Objective
Our research focuses on developing a new, faster, and safer type of insulin-producing mini-organ called GINS (gastric insulin-secreting organoids). These are derived from stem cells found in the stomach, rather than the pancreas, and can be generated within about 10 days, much faster than current stem cell-derived islets. Preliminary work shows that GINS produce insulin and have intrinsically low immunogenicity, meaning they trigger much weaker immune reactions than typical β-cell grafts. When exposed to immune cells from other individuals in laboratory tests, GINS are less likely to be recognized and destroyed.
We have also discovered that GINS express high levels of a protein called HVEM (Herpesvirus Entry Mediator), which interacts with another molecule, BTLA, found on T cells, the immune cells responsible for attacking grafts. This HVEM/BTLA interaction acts as a natural “brake,” calming T cells and reducing their ability to kill target cells. This same mechanism is known to help some tumors escape immune attack, but here it could be repurposed for therapeutic benefit, helping transplanted cells survive safely in people with diabetes.
The objective of this project is to confirm and measure how much this HVEM/BTLA pathway contributes to the natural immune protection of GINS, and to determine whether this protection holds up in a realistic, human-like environment. To do this, we will use an advanced “organ-on-a-chip” system: a miniature, transparent device lined with human blood-vessel cells that allows us to flow immune cells past GINS and observe their interactions in real time. This setup mimics how immune cells encounter transplanted tissue in the body and lets us measure how well GINS withstand attack under blood-like flow.
We will compare GINS to conventional stem cell-derived islets, track T cell activation and killing, and test what happens when the HVEM/BTLA pathway is blocked. We will also analyze how the surrounding endothelial (blood-vessel) cells respond, since their activation can amplify or dampen immune damage. The outcome will be a set of quantitative metrics linking immune protection to molecular markers, creating a framework for predicting how “immune-safe” a graft is before transplantation.
If GINS are confirmed to use HVEM/BTLA to protect themselves, it would open the door to reducing the need for lifelong immunosuppression in β-cell replacement therapy. In the future, this could mean shorter, milder drug regimens or even drug-free graft survival. Clinically, that would make cell therapy safer and more accessible to children, women planning pregnancy, and others currently excluded. Scientifically, the project will establish a blueprint for engineering or selecting grafts that naturally engage immune tolerance, accelerating the path toward a durable, functional, and safer cure for Type 1 diabetes.
Background Rationale
For over a century, insulin injections have kept people with Type 1 Diabetes (T1D) alive but cannot replicate the body’s precise, minute-to-minute control of blood sugar. Even with advanced pumps and sensors, patients still face unpredictable glucose swings and long-term complications affecting the eyes, kidneys, and heart.
Scientists have long pursued a more complete solution: restoring the body’s own ability to make insulin by replacing the lost β-cells. Transplantation of pancreatic islets from organ donors can, in some cases, free patients from insulin injections for years. However, donor tissue is extremely limited, and even when successful, recipients must take powerful immune-suppressing drugs to prevent rejection. These medications carry serious risks, including infection, cancer, and kidney toxicity, making the treatment unsuitable for children and many adults. The next frontier in diabetes research is therefore to create renewable, immune-tolerant insulin-producing cells that can be transplanted safely without heavy, lifelong immunosuppression.
Current work focuses on β-cells derived from pluripotent stem cells. While promising, these cells are recognized as “foreign” and attacked by the immune system. Researchers have tried to hide them by removing “identity markers” that trigger rejection or by adding protective molecules like PD-L1. These approaches can help but require heavy genetic manipulation, raising concerns about genomic safety and durability. An alternative is to discover cell types that are naturally less visible to immune attack, cells that can “fly under the radar” without extensive editing.
Our work builds on this second idea. We recently developed gastric insulin-secreting organoids, or GINS, small clusters of cells derived from the stomach’s own stem cells that have been reprogrammed to produce insulin. Remarkably, these GINS can be generated in about ten days, compared with six weeks or more for conventional stem-cell-derived islets. Preliminary experiments show that GINS can lower blood glucose and reverse diabetes in animal models without forming tumors. Even more intriguing, GINS appear to be intrinsically hypoimmunogenic-their molecular profile and early immune tests suggest they provoke weaker T cell responses than standard β-cell grafts from the same donor.
Through single-cell RNA sequencing, we found that GINS express high levels of a receptor called HVEM (Herpesvirus Entry Mediator). HVEM interacts with an inhibitory molecule on immune cells known as BTLA (B and T Lymphocyte Attenuator). When HVEM binds BTLA, it sends a “stop” signal that dampens T cell activation, acting as a natural brake on immune attack. Interestingly, this same pathway has been exploited by tumors to escape immune surveillance. We propose that GINS may be using a similar, but beneficial, mechanism to protect themselves from destruction, a form of built-in immune tolerance that could be harnessed to make transplants safer.
To test this, we will use an advanced vascularized microfluidic “organ-on-a-chip” platform. This tiny, transparent device mimics blood flow and is lined with human endothelial (vessel) cells, allowing us to model how immune cells move, adhere, and interact with grafts in real time. Within this system, we can compare GINS and conventional islets, observe whether HVEM/BTLA signaling reduces T cell-mediated damage, and explore how endothelial activation influences graft protection.
Understanding this mechanism matters because it could reveal a new, local immune-regulatory pathway that limits rejection at the graft site. If GINS truly use HVEM–BTLA to achieve immune calm, future therapies could enhance this pathway, either by engineering HVEM-rich grafts or by giving short-term BTLA-activating treatments at transplantation, to reduce or even replace systemic immunosuppression. Ultimately, this research aims to transform β-cell replacement into a safer, more accessible therapy for people with Type 1 Diabetes, offering durable insulin independence without lifelong drug exposure.
Description of Project
Type 1 diabetes happens when the body’s immune system destroys the cells that make insulin. Transplants of insulin-making cells, such stem cell-derived β-cells, can help, but today they usually require strong, lifelong immune-suppressing drugs. Those drugs carry risks and keep many people, like kids or people planning pregnancy, from being eligible.
Our team is developing a different kind of insulin-making cell, called GINS, differentiated from stomach cells in the lab. Early results suggest GINS naturally are less susceptible to the immune system attack than current lab-made islet cells. We also found signs of a built-in “brake” that helps calm down attacking T cells. This brake involves two proteins that talk to each other, HVEM on the GINS and BTLA on immune cells.
In this project, we’ll test whether that HVEM/BTLA “peace signal” truly protects GINS during an immune attack. To make the tests realistic, we’ll use a tiny, blood-vessel-lined chip that lets immune cells flow past the graft, similar to what happens in the body. In addition we will assess the vessel contribution to the protection measuring how often immune cells stick, how quickly they kill, and whether the blood-vessel lining becomes leaky due to the attack.
If GINS are protected by this natural brake under lifelike conditions, it points to a future where less drug treatment is needed at the time of transplant. That could expand eligibility, improve safety, and make cell therapy more accessible and affordable. Even better, the “peace signal” and our chip-based test could guide improvements to many kinds of insulin-making cells, not just GINS, speeding progress toward durable, drug-lighter treatments for people with Type 1 diabetes.
Anticipated Outcome
This project will determine whether GINS (gastric insulin-secreting organoids) possess a natural ability to resist immune attack through the HVEM/BTLA pathway, a built-in “peace signal” between the graft and T cells. By testing GINS in a lifelike, blood-vessel-lined microfluidic chip, we will directly measure how effectively this mechanism prevents immune cells from recognizing and killing the transplanted tissue.
We expect to find that when the HVEM/BTLA interaction is intact, T cells remain less activated and cause minimal damage to GINS, while blocking this signal restores immune aggression. These findings would confirm that GINS use a self-protective checkpoint to maintain tolerance under physiological flow conditions.
Alongside this mechanistic insight, we will generate a quantitative set of immune-safety metrics, including T cell activation, graft survival, and endothelial barrier stability, that can serve as early indicators of how immunogenic a graft is before transplantation. This will be valuable not only for GINS, but for any β-cell-like product being developed for Type 1 Diabetes therapy.
If our hypothesis is correct, the study will provide a path to reduce the intensity or duration of systemic immunosuppression in future transplantation models. In the long term, these results could lead to β-cell replacement therapies that are safer, more accessible, and potentially drug-free.
Beyond diabetes, defining HVEM/BTLA-mediated tolerance will broaden our understanding of how human tissues communicate with the immune system, offering new strategies for designing immune-evasive grafts and improving the success of regenerative cell therapies across many diseases.
Relevance to T1D
HVEM/BTLA protection axis validation will shift the therapeutic paradigm from global immune suppression to targeted, graft-specific immune modulation. Clinically, strategies could include selecting or engineering β-cell grafts with high HVEM expression that preferentially binds to BTLA or using biomaterials that present HVEM ligands locally. Each approach aims to contain immune regulation to the graft site, minimizing drug exposure while preserving immune competence elsewhere. In summary, dissecting the HVEM/BTLA axis in GINS not only explains their natural immune resistance but also provides a rational, mechanistically grounded path toward lower-dose, shorter-term, or localized immunosuppression, making durable β-cell replacement safer and more widely accessible for people with Type 1 Diabetes. In addition we will analyse the role that the vascular endothelium, the thin layer of cells lining blood vessels, plays in shaping immune recognition and attack during β-cell autoimmunity and transplantation. In Type 1 Diabetes, inflammatory cytokines and autoreactive T cells not only target β-cells but also activate nearby endothelial cells, increasing expression of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin. This endothelial activation recruits more immune cells to the islet microvasculature, amplifying local inflammation and accelerating β-cell destruction. Despite its central role, the endothelial component of graft immunogenicity remains poorly quantified in current β-cell replacement studies. Our project addresses this gap by integrating endothelial contribution metrics into a vascularized microfluidic “immune-on-chip” platform. In this system, insulin-producing organoids (GINS or iPSC-islets) are surrounded by human endothelial cells exposed to physiological flow. Measuring endothelial activation (ICAM-1, VCAM-1, VE-cadherin, E-selectin), barrier permeability, and immune-cell trafficking provides quantitative insight into how the vascular niche either amplifies or restrains immune injury. These readouts are directly relevant to T1D because they model the earliest microvascular events that govern whether an immune response becomes destructive or tolerogenic. Comparing endothelial activation between hypoimmunogenic GINS and standard β-cell grafts will reveal whether immune protection extends beyond the graft cells to their surrounding vasculature. If GINS induce a “quieter” endothelial state, marked by intact barrier function and reduced adhesion molecule expression, it would demonstrate a dual mechanism of immune tolerance: graft-intrinsic (HVEM/BTLA) and vascular-modulated. Ultimately, establishing endothelial contribution metrics will enable predictive, quantitative evaluation of new β-cell products before transplantation. This will accelerate the design of safer, immune-evasive therapies for T1D by providing mechanistic, human-relevant criteria for graft acceptance under physiological flow conditions.