how islets best survive and function after they are transplanted. If successful, we can reduce the risks of transplantation, increase the likelihood of single donor insulin independence, establish long-term durable graft function, and broaden the spectrum of T1D patients who will be eligible to receive personalized curative β-cell replacement therapies.