Objective
This project aims to develop and evaluate a clinically translatable encapsulation platform that enables long-term islet transplantation without the need for systemic immunosuppression. Type 1 Diabetes (T1D) is an autoimmune disease, where persistent attack of autoreactive immune cells targets and destroys insulin-producing β-cells. This pre-existing autoimmunity significantly increases the risk of graft-specific immune attack in islet transplantation, even when encapsulated islets are used. While encapsulation can shield islets from direct immune cell contact, its benefits are often undermined by the foreign body response (FBR), which leads to fibrotic overgrowth and progressive loss of graft function. Systemic immunosuppression can delay rejection but carries severe off-target risks, including infection, malignancy, and organ toxicity, making it unsuitable for long-term use in T1D patients. Therefore, successful transplantation strategies must address generalized alloimmune rejection and the β-cell-specific autoimmunity unique to T1D, while minimizing systemic immune suppression.
Our approach leverages the immunoregulatory anti-inflammatory cytokine, which has been shown to mitigate foreign body response and help the immune system tolerate transplanted cells. Previously, cytokines have been explored in the clinic, but they have not demonstrated effectiveness because of their short half-life and dose-limiting toxicity. We propose using engineered cells to continuously deliver an anti-inflammatory cytokine directly at the graft site to overcome these limitations. These cells will be co-encapsulated with pancreatic islets in small molecule–modified alginate, a biomaterial shown to reduce fibrotic encapsulation.
This two-year study will test the platform in murine and nonhuman primate models to demonstrate its ability to maintain long-term islet function without systemic immunosuppression. The goal is to establish a scalable, ready-to-use therapy that overcomes the specific immune barriers in T1D and advances toward clinical translation.
Background Rationale
About 2 million Americans live with Type 1 Diabetes (T1D), an autoimmune disease in which the body’s immune system destroys insulin-producing islet cells in the pancreas. These cells normally sense changes in blood sugar and release insulin to bring levels back to a healthy range. Without them, blood sugar rises above normal, damaging the heart, kidneys, nerves, and other organs over time. Prolonged hyperglycemia accelerates these complications, while dangerously low blood sugar can cause immediate, life-threatening emergencies. Because blood sugar rises after every meal, people with T1D must constantly monitor their glucose and administer insulin. Even with advanced devices like continuous glucose monitors and insulin pumps, maintaining tight glucose control remains a daily challenge, and fewer than one-third of patients consistently achieve target levels.
Cell-based therapies, such as islet transplantation, offer a powerful alternative because living cells can sense glucose and secrete insulin in real time. However, islet transplantation requires lifelong systemic immunosuppression to prevent immune rejection. Long-term systemic immunosuppression carries serious risks, including infections, organ damage, and cancer. Encapsulation technologies, where islets are enclosed in protective biomaterials, can physically block immune cells from attacking the graft. Yet, even with encapsulation, the body mounts a foreign body response that forms a fibrotic layer around the capsule, restricting nutrient and oxygen exchange, limiting insulin release, and ultimately leading to graft failure. To address these challenges, we are engineering cytokine-secreting cells that, when co-encapsulated with islets in small molecule–modified alginate, can locally modulate the immune response and prevent fibrosis. By delivering targeted, continuous immune regulation at the implant site, we aim to protect islets, maintain long-term function, and eliminate the need for systemic immunosuppression.
The goal of this grant is to advance this platform toward clinical translation by optimizing the engineered cell-islet ratio, capsule design, and dosing in both mouse and nonhuman primate models. Success will lay the groundwork for a scalable, off-the-shelf islet therapy that could be accessible to all T1D patients, without the risks of lifelong immune suppression.
Description of Project
Type 1 Diabetes (T1D) affects more than 9.5 million people worldwide, a number projected to rise to between 13.5 and 17.4 million by 2040. In T1D, the immune system destroys the insulin-producing β-cells in the pancreatic islets, creating a lifelong dependence on externally administered insulin. Despite significant advances in insulin delivery systems and continuous glucose monitoring, current therapies cannot fully replicate the body’s natural, glucose-responsive insulin secretion. As a result, fewer than one-third of individuals with T1D consistently achieve recommended blood glucose targets. Restoring the body’s own insulin production through islet transplantation is a promising approach. However, its success is hampered by the requirement for lifelong systemic immunosuppression to prevent graft rejection. These immunosuppressive drugs carry substantial risks, including serious infections, increased cancer risk, β-cell toxicity, and long-term organ damage. To overcome these limitations, strategies that aim to modulate immune responses have been developed to create a localized tolerance-inducing environment around transplanted islets. While these methods have shown encouraging results, they have yet to be transplanted to the clinic due to the reliance on systemic agents, frequent re-dosing requirements, or limited capacity for precise, long-term immune regulation.
There is a critical need for a durable, targeted, and self-sustaining local immunomodulation strategy that can prevent graft rejection and maintain long-term islet function without compromising systemic immune defense. We propose a clinically translatable encapsulation platform that integrates immunomodulatory cell therapy with advanced biomaterial engineering. By co-encapsulating engineered cells that constantly secrete anti-inflammatory cytokine with pancreatic islets in small molecule–modified alginate, we aim to establish an immune-privileged microenvironment that protects the graft and maintains its function without systemic immunosuppression. This approach will be evaluated in mouse and nonhuman primate models to develop a scalable, off-the-shelf therapeutic solution for people with T1D.
Anticipated Outcome
By the conclusion of this project, we expect to deliver a fully optimized, clinically relevant cell therapy platform that combines insulin-producing islets with engineered support cells inside advanced protective capsules. These support cells will continuously release a potent anti-inflammatory and anti-fibrotic cytokine directly at the transplant site, reducing immune attack and foreign body response while preserving long-term islet function.
In Aim 1, we will create stable, high-output cytokine-producing monoclonal cell lines and demonstrate that, when co-encapsulated with islets, they maintain biocompatibility, minimize fibrosis, and deliver sustained local immune modulation in both mice and nonhuman primates. The outcome will be a safe, scalable encapsulation system capable of providing targeted immune protection without systemic immunosuppression.
In Aim 2, we will prove that this approach can restore normal blood sugar control and preserve islet health over extended periods in diabetic animal models. In mice, we anticipate achieving long-term reversal of hyperglycemia with minimal fibrotic overgrowth and strong local immune regulation. In diabetic nonhuman primates, we expect to confirm sustained glycemic control, preserved capsule function, and absence of systemic toxicity over four months.
The end result will be a translatable, off-the-shelf islet transplantation platform validated in both small and large animal models, positioning it for advancement toward human clinical trials as a durable, immunosuppression-free therapy for Type 1 Diabetes.
Relevance to T1D
Type 1 Diabetes (T1D) is an autoimmune disease in which the body’s immune system destroys the insulin-producing islet cells in the pancreas. Without insulin, blood sugar levels rise to dangerous levels, leading to long-term damage to the heart, kidneys, eyes, and nerves, and putting patients at risk for life-threatening complications. Current treatment requires lifelong insulin therapy, which cannot fully replicate the body’s natural ability to control blood sugar, and fewer than one-third of people with T1D consistently meet their glucose targets. Transplanting healthy islets can restore natural insulin production, but in people with T1D, the immune system attacks the graft due to both transplant rejection and the underlying autoimmunity that caused the disease. To prevent this, patients must take strong immunosuppressive drugs, which carry serious risks such as infections, cancer, and organ damage, and make islet transplantation unsuitable for most patients, especially children.
This project addresses a major unmet need by developing a new cell therapy platform that combines insulin-producing islets with engineered support cells that locally release an anti-inflammatory cytokine around the transplant site. This approach is designed to protect transplanted islets from immune attack and foreign body response without the need for systemic immunosuppression. If successful, it could make islet transplantation a safe, long-lasting, and widely available treatment option for people living with T1D.