Objective
This research aims to advance a new immune-based strategy to improve the success and safety of islet transplantation for people with Type 1 diabetes (T1D). Islet transplantation can restore the body’s ability to produce insulin, but its broader use is limited by immune rejection, early loss of transplanted cells, and the need for lifelong immune-suppressing drugs. These drugs increase the risk of infections, cancer, and other complications, and restrict the procedure to a small group of individuals with the most severe disease. Proposed studies look to harness a specialized population of immune cells, called IL-10-producing group 2 innate lymphoid cells (ILC210), that naturally regulate immune responses and support tissue health. Our prior work has shown that ILC210 can protect transplanted islets and improve their function in preclinical models. The objective of this project is to generate the essential preclinical evidence needed to determine whether ILC210 could be developed into a safe, effective cell therapy to support islet transplantation.
Background Rationale
Type 1 diabetes (T1D) is a lifelong autoimmune disease in which the immune system mistakenly destroys insulin-producing cells in the pancreas. Without these cells, individuals must rely on external insulin to control blood sugar levels. Although insulin therapy is lifesaving, it does not fully replicate the body’s natural glucose regulation and does not prevent long-term complications in all patients. Islet transplantation offers a promising alternative by restoring the body’s ability to produce insulin. In this procedure, insulin-producing cells (islets) from a donor are transplanted into a person with T1D, where they can help stabilize blood sugar levels and reduce severe hypoglycemia. However, islet transplantation is not widely used because transplanted cells are vulnerable to early inflammatory injury, immune rejection, and damage caused by the transplantation process itself. To prevent rejection, patients must take lifelong systemic immunosuppressive drugs, which increase the risk of infection, cancer, and other serious side effects. These challenges have limited islet transplantation to a small subset of individuals with severe disease.
A major unmet need in the field is the development of strategies that protect transplanted islets without broadly suppressing the immune system. Ideally, such an approach would regulate harmful immune responses only at the transplant site while preserving normal immune function elsewhere in the body.
Recent advances in immunology have revealed that the immune system contains specialized regulatory cells capable of both controlling inflammation and supporting tissue repair. Among these are group 2 innate lymphoid cells (ILC2s), which respond rapidly to tissue injury and help coordinate immune responses and healing. A subset of these cells that produces the anti-inflammatory molecule IL-10 that are referred to here as ILC210 has emerged as a potentially important regulator of inflammation, but whether they could be targeted or harness in immunotherapy approaches has not been explored.
Our research builds on this emerging biology by developing methods to isolate and expand human ILC210 and testing their ability to protect transplanted islets in preclinical models. Early studies suggest that these cells can reduce harmful immune responses, preserve insulin-producing islet cells, and support tissue health at the transplant site. However, before ILC210 can be considered for clinical testing, critical questions remain regarding how they function, where they act in the body, and whether they can be used safely and effectively in clinically relevant settings.
This project is designed to address these gaps by generating the foundational preclinical knowledge needed to determine whether ILC210 can form the basis of a new, localized immune-regulatory strategy for islet transplantation in Type 1 diabetes.
Description of Project
Type 1 diabetes (T1D) occurs when the immune system mistakenly destroys insulin-producing β islet cells in the pancreas. Islet transplantation can restore natural insulin production and improve quality of life for some individuals with T1D, but its broader use is limited by immune rejection, early loss of transplanted islets, and the need for lifelong systemic immunosuppression, which carries significant risks. This project seeks to address these barriers by developing an immune-based approach designed to protect transplanted islets locally, without broadly suppressing the immune system.
Group 2 innate lymphoid cells (ILC2s) are a specialized population of immune cells involved in immune regulation and tissue repair. A subset of ILC2s that produces the anti-inflammatory cytokine IL-10, referred to as ILC210, has been identified and shown to play key roles in limiting harmful inflammation. Building on these findings, we developed methods to isolate and expand human ILC210 from blood, enabling their evaluation as an “off-the-shelf” cell therapy. In preclinical studies, human ILC210 improved the survival and function of transplanted islets in humanized mouse models by reducing harmful immune responses, preserving insulin-producing cells, and improving blood glucose control. Collectively, these studies provide strong proof-of-concept for harnessing ILC210 in cell therapies for islet transplantation and T1D.
The proposed research is designed to generate the essential preclinical evidence needed to advance ILC210 toward clinical testing in islet transplantation. We will evaluate alternative delivery strategies for ILC210, and assess their capacity to support islet engraftment and function across distinct anatomical sites under clinically relevant conditions. Building on these findings, we will conduct regulatory-aligned safety, biodistribution, and persistence studies using GMP-like ILC210 products and delivery strategies informed by upstream efficacy and mechanistic data to inform the design and feasibility of potential first-in-human trials.
Together, these studies will improve understanding of how these regulatory immune cells influence immune responses and tissue health following islet transplantation. By defining how ILC210 act, where they localize, and how they interact with transplanted islets, this project will provide a stronger biological and translational foundation for strategies aimed at protecting islets while preserving normal immune function.
Anticipated Outcome
The anticipated outcome of this research is a clear, evidence-based understanding of whether ILC210 can be safely and effectively developed as a supportive cell therapy for islet transplantation. By completing this work, we expect to define how these cells behave after transplantation in preclinical models, where they localize, how long they persist, and whether they cause any unintended effects in non-target tissues.
This project will also clarify how ILC210 interact with transplanted islets and the surrounding immune environment. These insights will improve understanding of how these innate immune regulatory cells influence both immune responses and tissue health following transplantation. Importantly, the results will identify delivery strategies that best support islet survival and function, and will establish the safety parameters required for regulatory review.
Even if challenges are identified, the data generated will guide next steps, such as refining delivery approaches or improving cell design. Overall, this work is expected to provide the foundational preclinical evidence needed to determine whether ILC210-based therapies are suitable for clinical testing and to inform the design of future first-in-human trials.
Relevance to T1D
For people living with Type 1 diabetes, maintaining stable blood sugar levels remains a daily challenge, even with advanced insulin delivery systems. Islet transplantation offers a potential path toward restoring natural insulin production, but immune rejection and the risks of lifelong immunosuppression limit its availability and long-term success.
This project is directly relevant to T1D because it addresses one of the central barriers to effective islet transplantation, namely the immune response that damages transplanted islets. By studying ILC210, a naturally occurring immune cell population that regulates inflammation and supports tissue health, this research explores a new way to protect transplanted islets without broadly suppressing the immune system.The insights gained may inform future strategies to better harness or engineer immune regulatory cells, improve transplantation outcomes, and guide the development of safer immune-modulating therapies. While this research is preclinical, it represents an important step toward more durable, safer, and accessible cell-based treatments for people with Type 1 diabetes.