Objective
The objective of this research is to understand and interrupt the local immune processes that drive the destruction of insulin-producing cells in type 1 diabetes (T1D). Although T1D is commonly described as an autoimmune disease in which the immune system attacks pancreatic beta cells, many existing treatments focus on suppressing immune activity throughout the body rather than addressing what happens directly inside the pancreas. Increasing evidence suggests that immune attacks in T1D are maintained locally within the pancreatic tissue itself, even when immune activity in the bloodstream appears controlled. This project aims to identify and target the specific tissue-level mechanisms that allow autoimmune responses to persist and intensify within the pancreas.
A central focus of this work is on structures called tertiary lymphoid structures, or TLSs. TLSs are organized clusters of immune cells that form in tissues exposed to long-term inflammation. In T1D, TLSs can form within or near pancreatic islets and resemble small lymph nodes. They contain B cells, T cells, specialized blood vessels, and supportive stromal cells that help organize immune responses. Rather than being passive byproducts of inflammation, TLSs may actively sustain and amplify autoimmune attacks against beta cells by repeatedly presenting beta cell antigens to immune cells.
The primary objective of this project is to determine whether TLSs actively drive autoimmune damage in T1D and whether disrupting specific molecular pathways within TLSs can halt disease progression. The project focuses on a key immune amplification mechanism involving the complement system, a part of the immune response that marks antigens for recognition. Complement fragments can bind to antigens released from damaged beta cells and engage a receptor on B cells called CD21. This interaction strengthens B-cell activation and promotes ongoing immune stimulation within TLSs.
To address this, the project has two main goals. First, it will test whether blocking the interaction between complement fragments and CD21 can reduce chronic immune activation within pancreatic TLSs and prevent or delay diabetes in a well-established mouse model of T1D. Second, it will develop a more advanced strategy that selectively silences the most pathogenic B cells within TLSs using a dual-targeting approach, while leaving protective immune functions intact.
In parallel with animal studies, the project will examine blood and pancreatic tissue from people with T1D to determine whether similar immune signatures are present in humans. This includes measuring specific B-cell populations in blood that reflect chronic immune stimulation and linking them to immune structures found in pancreatic tissue. Together, these studies aim to bridge laboratory discoveries with human disease.
Ultimately, the objective of this research is to shift the treatment paradigm for T1D. Instead of broadly suppressing the immune system or repeatedly replacing destroyed beta cells, this work seeks to dismantle the local immune environments that sustain autoimmunity. By targeting the underlying tissue-level mechanisms, the project aims to open new paths toward safer, more durable therapies that preserve insulin-producing cells and improve long-term outcomes for people with T1D.
Background Rationale
Type 1 diabetes develops when the immune system mistakenly attacks insulin-producing beta cells in the pancreas. While insulin therapy is lifesaving, it does not address the underlying autoimmune process. Even newer immune-based treatments have had limited success because they often suppress immune activity throughout the body rather than targeting the specific sites where immune damage occurs. A major unanswered question in T1D research is why immune attacks continue inside the pancreas even when immune activity elsewhere is reduced.
Recent research has highlighted the importance of tertiary lymphoid structures (TLSs) in chronic autoimmune diseases. TLSs are organized immune structures that form in tissues experiencing long-term inflammation. In the pancreas, TLSs can arise within or near insulin-producing islets and resemble miniature lymph nodes. They contain organized regions of immune cells, including B cells and T cells, as well as specialized stromal cells that support immune cell survival and interaction. Unlike lymph nodes, TLSs are embedded directly in damaged tissue and are constantly exposed to self-antigens released from injured cells.
The rationale for this project is based on the idea that TLSs act as local immune “command centers” that perpetuate autoimmune activity in T1D. Within TLSs, specialized stromal cells can retain immune complexes that contain beta cell antigens tagged by complement proteins. This creates a persistent source of antigen that repeatedly stimulates B cells. A key molecule in this process is CD21, a receptor on both FDCs and B cells that binds complement-tagged antigens and amplifies immune signaling. This repeated stimulation can drive antibody diversification, recruitment of additional immune cells, and ongoing beta cell destruction.
Importantly, chronic immune stimulation leaves detectable traces in the blood. B cells exposed to repeated activation often reduce their expression of CD21, creating a population known as CD21-low B cells. These cells have been observed in several autoimmune diseases and may serve as indicators of ongoing tissue-level immune activity. Studying these cells in people with T1D provides a way to connect blood-based immune signatures with what is happening inside the pancreas.
The rationale for targeting the CD21 pathway is that it plays a central role in amplifying immune responses but is not required for normal immune protection. Blocking this pathway could selectively dampen harmful immune activity within TLSs while preserving the body’s ability to fight infections and respond to vaccines. This approach differs fundamentally from therapies that eliminate B cells entirely or suppress immunity globally, which can increase infection risk and require long-term treatment.
In addition, the project explores a second strategy that selectively targets the most pathogenic B cells within TLSs using a dual-recognition system. This approach is designed to silence immune cells only when they display a specific combination of markers associated with TLS engagement, providing an additional layer of precision.
Together, these ideas form the rationale for a new therapeutic strategy focused on dismantling local autoimmune niches rather than broadly suppressing immunity or replacing destroyed cells.
Description of Project
Type 1 diabetes (T1D) develops when the immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. Many current treatments manage blood sugar but do not stop the underlying autoimmune process. Even newer immunotherapies that can delay disease onset often do not provide a durable cure, in part because immune attacks can continue locally within the pancreas even when immune activity in the blood appears controlled. A growing body of evidence suggests that a key reason for this persistence is the formation of tertiary lymphoid structures (TLSs). TLSs are organized clusters of immune cells that arise in chronically inflamed tissues. In T1D, these structures can form within or near pancreatic islets and resemble miniature lymph nodes.
This project focuses on the idea that TLSs are not simply signs of inflammation. Instead, they may actively maintain the autoimmune process by creating a local “immune niche” that repeatedly stimulates B cells and T cells with beta cell antigens. Within TLSs, specialized stromal networks, similar to follicular dendritic cells, can retain immune complexes. These are packages of antigen bound to antibodies and complement fragments such as C3d. This retention can provide a long-lasting source of antigen that repeatedly triggers B cells. Over time, this repeated stimulation can drive germinal center–like activity, diversification of autoantibodies, and epitope spreading. It can also leave a measurable signature in the blood. Chronically stimulated B cells often downregulate CD21, generating CD21-low B-cell populations that are thought to reflect repeated follicular activation.
We propose a new therapeutic strategy aimed at interrupting this local amplification circuit rather than broadly suppressing immunity or eliminating B cells. We identified peptides that bind CD21 and block the natural interaction between CD21 and C3d. In NOD mice, a well-established model of T1D, we will test whether blocking C3d–CD21 can prevent or delay diabetes by reducing TLS maturation, decreasing local immune activation, and preserving beta cell mass. We will also verify that this approach preserves normal immune protection by monitoring antibody levels and vaccine-like recall responses to a standard model antigen.
In parallel, we will leverage access to blood samples and pancreatic tissue from T1D patients and age matched non-diabetic people to determine whether we can identify evidence of chronic stimulation signatures of B cells in T1D patients. We will measure CD21-low B-cell populations in blood and relate them to pancreatic TLS features in tissue. These studies will connect mechanism to human disease and identify biomarkers that can guide future clinical development.
In addition, we harness lysosomal degrader technology, is a new type of treatment that works by tagging unwanted proteins on the surface of cells and directing them to the cell’s recycling system, where they are safely broken down, turning off harmful signals without destroying the cell itself. We will develop a highly targeted molecule that acts only on the B cells most responsible for sustaining the autoimmune attack. Instead of killing these cells, it gently disables their ability to capture and present antigens, which are the signals that keep the immune response going. This precision approach is intended to quiet the damaging immune activity in the pancreas while leaving the rest of the immune system free to protect against infections and respond normally to vaccines.
If successful, this work will establish a new way to treat T1D by dismantling the tissue-local immune structures that sustain autoimmunity, potentially enabling safer and more durable disease modification than current immune-depleting or cell replacement strategies.
Anticipated Outcome
If successful, this research is expected to deliver several important outcomes that advance understanding and treatment of type 1 diabetes. First, it will clarify whether tertiary lymphoid structures actively drive autoimmune damage in the pancreas rather than merely reflecting inflammation. Demonstrating that disrupting specific pathways within TLSs can halt or slow disease progression would fundamentally change how T1D is understood and treated.
One anticipated outcome is evidence that blocking the interaction between complement fragments and the CD21 receptor reduces chronic immune activation within pancreatic tissue. In animal models, this would be reflected by fewer or less mature TLSs, reduced immune cell activation, and preservation of insulin-producing beta cells. Importantly, these benefits are expected to occur without impairing normal immune responses elsewhere in the body.
Another expected outcome is the identification of blood-based immune markers that reflect ongoing autoimmune activity within the pancreas. Measuring CD21-low B cells in people with T1D and linking them to pancreatic immune structures could provide new biomarkers to track disease progression and treatment response. Such biomarkers would be invaluable for future clinical trials and personalized treatment strategies.
The project also aims to demonstrate the feasibility of a highly selective immune-modulating strategy using a dual-targeting molecular approach. If successful, this would show that it is possible to silence pathogenic immune cells within TLSs without killing them or affecting the broader immune system. This concept could be applied beyond T1D to other autoimmune diseases where TLSs contribute to tissue damage.
In the longer term, successful completion of this work would lay the foundation for developing human therapies that target tissue-level immune circuits. These therapies could complement existing treatments or be used earlier in disease to preserve remaining beta cell function. They could also reduce the need for chronic immunosuppression or repeated cell replacement procedures.
Overall, the anticipated outcomes include new mechanistic insights, new biomarkers, and new therapeutic strategies that together could significantly improve how T1D is treated.
Relevance to T1D
Type 1 diabetes affects millions of people worldwide and requires lifelong management. Despite decades of research, there is still no cure, and most treatments focus on managing blood sugar rather than stopping the immune attack that causes the disease. This research is highly relevant to T1D because it addresses a central reason why current therapies have fallen short: they do not eliminate the local immune environments within the pancreas that sustain autoimmune destruction.
The discovery that organized immune structures can form inside the pancreas helps explain why immune attacks persist even when systemic immune activity is controlled. These tertiary lymphoid structures provide a protected niche where immune cells can repeatedly interact with beta cell antigens, reinforcing autoimmune responses over time. By focusing on these structures, the proposed research targets the disease at its source rather than its consequences.
This work is particularly relevant given the limitations of existing approaches. Broad immune suppression can delay disease progression but carries risks of infection and cancer. B-cell depletion therapies can reduce immune activity temporarily but do not prevent disease recurrence once treatment stops. Islet replacement therapies can restore insulin production but do not address the autoimmune processes that destroyed the original cells, leaving new cells vulnerable to attack and requiring long-term immunosuppression.
By contrast, targeting specific pathways that sustain immune activation within TLSs offers a more precise and potentially safer approach. Blocking complement-mediated B-cell activation or selectively silencing pathogenic B cells could reduce autoimmune damage while preserving the immune system’s ability to fight infections and respond to vaccines. This is especially important for children and young adults, who make up a large proportion of people with T1D.
In addition, the use of patient blood and pancreatic tissue in this research ensures that findings are directly relevant to patients. Identifying immune signatures that reflect pancreatic autoimmunity could lead to better disease monitoring and more personalized treatment decisions.
In summary, this research is highly relevant to T1D because it tackles the underlying immune mechanisms that drive the disease, offers a path toward more durable and safer therapies, and has the potential to change how autoimmune diabetes is treated in the future.