Objective
Type 1 diabetes (T1D) is an autoimmune disease in which the body’s immune system attacks insulin producing cells in the pancreas. Current treatments manage blood sugar but do not stop the underlying autoimmune process. The objective of this research is to develop a novel therapy that retrains the immune system to prevent or treat T1D by targeting specific immune cells.
Our approach uses tiny biodegradable particles, called microparticles (MPs), made from a polymer called acetalated dextran (Ace-DEX). These particles are designed to specifically bind to B cells, a type of immune cell that plays a central role in T1D. Once bound, the particles convert B cells into regulatory B cells (Bregs). These Bregs then communicate with other immune cells, including regulatory T cells, to suppress the autoimmune attack. This coordinated network of regulatory cells can target the immune system in a highly specific way, potentially preventing the destruction of insulin producing cells while leaving the rest of the immune system intact.
This approach is innovative because, unlike other therapies, our particles do not require added targeting molecules or drugs to induce immune regulation. They naturally bind B cells and trigger a broad regulatory response, generating multiple types of regulatory cells, including FoxP3+ Tregs and Type-1 regulatory cells (Tr1). This multi-layered response mimics natural immune tolerance more closely than existing strategies that typically focus on a single type of regulatory cell.
Preliminary studies in animal models have been encouraging. In models of multiple sclerosis and T1D, our Ace-DEX particles successfully bound B cells, induced Bregs, and generated regulatory T cells. In a mouse model of T1D, particles carrying disease related antigens delayed the onset of diabetes and reduced pancreatic inflammation, demonstrating that this strategy can modify the autoimmune response in a meaningful way.
The specific aims of this project are to (1) synthesize and characterize Ace-DEX microparticles carrying T1D-related antigens, and (2) test these particles in a mouse model that develops T1D, assessing their ability to prevent disease onset, maintain long-term protection, and generate regulatory immune cells. These studies will determine the optimal particle formulation, dosing schedule, and antigen combination needed to produce the most effective treatment.
If successful, this research could establish a first of its kind therapy for T1D that induces antigen specific immune tolerance, offering a targeted, long lasting approach to preventing or treating the disease. This platform could also be adapted for other autoimmune disorders. If challenges arise, we have plans to adjust particle design, dosing, or antigens to enhance the therapeutic effect.
In summary, this project aims to develop a novel particle-based therapy that retrains the immune system to stop the autoimmune attack in T1D, using a precise, multi-cell regulatory strategy to prevent or treat the disease safely and effectively.
Background Rationale
Type 1 diabetes (T1D) is an autoimmune disease in which the body’s immune system mistakenly attacks insulin-producing cells in the pancreas. This results in lifelong dependence on insulin and the risk of severe complications such as cardiovascular disease, kidney failure, and vision loss. Current therapies focus on managing blood sugar but do not address the underlying autoimmune attack, leaving patients vulnerable to progressive beta cell loss. A major challenge in developing a cure is finding a way to retrain the immune system to selectively tolerate insulin producing cells without broadly suppressing immunity, which could increase the risk of infection or cancer.
Our research addresses this challenge by leveraging a novel particle based approach to induce targeted immune tolerance. We have developed biodegradable microparticles (MPs) made from a polymer called acetalated dextran (Ace-DEX). These MPs are designed to bind specifically to B cells, which play a critical role in initiating and sustaining the autoimmune response in T1D. Once bound, the MPs convert B cells into regulatory B cells (Bregs), which then instruct other immune cells, including regulatory T cells (Tregs and Tr1 cells), to suppress harmful immune activity. This approach creates a coordinated network of regulatory cells capable of inducing antigen specific immune tolerance while minimizing unintended immune suppression.
The rationale for this strategy is supported by our prior work and unique observations. Unlike other particle based or cellular therapies, our Ace-DEX MPs do not require additional targeting molecules or immunosuppressive drugs. Preliminary studies show that these MPs naturally bind to B cells in the blood and tissues, triggering production of anti-inflammatory cytokines such as IL-10, a key marker of Breg function. These Bregs then act as antigen presenting cells, promoting the expansion of multiple regulatory T cell populations, including FoxP3+ Tregs and Type-1 regulatory cells (Tr1). This multi-layered regulatory response is likely to be more effective and durable than existing approaches that focus on a single regulatory cell type, which may not fully recapitulate the cooperative network of immune cells needed to control autoimmunity.
Our preclinical studies have been highly encouraging. In a mouse model of T1D, treatment with MPs carrying disease-relevant antigens delayed the onset of diabetes and reduced pancreatic inflammation. In models of multiple sclerosis, intravenous delivery of MPs carrying specific antigens dramatically reduced disease severity, highlighting the potential for systemic induction of tolerance. These results provide strong evidence that our particle platform can generate a broad and functional regulatory immune response capable of modifying autoimmune disease.
The significance of this work is further enhanced by the potential for antigen specific “infectious tolerance,” where the regulatory network generated by Bregs can suppress not only the targeted autoimmune response but also other bystander immune attacks. This could allow for a broader protective effect while avoiding generalized immunosuppression. By combining targeted B cell modulation with induction of multiple regulatory cell types, our approach represents a first of its kind strategy for preventing or treating T1D.
In summary, the background and rationale for this proposal are grounded in the urgent need for immune-targeted therapies in T1D, the unique ability of Ace-DEX MPs to induce multiple regulatory cell populations, and strong preliminary evidence from animal models. This project aims to advance a novel, safe, and potentially durable approach to retraining the immune system, with the ultimate goal of preventing or reversing T1D while establishing a platform that could be adapted to other autoimmune diseases in the future.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease in which the body’s immune system mistakenly attacks insulin-producing cells in the pancreas. Our project introduces a completely new approach to treating T1D by retraining the immune system to tolerate these cells rather than destroy them.
We have developed a microscopic delivery system made from a biodegradable material called acetalated dextran, or Ace-DEX. When formed into microparticles (MPs), this material has a remarkable and unexpected property: it binds naturally to B cells, a type of immune cell, without the need for special targeting molecules. Once attached, these MPs can reprogram B cells to become “regulatory” B cells (Bregs). Bregs are known to calm down harmful immune responses and promote the growth of other helpful regulatory cells, including FoxP3-positive regulatory T cells (Tregs) and Type-1 regulatory cells (Tr1). Together, these regulatory cells can prevent the immune system from attacking the body’s own tissues.
Our research suggests that this approach could lead to a new kind of antigen-specific immunotherapy for T1D. That means our treatment would teach the immune system to specifically tolerate the antigens (or molecular targets) involved in diabetes, rather than suppressing the entire immune system. We also expect to benefit from “infectious tolerance,” a process where trained regulatory cells can spread their calming effect to other immune cells, further reinforcing immune balance.
In preliminary studies, we showed that Ace-DEX MPs can both bind to B cells and trigger them to produce the anti-inflammatory signal IL-10, which marks their conversion into Bregs. These Bregs can then help stimulate the growth of FoxP3-positive Tregs and Tr1 cells, which are both critical for maintaining immune tolerance. This multi-layered regulatory network may achieve more durable and comprehensive immune control than existing therapies that target only one cell type.
We have already tested our technology in a mouse model of multiple sclerosis (MS), another autoimmune disease. When treated with Ace-DEX MPs carrying a specific MS-related antigen, mice showed dramatic improvement in disease symptoms, far greater than what has been reported with other therapies. We also observed encouraging early results in a diabetes model, where mice treated with our antigen-loaded MPs showed delayed onset of diabetes compared to untreated controls.
With support from Breakthrough T1D, we now aim to apply this technology to T1D specifically. Our project has two main goals:.
Aim 1 is to synthesize and characterize the Ace-DEX MPs loaded with several T1D-related antigens. We will confirm their physical properties and measure how efficiently they release their contents.
Aim 2 is to test these MPs in a well-established mouse model of T1D. We will deliver the particles and monitor whether they prevent or delay the onset of diabetes. We will also measure how well they expand regulatory immune cells and protect pancreatic tissue.
If successful, this work could represent a major step forward in treating autoimmune diseases. By teaching the immune system to tolerate specific antigens, we could stop disease progression without weakening overall immunity. This strategy may eventually reduce or eliminate the need for lifelong insulin therapy and other immunosuppressive drugs.
Looking ahead, we plan to expand this platform to additional diseases, explore licensing or company formation, and seek further NIH support to study the underlying mechanisms. If our initial results fall short, we will refine the design by adjusting the antigens used or adding compounds that further enhance regulatory responses.
This project introduces a completely new way to achieve long-lasting immune tolerance, with the potential to transform how T1D and other autoimmune diseases are treated.
Anticipated Outcome
The anticipated outcome of this project is the demonstration that our novel microparticle (MP) platform, made from acetalated dextran (Ace-DEX), can induce antigen specific immune tolerance in a mouse model of T1D. These MPs are designed to bind specifically to B cells and convert them into regulatory B cells (Bregs). In turn, Bregs instruct other immune cells, including regulatory T cells (Tregs and Tr1 cells), to suppress autoimmune responses. By generating multiple types of regulatory cells, this approach aims to create a coordinated network capable of controlling the immune attack against insulin producing cells.
We expect that administration of these MPs carrying T1D associated antigens will delay or prevent the onset of diabetes in mice, even in the presence of ongoing autoimmune activity. Treated mice are anticipated to show reduced inflammation in the pancreas, preservation of insulin producing cells, and the sustained presence of regulatory immune cells in key tissues such as the pancreas, lymph nodes, and spleen. This outcome would demonstrate that a single particle-based therapy can induce a broad, durable, and targeted immune regulatory response.
In addition to preventing disease, this project is expected to provide critical insight into the mechanisms by which Bregs and Tregs interact to maintain immune tolerance. By studying multiple antigens relevant to T1D, we anticipate identifying combinations that are most effective at inducing protective regulatory networks. These findings will inform the design of a therapy capable of long term protection in individuals at risk for T1D.
A key anticipated outcome is proof that our MP system can trigger antigen specific “infectious tolerance,” where regulatory cells not only suppress the targeted autoimmune response but also limit bystander immune attacks. This effect could broaden protection without causing generalized immune suppression, addressing a major limitation of current immunotherapies.
Ultimately, if successful, this project will provide strong preclinical evidence that Ace-DEX MPs represent a safe, targeted, and versatile platform for preventing or treating T1D. The findings are expected to support further development toward clinical translation, including optimization of particle formulation, dosing schedule, and antigen selection. In parallel, these studies will generate a foundation for exploring the platform in other autoimmune diseases, potentially expanding its therapeutic impact beyond T1D.
If challenges arise, we have planned mitigation strategies, including adjusting particle dose, antigen selection, or incorporating small molecules to enhance Breg responses. These adaptations are expected to preserve the therapeutic potential of the platform even if initial studies do not fully achieve the desired outcomes.
In summary, the anticipated outcome of this project is the establishment of a first-of-its-kind immune therapy capable of retraining the immune system to prevent or treat T1D. This therapy would leverage a network of regulatory cells to achieve antigen-specific tolerance, providing a pathway toward durable, safe, and effective treatment for autoimmune diabetes and potentially other autoimmune diseases.
Relevance to T1D
Type 1 Diabetes (T1D) is an autoimmune disease in which the body’s immune system mistakenly attacks the insulin producing cells in the pancreas. There is currently no cure, and most treatments focus on managing blood sugar levels rather than stopping the immune attack that causes the disease. Our research aims to change that by developing a new kind of immune therapy that retrains the body to stop attacking itself without shutting down the entire immune system.
Our team has created tiny biodegradable particles, called acetalated dextran (Ace-DEX) microparticles, that carry fragments of the same proteins targeted by the immune system in T1D. When injected, these microparticles attach to B cells, a type of immune cell, and convert them into B regulatory cells (Bregs). These Bregs act like peacekeepers in the immune system. They release calming signals and help train other immune cells, especially regulatory T cells (Tregs), to recognize these target proteins as safe. This process, called antigen specific tolerance, teaches the immune system to ignore the pancreatic cells it was mistakenly attacking while still protecting the body from infections.
This approach is innovative because it specifically targets B cells without requiring extra drugs or special targeting molecules and generates multiple types of regulatory cells, including Bregs, Tregs, and Tr1 cells. This creates a stronger and more lasting tolerance network. Unlike traditional therapies that focus on expanding just one type of regulatory cell or that broadly suppress the immune system, our technology works with the body’s natural immune pathways, reducing the risk of side effects. To our knowledge, no other technology has been shown to bind directly to B cells and convert them into a regulatory state without additional compounds.
We will first test our microparticles in NOD mice, a well-established model that mimics human T1D. These studies will measure how well the therapy prevents diabetes in mice at risk of developing the disease, whether it reduces inflammation in the pancreas, and how long the protective immune response lasts. Our preliminary studies are promising. In related experiments for multiple sclerosis, another autoimmune disease, our particles significantly reduced disease severity. Early data in diabetic models also show a delay in disease onset, suggesting that our approach can slow or even stop the progression of T1D.
If successful, this research could lead to a first-of-its-kind therapy that prevents or halts T1D by retraining the immune system without lifelong immune suppression. It could be used in people who are at risk but not yet diabetic to prevent disease onset, or in newly diagnosed patients to preserve their remaining insulin-producing cells. Because it addresses the root cause of T1D, which is the mistaken immune attack, this therapy could offer a safe, precise, and lasting solution. Moreover, it may be adaptable to treat other autoimmune diseases that share similar underlying mechanisms.