Table of Contents
Introduction: The Promise and Challenge of Islet Cell Transplantation
For millions of people living with type 1 diabetes worldwide, the prospect of freedom from daily insulin injections represents more than convenience—it represents a fundamental transformation in quality of life. Islet cell transplantation has emerged as a promising avenue for functionally replacing endogenous insulin production and achieving long-term glycemic stability. This innovative procedure involves transferring insulin-producing cells from a donor pancreas into a recipient, offering the potential to restore natural blood sugar regulation and eliminate the constant burden of diabetes management.
Despite remarkable advances in recent years, one formidable obstacle continues to limit the widespread adoption of this potentially life-changing therapy: immune rejection. Immune rejection and insufficient vascularization hinder the survival and function of transplanted islets. The recipient’s immune system, designed to protect against foreign invaders, often recognizes transplanted islet cells as threats and mounts an aggressive attack that can destroy the graft. This fundamental immunological challenge has driven researchers worldwide to develop innovative strategies that could make islet transplantation a viable, long-term solution for diabetes treatment.
The field is now experiencing a renaissance of innovation, with groundbreaking immunomodulation strategies emerging from laboratories and clinical trials around the globe. From genetically engineered cells that evade immune detection to sophisticated encapsulation technologies and precision immunotherapy approaches, researchers are developing multiple pathways to overcome the rejection barrier. This article explores the cutting-edge immunomodulation strategies that are transforming islet cell transplantation from an experimental procedure requiring lifelong immunosuppression into a potentially curative therapy for type 1 diabetes.
Understanding Islet Cell Transplantation: From Concept to Clinical Reality
What Are Islet Cells and Why Are They Important?
Pancreatic islets, also known as islets of Langerhans, are clusters of specialized cells within the pancreas that play a crucial role in blood sugar regulation. These microscopic cell clusters contain several cell types, with beta cells being the most critical for diabetes treatment. Beta cells produce and secrete insulin, the hormone responsible for allowing glucose to enter cells throughout the body for energy. In type 1 diabetes, the immune system mistakenly destroys these beta cells, leaving patients unable to produce insulin naturally and dependent on external insulin administration.
The concept of islet transplantation is elegantly simple: replace the destroyed insulin-producing cells with healthy ones from a donor. However, the execution of this concept has proven extraordinarily complex, requiring sophisticated isolation techniques, careful preservation methods, and strategies to ensure the transplanted cells survive and function in their new environment.
The Evolution of Islet Transplantation Protocols
Remarkable progress has occurred in the last three years, with dramatic improvements in outcomes after clinical islet transplantation. The introduction of a steroid-free, sirolimus-based, anti-rejection protocol and islets prepared from two (or rarely three) donors led to high rates of insulin independence. This breakthrough, known as the Edmonton Protocol, marked a turning point in the field when it was introduced in 2000.
The Edmonton protocol (2000) marked a shift away from glucocorticoids to prevent β cell damage specifically. This transition led to the development of combination immunosuppressive therapies and the emergence of less toxic immunosuppressive and anti-inflammatory drugs. The protocol’s success demonstrated that islet transplantation could achieve insulin independence in carefully selected patients, though it also highlighted the ongoing challenges related to long-term graft survival and the burden of immunosuppression.
More recently, the Food and Drug Administration (FDA) approval of Lantidra (donislecel-jujn) in 2023, the first FDA-approved allogeneic cellular therapy made from donor pancreatic islet cells for the treatment of T1D represented another milestone, validating islet transplantation as a legitimate therapeutic option for patients with severe type 1 diabetes who experience dangerous hypoglycemic episodes.
Current Clinical Applications and Patient Selection
Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness and high risk of severe hypoglycemia. However, intensive immunosuppression is required to prevent immune rejection of the graft, that may in turn lead to undesirable side effects such as toxicity to the islet cells, kidney toxicity, occurrence of opportunistic infections, and malignancies.
Currently, islet transplantation is primarily reserved for patients with type 1 diabetes who experience severe complications despite optimal medical management. These include individuals with hypoglycemia unawareness—a dangerous condition where patients cannot detect when their blood sugar drops to dangerously low levels—and those with frequent severe hypoglycemic episodes that significantly impair quality of life and pose serious health risks.
The procedure typically involves infusing isolated islet cells into the hepatic portal vein, where they lodge in the liver and begin producing insulin. Daclizumab (non-depleting monoclonal anti-interleukin-2 receptor antibody) and/or anti-thymocyte globulin is administered as pre-procedural induction immunosuppression, whereas low-dose tacrolimus (calcineurin inhibitor) in combination with mycophenolate mofetil or sirolimus is prescribed for maintenance immunosuppression. While this approach has proven effective, the requirement for lifelong immunosuppression remains a significant limitation that researchers are working diligently to overcome.
The Immunological Challenge: Why Transplanted Islets Face Rejection
Understanding Immune Rejection Mechanisms
The human immune system is a sophisticated defense network designed to identify and eliminate foreign substances, including transplanted cells from another individual. When islet cells from a donor are introduced into a recipient’s body, the immune system recognizes these cells as “non-self” through molecular markers called major histocompatibility complex (MHC) molecules, also known as human leukocyte antigens (HLA) in humans.
This recognition triggers a cascade of immune responses involving multiple cell types and signaling pathways. T cells, particularly CD4+ helper T cells and CD8+ cytotoxic T cells, play central roles in orchestrating and executing the rejection response. B cells contribute by producing antibodies against donor antigens, while innate immune cells such as macrophages and natural killer cells can also participate in graft destruction.
Although current immunosuppressive protocols effectively prevent the acute rejection associated with initial T cell activation in recipients, chronic rejection has remained an obstacle for achieving long-term allogeneic islet engraftment. Acute rejection typically occurs within days to weeks after transplantation and involves rapid immune cell infiltration and destruction of the graft. Chronic rejection develops more gradually over months to years and involves progressive fibrosis, vascular changes, and gradual loss of graft function.
The Dual Challenge: Alloimmunity and Autoimmunity
Islet transplantation in type 1 diabetes patients faces a unique double challenge. Not only must the transplanted cells contend with alloimmune rejection—the recipient’s immune response to foreign donor tissue—but they must also survive in an environment where autoimmunity originally destroyed the patient’s own beta cells.
Both alloimmune and autoimmune barriers must be controlled, if stable graft function is to be maintained long-term. The autoimmune response that caused the original diabetes can potentially attack transplanted islets, even if they are from a different donor. This means that successful immunomodulation strategies must address both forms of immune attack simultaneously.
Induction of immunosuppression with anti-thymocyte globulin as compared to daclizumab, and maintenance of immunosuppression with tacrolimus as compared to sirolimus, has been shown to increase risk of autoantibody recurrence in islet transplantations. This study highlighted the “off-target” effects of immunosuppressants, particularly how immunosuppressants influence the profile of regulatory T cells (Tregs), which are an important subset of immunomodulatory T cells responsible for promoting immune tolerance. This finding underscores the complexity of managing the immune response in islet transplantation and the need for more sophisticated, targeted approaches.
The Burden of Traditional Immunosuppression
The need for systemic immunosuppression remains the primary barrier to making islet transplantation a more widespread therapy for patients with T1D. Traditional immunosuppressive drugs work by broadly dampening immune system activity, which prevents rejection but comes at a significant cost.
Most of these ISDs require life-long administration and have increased risk of multiple adverse reactions, including susceptibility to infection and incidence of secondary cancers. In addition, survival of the transplanted islets is shortened due to direct toxic effects of the ISDs on islet β cells. Common immunosuppressive medications like tacrolimus can cause kidney damage, while others may increase the risk of cardiovascular disease, metabolic complications, and opportunistic infections.
The paradox is clear: the very drugs needed to protect transplanted islets from immune destruction can themselves damage those islets and harm the patient’s overall health. Short-term side effects and long-term health risks of lifelong systemic immunosuppression compromise the otherwise extraordinary benefits that accrue from a successful graft. This reality has driven the search for alternative approaches that can protect transplanted islets without the broad immunosuppression that current protocols require.
Breakthrough Immunomodulation Strategies: A New Era of Possibilities
The limitations of traditional immunosuppression have catalyzed an explosion of innovative research into alternative strategies for protecting transplanted islets. Innovations such as encapsulation devices, universal stem cells, and immunomodulatory strategies are being developed to mitigate immune rejection and prolong the function of the transplant. These approaches represent fundamentally different paradigms—rather than broadly suppressing the entire immune system, they aim to create localized protection, induce specific tolerance, or engineer cells that can evade immune detection altogether.
Tolerance Induction: Teaching the Immune System to Accept Transplanted Cells
The development of donor-specific immune tolerance to the allograft is the ultimate goal given its potential ability to overcome chronic rejection and disregard the need for maintenance immunosuppression, which may be toxic to islet grafts. Tolerance induction represents the holy grail of transplantation immunology—a state where the recipient’s immune system specifically accepts the transplanted tissue as “self” while maintaining normal immune function against pathogens and cancer cells.
Apoptotic Donor Leukocytes: A Promising Approach
Recently, a breakthrough in tolerance induction during allogeneic islet transplantation using apoptotic donor lymphocytes (ADLs) in a non-human primate model had been reported. As recently as 2019, Sigh et al. reported on a breakthrough in the tolerance induction protocol for allogeneic islet transplantation in non-human primate (NHP) models.
This approach for inducing donor-specific tolerance is unique in that it involves the strategic exposure of the recipient to donor antigens prior to transplantation. The technique uses donor white blood cells that have been treated to undergo apoptosis (programmed cell death) and then infused into the recipient around the time of transplantation. When the immune system encounters these apoptotic cells, it responds differently than it would to living foreign cells—instead of mounting an aggressive attack, it can develop tolerance to the donor antigens.
Their protocol involves peritransplant infusions of MHC-DRB allele-matched apoptotic donor leukocytes under short-term immune suppressions, including antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor, and anti-interleukin 6 receptor antibody. This combination approach has shown remarkable success in non-human primate models, achieving long-term islet graft survival without the need for chronic immunosuppression.
Costimulation Blockade and Mixed Chimerism
New protocols based on costimulation blockade have brought us close to that goal, inducing states of both peripheral and central transplantation tolerance. Costimulation blockade works by interrupting the secondary signals that T cells need to become fully activated. Without these costimulatory signals, T cells that recognize donor antigens may become anergic (unresponsive) or die, rather than attacking the transplant.
Another sophisticated tolerance induction strategy involves creating mixed chimerism—a state where both donor and recipient immune cells coexist in the recipient’s body. This strategy has been used to achieve tolerance of allogeneic kidneys in multiple clinical studies, and has been shown to promote survival of allogeneic islets after withdrawal of immunosuppression in NHP pre-clinical models. By establishing a population of donor-derived immune cells in the recipient, the immune system can be “educated” to recognize donor tissues as self.
Two most promising cell-based therapeutic strategies for inducing immune tolerance include T regulatory cells (Tregs) and donor and recipient hematopoietic mixed chimerism. These approaches represent fundamentally different mechanisms for achieving the same goal: long-term graft acceptance without chronic immunosuppression.
Regulatory T Cells: Harnessing the Body’s Natural Tolerance Mechanisms
Regulatory T cells (Tregs) are a specialized subset of T cells that naturally suppress immune responses and maintain self-tolerance. By virtue of their role in controlling alloreactive T cell responses to organ and tissue grafts, regulatory T cells (Tregs) are considered as promising alternatives to pharmacologic agents to promote engraftment and survival of the transplanted organs/tissues. Peripheral tolerance established by Tregs is crucial to prevent immune-mediated rejection of the transplanted graft.
Adoptive Treg Therapy
One promising strategy in preclinical studies is the adoptive transfer of in vitro culture expanded Tregs to prevent the rejection of donor islet grafts and at least one clinical trial testing this approach is underway (NCT03444064). This phase I clinical trial aims to assess the safety and feasibility of autologous polyclonal Tregs in islet transplant patients.
The approach involves isolating Tregs from the patient’s blood, expanding them to large numbers in the laboratory, and then infusing them back into the patient around the time of islet transplantation. These expanded Tregs can help suppress the immune response against the transplanted islets, potentially reducing or eliminating the need for traditional immunosuppressive drugs.
Immunophenotyping revealed reduced infiltration of CD4+ or CD8+ T effector cells and increased infiltration of T regulatory cells within the allografts cotransplanted with eMSCs compared to controls. This finding demonstrates that strategies promoting Treg accumulation at the graft site can significantly improve transplant outcomes.
Engineering Enhanced Tregs
Researchers are also developing genetically engineered Tregs with enhanced suppressive capabilities or specificity for donor antigens. Researchers developed stem cell-derived islets that secreted a combination of immunomodulatory cytokines: interleukin-10 (IL-10), transforming growth factor beta (TGFβ), and a modified IL-2 (IL-2 mutein N88D), designed to selectively expand Treg cells. This strategy created a local immunosuppressive environment at the graft site, significantly improving stem cell-derived islet survival and function.
This approach represents a sophisticated strategy where the transplanted islets themselves create a protective microenvironment by secreting factors that promote Treg expansion and activity. By engineering cells to produce these immunomodulatory molecules locally, researchers can achieve targeted immune regulation at the graft site without systemic effects.
Checkpoint Inhibitor Pathways: Leveraging Immune Regulation Mechanisms
Immune checkpoint molecules are regulatory proteins that normally prevent excessive immune activation and maintain self-tolerance. Researchers have discovered that manipulating these pathways can protect transplanted islets from rejection.
Targeting the PD-1/PD-L1 pathway was shown to regulate and delay immune destruction of allograft in cardiac, islet, and corneal transplantation. Similarly, the cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4-Ig) fusion protein, which competitively blocks the CD28-B7 pathways, was shown to inhibit T cell activation and prevent allograft rejection in skin, cardiac, liver, and islet transplantation.
Engineered Mesenchymal Stromal Cells
Researchers engineer programmed death ligand-1 and cytotoxic T lymphocyte antigen 4 immunoglobulin fusion protein–modified mesenchymal stromal cells (MSCs) as accessory cells for islet cotransplantation. The engineered MSCs (eMSCs) improved the outcome of both syngeneic and allogeneic islet transplantation in diabetic mice and resulted in allograft survival for up to 100 days without any systemic immunosuppression.
MSCs can improve the efficacy of IT in animal models, especially in regulating immune responses and protecting islet transplants. MSCs can improve insulin resistance in peripheral tissues through potential immunomodulatory and anti-inflammatory effects and promote pancreatic β-cell regeneration and protection. These multipotent cells can be easily obtained from various tissues including bone marrow, adipose tissue, and umbilical cord blood, making them an accessible resource for developing cell-based immunomodulation strategies.
The results suggest that the eMSCs can induce local immunomodulation and may be applicable in clinical islet transplantation to reduce or minimize the need of systemic immunosuppression and ameliorate its negative impact. This localized approach represents a significant advantage over systemic immunosuppression, as it concentrates immune regulation at the site where it’s needed most while preserving normal immune function elsewhere in the body.
Encapsulation Technologies: Physical Barriers Against Immune Attack
Encapsulation represents a fundamentally different approach to protecting transplanted islets—rather than modulating the immune response, it creates a physical barrier that shields the cells from immune attack while allowing nutrients, oxygen, and insulin to pass through.
Biocompatible Encapsulation Devices
It uses the same pancreatic islet stem cells as VX-880, but these cells are encapsulated within a surgically implantable canal-arterial protective device to shield them from the recipient’s immune system. The completion of the study is aimed for May 2026 (NCT05791201). This approach, being developed by Vertex Pharmaceuticals as VX-264, represents one of several encapsulation strategies currently in clinical development.
Encapsulation devices typically consist of biocompatible polymers that form a semipermeable membrane around the islet cells. The pore size of these membranes is carefully engineered to allow small molecules like glucose, oxygen, and insulin to diffuse freely while blocking larger immune cells and antibodies from reaching the encapsulated islets.
When transplanted into immunocompetent diabetic animals (mice, rats, and pigs), these encapsulated human and rat islets maintained functionality and achieved durable blood glucose control for >140 days without requiring systemic IS. The demonstration of efficacy in both small and large animal models validates the engineering principles and confirms that scalable, off-the-shelf physical isolation is feasible for clinical application.
Advantages and Challenges of Encapsulation
The primary advantage of encapsulation is that it can potentially eliminate the need for immunosuppression entirely. Patients receiving encapsulated islets could theoretically achieve insulin independence without the risks and side effects associated with immunosuppressive drugs. Additionally, encapsulation devices could potentially be retrieved if problems arise, offering a level of reversibility not possible with unencapsulated cell transplants.
However, encapsulation also faces significant challenges. Ensuring adequate oxygen supply to encapsulated cells has been a persistent problem, as the capsule material itself can impede oxygen diffusion. Foreign body responses to the encapsulation material can lead to fibrosis and reduced function over time. Additionally, the size and placement of encapsulation devices require careful consideration—some devices are small enough to inject, while others require surgical implantation.
In 2017, ViaCyte conducted phase 1/2 clinical trial (VC-02, NCT03163511) utilizing the PEC-Encap system, which encapsulated pluripotent stem cell-derived pancreatic endoderm cells (PECs). However, since the encapsulated cells are pancreatic progenitor cells rather than fully matured islet β-cells, which may adversely affect the efficacy of the treatment. This highlights the importance of using fully differentiated, functional islet cells in encapsulation approaches.
Genetic Engineering: Creating Hypoimmunogenic Islet Cells
One of the most revolutionary approaches to overcoming immune rejection involves genetically engineering islet cells to make them “invisible” or less recognizable to the immune system. This strategy, often called creating “hypoimmunogenic” or “immune-evasive” cells, has shown remarkable promise in recent studies.
Breakthrough Clinical Results
On Jan 7, 2025 (Sweden), Sana Biotechnology released significant clinical data: the first person with type 1 diabetes (T1D) who received deceased donor islets engineered to evade the immune system is producing insulin without immunosuppression. At the Advanced Technologies & Treatment for Diabetes international conference held in Barcelona, Spain Per-Ola Carlsson, M.D., Ph.D., presented updated results from a Sana’s clinical trial involving a novel cell therapy approach designed to help transplanted islet cells evade immune attack via gene editing while continuing to produce insulin.
After 60 weeks, the single participant has reported no severe or unexpected adverse events, meeting the trial’s primary safety endpoint. At 14 months after transplantation, the participant continued to produce detectable C-peptide, indicating that the transplanted cells remained alive and functional. This landmark achievement represents the first demonstration that gene-edited, immune-evasive islet cells can function in a human patient without immunosuppression.
The single patient dosed with hypoimmune donor islets continues to produce insulin in response to a mixed meal tolerance test (MMTT) without the use of immunosuppressants. While this is still very early data from a single patient, it provides crucial proof of concept for this approach.
How Hypoimmunogenic Cells Work
Immune-evasive hPSC-derived islet cells can be developed through genome-editing of the hiPSC source to knock out MHC class I and II molecules and knock in other immunomodulatory markers to evade different T cell and NK cell recognition, creating a tolerogenic microenvironment for allogeneic transplantation. When transplanted in humanized diabetic mouse models, unedited allogeneic hiPSC-derived islet cells face graft rejection, whereas hypoimmunogenic allogeneic hiPSC-derived islet cells survive and are able to rescue diabetes to achieve normal blood glucose levels in mice.
The genetic modifications typically involve several key changes. First, genes encoding MHC class I and class II molecules are knocked out, reducing recognition by T cells. However, simply removing these molecules would make cells vulnerable to natural killer (NK) cells, which attack cells lacking MHC molecules. To prevent this, researchers knock in protective molecules like CD47, which provides a “don’t eat me” signal to immune cells.
Allogeneic transplantation of genetically engineered hypoimmune pseudo-islets (B2M−/−, CIITA−/−, CD47+) in diabetic nonhuman primates resulted in successful engraftment, stable endocrine function, and insulin independence without triggering any detectable immune response. This study demonstrated the potential for hypoimmune pseudo-islets to provide an immunosuppression-free treatment for type 1 diabetes mellitus, achieving immune evasion and stable insulin independence in diabetic nonhuman primates.
Safety Considerations and Future Directions
These studies indicate that the modification of islets or stem cell-derived islets through genetic engineering can induce localized immune tolerance and enhance graft survival without the need for continuous immunosuppression. Future research should address the safety and genetic stability of these engineered cells, the long-term effects of their engineered phenotype, and include mechanisms, such as safety switches, to remove the cells in case of uncontrolled growth.
Safety switches represent an important safeguard in genetically engineered cell therapies. These are genetic modifications that allow researchers or clinicians to selectively eliminate the transplanted cells if necessary, such as if the cells begin growing uncontrollably or if other safety concerns arise. Common approaches include incorporating genes that make cells sensitive to specific drugs or that can trigger cell death when activated by an external signal.
Biomaterial-Based Immunomodulation
Rapid advances and convergence of expertise in biomaterial sciences and immunology have led to the development of multiple strategies aimed at inducing tolerance to allogeneic islets without the need for systemic immunosuppression. By tuning biomaterial properties such as size, shape and surface chemistry, it is possible to create local immune privileged microenvironments or target specific immune cells.
Nanoparticle-Based Approaches
Liu et al. used injection of immunomodulatory nanoparticles to remodel the extrahepatic spleens of T1DM mice into a more hospitable transplant site that supported the engraftment, vascularization, and function of transplanted allo- and xenogeneic islets. Proof-of-concept transplants of human islets into macaques on different degrees of immunosuppression further advocated for the feasibility of the approach.
This innovative approach demonstrates how biomaterials can be used not just to protect islets directly, but to modify the transplant site itself to create a more favorable environment for graft survival. By remodeling the spleen with immunomodulatory nanoparticles, researchers created a site with enhanced vascularization and reduced immune reactivity.
Biomaterials strategies for promoting islet transplantation tolerance typically focus on two approaches: the controlled release of small molecule drugs and proteins, and the conjugation of immunomodulatory ligands on the surface of biomaterials. These strategies can be further categorized into local immunomodulation for avoidance of systemic side effects and targeting of antigen-presenting cells in the lymph nodes.
PLGA and Other Polymer Systems
The most commonly investigated polymeric biomaterial is poly(lactic-co-glycolic acid) (PLGA) as it is used in multiple FDA approved cancer therapies and has served as the delivery vehicle for the formulation of multiple tolerance-inducing therapies. PLGA’s advantages include its biocompatibility, biodegradability, and FDA approval for other applications, which can accelerate the path to clinical translation.
These polymer-based systems can be designed to release immunomodulatory drugs gradually over time, maintaining therapeutic concentrations at the graft site while minimizing systemic exposure. Alternatively, polymers can be surface-modified to present immunomodulatory molecules that interact with immune cells as they encounter the material.
Stem Cell-Derived Islets: Solving the Donor Shortage Problem
The limited availability of human cadaveric islet donors and the need for ongoing administration of immunosuppressive agents post-transplantation hinder the widespread use of this treatment. Stem cell-derived islet organoids have emerged as an effective alternative to primary human islets. The shortage of donor pancreases represents a fundamental limitation to expanding islet transplantation to the millions of patients who could potentially benefit from it.
Clinical Success with Stem Cell-Derived Islets
In 2021, a pharmaceutical based in Boston initiated the phase 1/2 clinical trial with fully differentiated SC-islets (VX-880, NCT04786262). Similar to islet transplantation, SC-islets were administrated into the portal vein of T1D patients, alongside immunosuppressive therapy. This trial proved successful as the first T1D patient became insulin-independent and was functional cured following SC-islet cell therapy. Further positive data related to this trial has been released in 2023, showing 7 of 10 patients can avoid exogenous insulin completely.
These remarkable results demonstrate that stem cell-derived islets can function as effectively as cadaveric islets in restoring insulin production and achieving glycemic control. The ability to generate functional islets from stem cells in the laboratory offers the potential for an unlimited supply of transplantable cells, removing one of the major barriers to widespread adoption of islet transplantation.
Autologous Stem Cell Approaches
Remarkably, the patient achieved insulin independence within 75 days and sustained over 98% time-in-range glycemic control for a year, with glycated hemoglobin (HbA1c) reduced to non-diabetic levels. While the approach used patient-specific CiPSCs, the patient was receiving immunosuppressive drugs in connection with previous allogeneic organ transplantation.
Using a patient’s own cells to generate islets offers the theoretical advantage of avoiding alloimmune rejection entirely, as the cells would be genetically identical to the recipient. However, several challenges remain that could limit the broader application of CiPSC-derived islets. One key issue is scalability. While the differentiation protocol used to generate islet-like cells showed high efficiency, translating this process into a scalable, cost-effective production system for widespread clinical use poses significant logistical and economic challenges for millions of patients in the autologous setting.
Additionally, autologous approaches in type 1 diabetes patients must still contend with the autoimmune response that destroyed the original beta cells. The transplanted cells, even if derived from the patient’s own stem cells, would still be vulnerable to the same autoimmune attack unless additional immunomodulation strategies are employed.
Combining Stem Cell Technology with Immunomodulation
The most promising future direction involves combining stem cell-derived islets with the immunomodulation strategies described earlier. Breakthrough T1D believes that the best chance for T1D cures lies in stem cell-based therapies since deceased donor islets are in short supply, while stem cell-derived islets can be produced at scale. Engineering cells to evade immune attack is a new path forward to protect the insulin-producing beta cells and avoid the use of immunosuppressants. Most importantly, this technology is being studied to apply to stem cell-based therapies, which is a scalable solution for many more people with T1D.
By generating stem cell-derived islets and then genetically engineering them to be hypoimmunogenic, or encapsulating them in protective devices, researchers could create an off-the-shelf cell therapy product that could be used for any patient without the need for immunosuppression or donor matching. This represents the ultimate goal: a readily available, safe, and effective cure for type 1 diabetes.
Alternative Transplant Sites and Delivery Methods
While most islet transplantation procedures involve infusing cells into the hepatic portal vein, where they lodge in the liver, researchers are exploring alternative transplant sites that might offer advantages for graft survival and function.
The Spleen as a Transplant Site
Islet transplants growing in tissue-remodeled spleens restore normoglycemia in diabetic mice and macaques. The spleen offers several potential advantages as a transplant site, including rich vascularization and accessibility for monitoring and intervention if needed. This study supports further safety and efficacy testing of the remodeled spleen as an islet transplant site for ameliorating insulin-deficient diabetes.
The liver, while convenient for cell delivery through the portal vein, presents some challenges as a transplant site. The immediate blood-mediated inflammatory reaction (IBMIR) that occurs when islets contact blood can destroy a significant portion of transplanted cells. Additionally, the liver’s role in drug metabolism means that immunosuppressive drugs may reach particularly high concentrations there, potentially damaging the transplanted islets.
Subcutaneous and Other Sites
Subcutaneous sites offer the advantage of accessibility—cells could be transplanted through a simple injection or minor surgical procedure, and the site could be easily monitored or accessed if intervention is needed. However, subcutaneous sites typically have less robust vascularization than the liver or spleen, which can compromise islet survival and function.
Researchers are developing strategies to enhance vascularization at subcutaneous sites, such as pre-vascularizing the site before islet transplantation or co-transplanting islets with factors that promote blood vessel growth. Some encapsulation devices are specifically designed for subcutaneous implantation, combining the advantages of physical immune protection with an accessible transplant location.
Xenotransplantation: Porcine Islets as an Alternative Source
Islet transplantation has emerged as a curative therapy for diabetes in select patients but remains rare due to shortage of suitable donor pancreases. Islet transplantation using porcine islets has long been proposed as a solution to this organ shortage. Pigs offer several advantages as potential islet donors: their insulin is very similar to human insulin, they can be bred in controlled environments, and genetic engineering technologies allow for modification of pig cells to reduce immunogenicity.
Genetic Modifications to Reduce Xenogeneic Rejection
Another strategy to enhance graft survivability is to utilize genetically-modified pigs with alterations in expression of known xeno-antigens, and modification of the complement and coagulation systems to improve immunological compatibility between pigs and NHPs. In one example, cardiac xenografts from genetically-modified pigs with alpha 1-3 galactosyltransferase gene knockout, expression of human complement regulatory protein CD46 and human thrombomodulin, were transplanted into baboons.
Xenotransplantation faces additional immunological challenges beyond those encountered in allogeneic transplantation. The immune response to xenogeneic tissue is typically more vigorous and involves additional mechanisms, including hyperacute rejection mediated by pre-existing antibodies against pig antigens. Genetic engineering of donor pigs to remove or modify these antigens has made significant progress in overcoming these barriers.
Progress in the field of kidney and heart xenotransplantation with the development of rapid genome editing technologies, novel immunosuppression regimens, and even tolerance induction strategies has led to significant improvements in pig-to-NHP heart and kidney graft survival in recent years. These advances in other organs are now being applied to islet xenotransplantation, with promising results in preclinical studies.
Challenges and Considerations
Porcine islets have been considered as another source of insulin-secreting cells for transplantation in T1D patients, though xeno-transplants raise concerns over the risk of endogenous retrovirus transmission and immunological incompatibility. The risk of transmitting porcine endogenous retroviruses (PERVs) to human recipients has been a significant concern, though extensive screening and genetic engineering approaches are being developed to address this issue.
Additionally, there are ethical considerations surrounding the use of animals for xenotransplantation, as well as regulatory challenges in bringing xenogeneic cell therapies to clinical application. Despite these challenges, the potential of xenotransplantation to provide an unlimited supply of islets makes it an important area of ongoing research.
Current Clinical Trials and Recent Breakthroughs
The field of islet transplantation is experiencing rapid progress, with multiple clinical trials testing novel immunomodulation strategies and cell sources. Understanding the current state of clinical development provides insight into which approaches are closest to widespread clinical application.
The VX-880 FORWARD Trial
The ongoing Phase I/II/III FORWARD trial (NCT04786262) evaluates VX-880, an allogeneic, fully differentiated embryonic stem cell-derived islet therapy, which provides definitive clinical validation of the potential for cell replacement to ‘functionally cure’ T1D. The abstract presented by de Koning outlined the enrolment of adults with established T1D and recurrent severe hypoglycaemic episodes (SHE) with impaired awareness of hypoglycaemia into the trial, a group with a high unmet medical need. Participants received a single infusion of VX-880 into the hepatic portal vein, alongside a standard IS regimen that included induction therapy with anti-thymocyte globulin (ATG) and IS with the calcineurin inhibitor (CNI), tacrolimus.
The functional success demonstrated by the VX-880 FORWARD trial provides the field with a high-water mark for restorative efficacy, proving that stem cell-derived islet replacement is capable of achieving a near-curative state for high-risk patients. While this trial still requires immunosuppression, it validates the concept that stem cell-derived islets can function as effectively as cadaveric islets in restoring insulin production.
Hypoimmune Islet Trials
While still very early, these findings provide important proof of concept that gene-edited, immune-evasive islet cells can survive and function in a person with T1D. If confirmed in larger studies, this approach could help move the field closer to cell therapies that work without long-term immune suppression—a major goal for the future of T1D cures.
The Sana Biotechnology trial represents a watershed moment in the field, demonstrating for the first time that genetically engineered immune-evasive islets can function in humans without immunosuppression. While the data comes from a single patient with limited follow-up, it provides crucial proof of concept that this approach is feasible and safe.
Another trial is in progress testing a similar approach (CRISPR) in Canada, indicating that multiple groups are pursuing this promising strategy. As these trials expand to include more patients and longer follow-up periods, the field will gain critical information about the durability and safety of immune-evasive islet transplantation.
Encapsulation Device Trials
Multiple encapsulation approaches are in various stages of clinical development. In 2023, Vertex received the approval of the FDA to conduct a phase 1/2 clinical trial for its other product, VX-264, which employs a unique strategy. It uses the same pancreatic islet stem cells as VX-880, but these cells are encapsulated within a surgically implantable canal-arterial protective device to shield them from the recipient’s immune system. The completion of the study is aimed for May 2026 (NCT05791201).
These trials will provide critical data on whether encapsulation can truly eliminate the need for immunosuppression while maintaining long-term islet function. Success in these trials could dramatically expand the eligible patient population for islet transplantation, as the risks associated with immunosuppression currently limit the procedure to patients with severe complications.
Regulatory T Cell Trials
Multiple clinical trials are in progress evaluating the efficacy of recipient Tregs in organ transplantation tolerance (clinicaltrials.gov). One promising strategy in preclinical studies is the adoptive transfer of in vitro culture expanded Tregs to prevent the rejection of donor islet grafts and at least one clinical trial testing this approach is underway (NCT03444064).
These trials are testing whether infusing expanded regulatory T cells can reduce or eliminate the need for traditional immunosuppressive drugs. The results will be crucial for determining whether Treg therapy can be a practical clinical strategy for promoting islet graft tolerance.
Challenges and Future Directions
While the progress in immunomodulation strategies for islet transplantation has been remarkable, significant challenges remain before these approaches can become standard clinical practice for the millions of people living with type 1 diabetes.
Scalability and Manufacturing
Many of the most promising immunomodulation strategies involve complex manufacturing processes. Generating stem cell-derived islets, genetically engineering cells, expanding regulatory T cells, or producing sophisticated encapsulation devices all require specialized facilities, expertise, and quality control measures. Scaling these processes to meet the needs of millions of potential patients while maintaining consistency and affordability represents a major challenge.
The regulatory pathway for these novel therapies also presents challenges. In the USA, allogeneic islet transplantation is regulated by the FDA as a biological drug under the Biologics License Application (BLA) pathway. This classification mandates extensive clinical trials, consistency in manufacturing, and strict adherence to safety and efficacy standards. While this regulatory framework is intended to maximize quality and long-term safety, it comes with significant challenges, including high costs, approval delays, and limited accessibility.
Long-Term Safety and Efficacy
Many of the novel immunomodulation strategies discussed in this article are still in early stages of clinical testing. While short-term results have been promising, long-term data on safety and efficacy are still limited. Questions remain about the durability of tolerance induction, the long-term stability of genetically engineered cells, and the potential for late complications with encapsulation devices.
For genetically engineered cells in particular, ensuring long-term safety is paramount. Future research should address the safety and genetic stability of these engineered cells, the long-term effects of their engineered phenotype, and include mechanisms, such as safety switches, to remove the cells in case of uncontrolled growth. Comprehensive long-term follow-up studies will be essential for establishing the safety profile of these novel approaches.
Combining Strategies for Optimal Outcomes
The emergence of precision immunomodulation, such as antigen-specific EngTregs activated only by pathogenic neoepitopes, and the refined immunomodulatory mechanism of hATG, suggests that targeted immune resetting and tolerance induction are rapidly maturing from theoretical concepts to clinical reality. Concurrently, breakthroughs in bioengineering, exemplified by the confirmed in vivo maturation of stem cell-derived islets within encapsulation systems and successful long-term immune evasion in large animals, offer an entirely orthogonal solution to the IS dilemma.
The future of islet transplantation likely lies not in a single approach, but in combining multiple strategies to achieve optimal outcomes. For example, using stem cell-derived islets that have been genetically engineered for immune evasion, combined with localized immunomodulation through biomaterials or co-transplanted regulatory cells, might provide synergistic benefits that exceed what any single approach could achieve.
These insights not only deepen our understanding of T-cell behavior in the context of transplantation but also offer potential avenues for developing targeted immunomodulatory therapies aimed at improving transplant tolerance and longevity. As our understanding of the complex immune responses in islet transplantation continues to grow, researchers will be better positioned to design rational combination therapies that address multiple aspects of the rejection response simultaneously.
Addressing Autoimmunity
A unique challenge in islet transplantation for type 1 diabetes is the need to address not only alloimmune rejection but also the autoimmune response that caused the original disease. Even if alloimmune rejection is successfully prevented through the strategies discussed in this article, transplanted islets could still be vulnerable to autoimmune attack.
Some immunomodulation strategies, such as tolerance induction protocols and regulatory T cell therapy, may address both alloimmunity and autoimmunity simultaneously. However, more research is needed to understand how different approaches affect the autoimmune response and whether additional interventions specifically targeting autoimmunity will be necessary for long-term graft survival in type 1 diabetes patients.
Cost and Accessibility
Even as these novel therapies prove successful in clinical trials, ensuring they are accessible to the patients who need them will be crucial. The complex manufacturing processes, specialized facilities, and extensive clinical monitoring required for many of these approaches come with substantial costs. Developing strategies to reduce costs while maintaining quality and safety will be essential for making these therapies available to a broad patient population.
Health economic analyses will be important for demonstrating the value of these therapies compared to lifelong insulin therapy and management of diabetes complications. While the upfront costs may be substantial, the potential for eliminating or greatly reducing the need for insulin, glucose monitoring, and treatment of complications could make these therapies cost-effective over a patient’s lifetime.
The Path Forward: Integration and Translation
The future trajectory of T1D therapy involves the integration of these successful stem cell-derived islet platforms with strategies that genetically or physically eliminate immune rejection. The convergence of multiple technological advances—stem cell biology, genetic engineering, biomaterials science, and immunology—is creating unprecedented opportunities for developing truly curative therapies for type 1 diabetes.
Personalized Approaches
As the field advances, there may not be a single “best” approach for all patients. Instead, personalized strategies based on individual patient characteristics, immune profiles, and clinical needs may emerge. Some patients might be best served by encapsulated islets, while others might benefit more from genetically engineered immune-evasive cells or tolerance induction protocols.
Biomarkers that can predict which patients are most likely to respond to specific immunomodulation strategies will be valuable for guiding treatment selection. Similarly, monitoring tools that can detect early signs of rejection or graft dysfunction will enable timely interventions to preserve graft function.
Expanding Beyond Type 1 Diabetes
While this article has focused primarily on type 1 diabetes, the immunomodulation strategies being developed for islet transplantation have potential applications in other forms of diabetes and beyond. Some patients with type 2 diabetes who have lost significant beta cell function might benefit from islet transplantation. Additionally, the principles and technologies being developed could be applied to other cell and organ transplantation scenarios.
In 2024, the cell therapy utilizing autologous SC-islets derived from endoderm stem cells (E-islets) was performed on a patient with Type 2 diabetes (T2D) and impaired islet function in China. This demonstrates that the field is already beginning to explore applications beyond type 1 diabetes.
Collaborative Research and Data Sharing
The rapid progress in islet transplantation immunomodulation has been facilitated by extensive collaboration between research groups, clinicians, industry partners, and patient advocacy organizations. Continued collaboration and data sharing will be essential for accelerating progress toward widely available curative therapies.
International registries tracking outcomes of islet transplantation with various immunomodulation strategies can provide valuable real-world data to complement controlled clinical trials. Sharing of protocols, reagents, and expertise can help avoid duplication of effort and accelerate the translation of promising approaches from the laboratory to the clinic.
Conclusion: A Transformative Era for Diabetes Treatment
Advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications. With the innovative research carried out on islet source acquisition, immunosuppression protocols, and graft site reselection for islet transplantation, this technology will certainly be driven to greater maturity.
The field of islet cell transplantation stands at a pivotal moment. After decades of incremental progress punctuated by occasional breakthroughs, multiple innovative immunomodulation strategies are now showing remarkable promise in preclinical studies and early clinical trials. From genetically engineered immune-evasive cells functioning without immunosuppression in human patients, to sophisticated encapsulation devices maintaining islet function for months in large animals, to tolerance induction protocols achieving long-term graft survival in non-human primates, the pieces are falling into place for a transformation in diabetes treatment.
The convergence of stem cell technology, genetic engineering, biomaterials science, and advanced immunology is creating opportunities that were unimaginable just a few years ago. Significant research efforts have focused on developing novel therapies that can establish specific immune tolerance towards transplanted islets while maintaining functional protective immunity. These efforts are bearing fruit, with multiple approaches showing the potential to protect transplanted islets without the broad immunosuppression that has limited the application of islet transplantation.
For the millions of people living with type 1 diabetes worldwide, these advances offer genuine hope for a future free from the constant burden of diabetes management. While challenges remain in scaling these technologies, ensuring long-term safety, and making them accessible to all who could benefit, the trajectory is clear: islet cell transplantation is evolving from an experimental procedure for a select few into a potentially curative therapy that could transform the lives of millions.
The next few years will be critical as multiple clinical trials mature and provide data on the long-term outcomes of these novel immunomodulation strategies. Success in these trials could lead to regulatory approvals and clinical implementation of approaches that eliminate or greatly reduce the need for immunosuppression, dramatically expanding the eligible patient population and moving the field closer to the ultimate goal: a safe, effective, and widely available cure for type 1 diabetes.
As research continues to advance, the integration of multiple complementary strategies—combining optimal cell sources with sophisticated immunomodulation approaches and ideal transplant sites—promises to deliver outcomes that exceed what any single approach could achieve alone. The future of diabetes treatment is being written now, in laboratories and clinical trials around the world, and that future looks increasingly bright for patients awaiting a cure.
Additional Resources
For readers interested in learning more about islet cell transplantation and immunomodulation strategies, several organizations provide valuable information and resources:
- Breakthrough T1D (formerly JDRF) – A leading organization funding type 1 diabetes research, including islet transplantation studies. Visit their website at https://www.breakthrought1d.org for information on current research and clinical trials.
- ClinicalTrials.gov – The U.S. National Library of Medicine’s database of clinical trials provides detailed information on ongoing and completed trials testing various immunomodulation strategies for islet transplantation. Search for “islet transplantation” to find relevant studies.
- American Diabetes Association – Provides comprehensive information on diabetes management and emerging therapies at https://www.diabetes.org.
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) – Offers evidence-based information on diabetes research and treatment options at https://www.niddk.nih.gov.
- The Transplantation Society – Provides scientific resources and information on advances in transplantation medicine, including islet transplantation, at https://www.tts.org.
Patients interested in participating in clinical trials should discuss options with their healthcare providers and search for relevant trials on ClinicalTrials.gov. As the field continues to advance rapidly, staying informed about new developments can help patients and families make educated decisions about treatment options and potential participation in research studies that may benefit both themselves and future patients.