Objective
This project’s objective is to test a new, highly targeted way to protect transplanted insulin-producing cells from immune attack in type 1 diabetes. The team is developing “Navacims,” tiny biodegradable nanoparticles that carry carefully selected immune signals. Instead of broadly suppressing the immune system (as current transplant drugs do), Navacims are designed to re-educate a small set of immune cells so they stop attacking insulin-producing cells and, importantly, help calm inflammation in the transplant site.
The specific goal is to demonstrate—using advanced “humanized” mouse models with functional human immune systems—that human beta-cell–specific Navacims can create a local, protective immune environment around stem cell–derived islet (SC-islet) grafts. In practical terms, the project aims to show that Navacims can trigger the formation of immune “peacekeeping” cells that travel to the graft, reduce harmful immune activation nearby, and promote a state of transplant tolerance (meaning the immune system accepts the graft rather than attacking it).
To accomplish this, the study will:
1. Produce standardized, high-quality SC-islets for transplantation;
2. Confirm that Navacims generate the intended protective immune response (regulatory T cells) in fully humanized mice; and
3. Test whether this immune training strategy can prevent or delay long-term (“chronic”) rejection of transplanted SC-islets.
If the objective is achieved, the work will establish a strong preclinical foundation for a transplant-protective therapy that is precise, long-lasting, and potentially safer than lifelong immunosuppression.
Background Rationale
For people with type 1 diabetes, the immune system mistakenly destroys the body’s insulin-producing beta cells. For a small but important group of patients—especially those with repeated, dangerous episodes of severe low blood sugar—transplanting insulin-producing islet cells can be transformative. However, long-term success is limited, because transplanted cells face two immune problems at once:
1. Transplant rejection: the immune system recognizes donor cells as foreign.
2. Autoimmune recurrence: the same autoimmune response that caused type 1 diabetes can reactivate and attack the new beta cells.
Doctors typically prevent rejection with lifelong, broad immunosuppressive drugs, but these weaken the entire immune system and increase risks such as infections and certain cancers. For islet or stem cell–derived islet therapy—where the goal is to improve quality of life—this risk–benefit tradeoff can be especially difficult.
Recent advances (including stem cell–derived islets and genetic strategies to make cells harder for the immune system to recognize) are promising, but they may not fully solve the problem of slow, chronic immune injury. Even if transplanted cells are engineered to avoid direct recognition, immune cells can still “learn” about graft and beta-cell proteins indirectly, gradually rebuilding an attack over time.
Navacims were created to address this gap. Rather than shutting down immune defenses broadly, they aim to teach the immune system to respond differently—turning potentially harmful T cells into regulatory cells that suppress damaging immune activity in the right place, while leaving normal infection-fighting immunity intact.
The proposal builds on strong prior mechanistic work showing how this platform induces regulatory networks, and it highlights feasibility demonstrated in demanding transplant settings (including suppression of kidney allograft rejection even in donor-sensitized hosts).
Description of Project
People with type 1 diabetes (T1D) who experience dangerous, hard-to-control low blood sugars can sometimes be helped by replacing the insulin-producing “islet” cells that the immune system has destroyed. Traditional islet transplantation can be life-changing, but it rarely delivers lasting insulin independence for most recipients. A major reason is that the transplanted cells face a double threat: the recipient’s immune system can recognize the graft as “foreign” (rejection), and the underlying autoimmune response that caused T1D can reactivate and attack the new beta cells again. Today, preventing these immune attacks typically requires long-term, broad immunosuppressive drugs—medications that lower immune defenses and raise risks of infection, cancer, and other complications. This creates an urgent need for safer, more precise ways to protect transplanted islets without shutting down the entire immune system.
This proposal tests a targeted immune “re-education” strategy based on a nanomedicine platform the team has developed over many years. The therapy uses tiny nanoparticles coated with specific immune “ID badges” (pMHC class II). These particles—also called “Navacims”—are designed to interact with a very small subset of T cells that recognize those badges. Instead of activating these T cells to attack, the nanoparticles reprogram them into regulatory T cells that calm harmful immune responses in a focused way. Importantly, prior work in multiple autoimmune models suggests these regulatory cells can also quiet nearby inflammatory immune activity, controlling a broader damaging response in the affected tissue—without undermining normal immunity to vaccines or infections.
A key insight behind this approach is where and how the nanoparticles work. After injection, most nanoparticles are rapidly cleared, but a special network of cells in the spleen can capture and hold the particles on their surface for extended periods. This creates a stable “display” of the immune ID badges that selectively engages a helper T cell population involved in antibody responses. The therapy drives these helper cells to convert into regulatory cells, which then travel to sites of tissue injury and inflammation—such as a transplanted graft—where they can suppress the local immune activation that leads to chronic rejection and recurrent autoimmunity.
The project’s overall goal is to show that this targeted reprogramming can protect stem-cell-derived islets (SC-islets) in a highly rigorous test system: “humanized” mice that carry functional human immune systems. This matters because SC-islets could eventually provide an “off-the-shelf” renewable source of replacement cells. But even when SC-islets are engineered to be less visible to the immune system (for example, by modifying HLA genes), chronic rejection and autoimmune relapse may still occur because the immune system can attack indirectly through inflammation and antigen presentation by the recipient’s own immune cells. The proposed nanomedicine is aimed specifically at this chronic, indirect process.
The work is organized into three aims. First, the team will generate high-quality SC-islets suitable for transplantation using established differentiation and quality control methods. Second, they will test whether human T1D-relevant Navacims (built around common T1D-associated HLA types and beta-cell proteins) trigger the expected regulatory T cell responses in advanced humanized mouse models that can mount more complete immune reactions than older models. Third, they will transplant SC-islets into these mice and determine whether treatment with these Navacims delays or prevents graft failure, while tracking immune markers in blood and tissues to confirm the mechanism and specificity.
If successful, this project would provide strong preclinical evidence for a new class of therapies that protect transplanted islets by inducing graft-specific immune tolerance—potentially reducing or eliminating the need for life-long immunosuppression. The approach could be adapted to other transplanted tissues, offering a scalable and broadly applicable strategy to make cell replacement therapies safer and more durable.
Anticipated Outcome
This project is expected to deliver three major outcomes:
1) Proof that Navacims can “train” a human immune system in a rigorous model.
A key milestone is showing that Navacims reliably generate the intended protective immune cell type (regulatory, inflammation-calming T cells) in advanced humanized mice that can mount more realistic immune responses than older models. The study will measure these effects in blood, lymphoid organs, and at the graft site to confirm the mechanism.
2) Evidence that this immune training can protect stem cell–derived islet grafts over time.
The central practical question is whether Navacim treatment can extend graft survival and function, measured by improved blood sugar control, human C-peptide (a marker of insulin production), and glucose tolerance over time. The project will also examine graft tissue directly to assess immune cell infiltration and preservation of healthy islet structure.
3) A clear “translation package” for moving toward human studies.
Even if graft rejection in the model is less robust than expected, the work will still yield valuable outcomes: it will document pharmacodynamic activity (what the therapy does to the immune system), define the identity and behavior of the induced regulatory cells, and refine dosing/timing strategies. Together, these data are intended to support a realistic path toward clinical testing in transplant recipients.
Overall, the anticipated outcome is a strong preclinical demonstration that a precision immune-modulating therapy can reduce chronic immune damage to SC-islet grafts without relying on blanket immunosuppression.
Relevance to T1D
Type 1 diabetes is fundamentally an immune disease: the immune system destroys the beta cells needed to make insulin. While insulin therapy is lifesaving, it does not fully prevent dangerous complications in everyone. A subset of people experience repeated, severe hypoglycemia and unstable control despite best medical care. For them, replacing beta cells through islet transplantation can dramatically improve safety and quality of life—but current approaches are constrained because long-term success often depends on lifelong immunosuppression and still may not prevent late graft failure.
This project is directly relevant to type 1 diabetes because it targets the core barrier to durable cell replacement: the immune system’s capacity to reject new beta cells and to restart the autoimmune attack. By aiming to create a focused, graft-protective immune response, Navacims could make beta-cell replacement therapies safer and more durable.
The work is also timely because stem cell–derived islets could eventually provide a scalable supply of replacement cells—potentially expanding access far beyond the limited availability of donor islets. But for SC-islet therapy to become broadly useful, we need a way to protect these cells long-term without exposing patients to unacceptable risks. If Navacims can achieve targeted immune tolerance, the impact would be substantial:
1.Fewer complications from broad immunosuppressive drugs;
2. Improved durability of graft function; and
3. A more realistic pathway to long-term insulin independence or major reductions in insulin needs for people with T1D.
In short, the proposal addresses a central unmet need in T1D: enabling safe, lasting restoration of insulin production through cell replacement.