Table of Contents
Islet cell transplantation represents a transformative therapeutic approach for patients with type 1 diabetes, offering the potential to restore endogenous insulin production and achieve sustained glycemic control. Islet cell transplantation has emerged as a promising avenue for functionally replacing endogenous insulin production and achieving long-term glycemic stability. However, despite significant advances in surgical techniques and donor islet preparation, immune rejection continues to pose a formidable challenge to long-term transplant success. The body’s immune system recognizes transplanted islets as foreign tissue, triggering complex rejection mechanisms that can destroy the graft and return patients to insulin dependence.
Recent years have witnessed remarkable progress in immunomodulation strategies designed to protect transplanted islets while minimizing the burden of systemic immunosuppression. The recent FDA approval of Lantidra, the first allogeneic islet therapy for T1D, established islet transplantation as a viable option for some patients, enabling tighter blood glucose control. This was a significant milestone for the field as it was the first cell therapy approved for the treatment of T1D. These innovative approaches range from advanced cell engineering techniques to novel biomaterial platforms, each aiming to create an environment where transplanted islets can survive and function without the need for lifelong, high-dose immunosuppressive medications. This comprehensive review explores the current state of immunomodulation in islet transplantation, examining both established protocols and cutting-edge experimental strategies that promise to revolutionize diabetes treatment.
Understanding the Immunological Barriers to Islet Transplantation
The immune response to transplanted islets is a multifaceted process involving both innate and adaptive immunity. When donor islets are introduced into a recipient’s body, the immune system immediately recognizes them as foreign through the detection of non-self antigens, particularly major histocompatibility complex (MHC) molecules that differ between donor and recipient. This recognition triggers a cascade of immune events that can ultimately lead to graft destruction.
The Innate Immune Response
The innate immune system provides the first line of defense against transplanted islets. Immediately following transplantation, damage-associated molecular patterns (DAMPs) released from islets stressed during isolation and transplantation activate innate immune cells including macrophages, neutrophils, and natural killer cells. In response to hypoxia, the transplanted islets can secrete inflammatory cytokines, propelling their destruction. This early inflammatory response creates a hostile microenvironment that can damage islets even before adaptive immunity is fully engaged.
The instant blood-mediated inflammatory reaction (IBMIR) represents a particularly critical challenge in portal vein islet transplantation, where islets come into direct contact with blood. This reaction involves complement activation, platelet aggregation, and coagulation, leading to significant early islet loss. Understanding and mitigating these innate immune responses has become a major focus of transplantation research.
Adaptive Immune Rejection Mechanisms
While innate immunity provides immediate responses, adaptive immunity orchestrates the more specific and sustained rejection of transplanted islets. T lymphocytes play the central role in this process, with both CD4+ helper T cells and CD8+ cytotoxic T cells contributing to graft destruction. CD4+ T cells recognize donor antigens presented on MHC class II molecules and coordinate immune responses by secreting inflammatory cytokines and activating other immune cells. CD8+ T cells directly kill islet cells by recognizing donor antigens on MHC class I molecules.
B lymphocytes also contribute to rejection through the production of donor-specific antibodies that can bind to transplanted islets and trigger complement-mediated destruction or antibody-dependent cellular cytotoxicity. The development of these antibodies represents a significant barrier to long-term graft survival and can lead to chronic rejection even in patients who initially respond well to transplantation.
The Autoimmune Component in Type 1 Diabetes
Patients with type 1 diabetes face an additional immunological challenge: the recurrence of autoimmunity against transplanted islets. Islet transplantation represents an attractive therapeutic approach for type 1 diabetes; however, it can also elicit alloreactive and autoreactive T cell responses capable of killing the transplanted islets. The same autoreactive T cells that destroyed the patient’s original beta cells can attack the transplanted islets, even if they are perfectly matched for MHC antigens. This dual challenge of alloimmunity and autoimmunity makes islet transplantation in type 1 diabetes particularly complex and necessitates immunomodulatory strategies that address both forms of immune attack.
Current Immunosuppressive Protocols and Their Limitations
The development of effective immunosuppressive regimens has been crucial to the success of islet transplantation. The Edmonton Protocol, introduced in 2000, marked a watershed moment in the field by demonstrating that insulin independence could be achieved in type 1 diabetes patients through islet transplantation combined with a steroid-free immunosuppressive regimen.
The Edmonton Protocol and Its Evolution
Recognizing the risks, 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 utilized a combination of daclizumab (an anti-IL-2 receptor antibody) for induction therapy, along with sirolimus and low-dose tacrolimus for maintenance immunosuppression. This approach avoided corticosteroids, which had been shown to be toxic to islet cells and impair their function.
While the Edmonton Protocol represented a major advance, long-term follow-up studies revealed that many patients eventually lost graft function and returned to insulin dependence. This highlighted the need for continued refinement of immunosuppressive strategies and the development of novel approaches to promote long-term graft survival.
Calcineurin Inhibitors
Calcineurin inhibitors, including tacrolimus and cyclosporine, form the backbone of many immunosuppressive regimens in transplantation. These drugs work by blocking T cell activation through inhibition of the calcineurin-NFAT signaling pathway, which is essential for the transcription of genes encoding inflammatory cytokines such as IL-2. While highly effective at preventing acute rejection, calcineurin inhibitors have several drawbacks.
CNIs such as cyclosporine (CsA) and tacrolimus are widely utilized immunosuppressive therapies in transplant recipients. These medications can be directly toxic to islet cells, impairing their insulin secretory capacity. They also carry significant risks of nephrotoxicity, which is particularly concerning for patients who may already have diabetic kidney disease. Additionally, calcineurin inhibitors can interfere with the development and function of regulatory T cells, potentially undermining efforts to induce immune tolerance.
Antimetabolites and mTOR Inhibitors
Antimetabolites such as mycophenolate mofetil work by inhibiting purine synthesis, thereby suppressing the proliferation of lymphocytes. These agents are commonly used in combination with calcineurin inhibitors to provide synergistic immunosuppression. However, they can cause gastrointestinal side effects and increase susceptibility to infections.
Mammalian target of rapamycin (mTOR) inhibitors, including sirolimus and everolimus, offer an alternative mechanism of immunosuppression by blocking T cell proliferation and activation. These drugs have the advantage of being less nephrotoxic than calcineurin inhibitors and may even have protective effects on islet cells. However, they can impair wound healing, cause hyperlipidemia, and have been associated with increased risk of proteinuria.
The Burden of Chronic Immunosuppression
However, this procedure requires extensive immunosuppression to prevent islet graft rejection. The heavy immunosuppressive regimen puts the patient at risk of infections, malignancies, worsening islet graft function, and organ damage. The side effects of chronic immunosuppression represent a major limitation to the widespread application of islet transplantation. Patients face increased risks of opportunistic infections, including cytomegalovirus, fungal infections, and reactivation of latent viruses. The long-term use of immunosuppressive drugs is also associated with increased cancer risk, particularly skin cancers and post-transplant lymphoproliferative disorders.
The need for systemic immunosuppression remains the primary barrier to making islet transplantation a more widespread therapy for patients with T1D. Here, we review recent progress in addressing the key limitations of islet transplantation as a viable treatment for T1D. For many patients with type 1 diabetes, the risks associated with lifelong immunosuppression may outweigh the benefits of islet transplantation, particularly when compared to modern insulin therapy with continuous glucose monitoring and insulin pumps. This reality has driven intense research efforts to develop alternative immunomodulatory strategies that can protect transplanted islets without the need for broad, systemic immunosuppression.
Regulatory T Cells: Harnessing Natural Tolerance Mechanisms
Regulatory T cells (Tregs) represent one of the most promising avenues for achieving transplant tolerance without chronic immunosuppression. These specialized immune cells naturally function to suppress excessive immune responses and maintain self-tolerance, making them ideal candidates for protecting transplanted islets from rejection.
The Biology of Regulatory T Cells
Regulatory T cells are a subset of CD4+ T lymphocytes characterized by the expression of the transcription factor FOXP3, which is essential for their development and suppressive function. It has been well established than an increased ratio of Tregs:Tconvs is observed in tolerance, and that this high ratio is likely necessary for tolerance to occur/be maintained. Tregs employ multiple mechanisms to suppress immune responses, including the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β, direct cell-to-cell contact-mediated suppression, and metabolic disruption of effector T cells through consumption of IL-2.
For this reason, a depleted Treg population has been implicated in T1D pathogenesis. Due to the anti-inflammatory nature of Tregs and their role in autoimmunity, they have been of interest for immunomodulatory therapies. In the context of transplantation, Tregs can suppress both alloimmune and autoimmune responses, making them particularly valuable for islet transplantation in type 1 diabetes patients.
Polyclonal versus Antigen-Specific Tregs
One consideration for therapeutic harnessing of Tregs in clinical settings is choosing which Tregs to use. Polyclonal Tregs are more easily expanded or isolated, but donor-specific Tregs are likely more effective. In a murine islet allograft model, after recipient pre-conditioning by T cell depletion, transfer of fewer donor-reactive than polyclonal Tregs achieved indefinite graft survival. This finding highlights the superior potency of antigen-specific Tregs, which can provide targeted immunosuppression at the graft site while preserving systemic immunity.
The challenge with antigen-specific Tregs lies in their isolation and expansion. These cells are present at very low frequencies in the peripheral blood, making it difficult to obtain sufficient numbers for therapeutic use. Researchers have developed various strategies to enrich or generate antigen-specific Tregs, including in vitro stimulation with donor antigens and genetic engineering approaches.
Chimeric Antigen Receptor Tregs: A Revolutionary Approach
One of the most exciting recent developments in Treg therapy is the engineering of chimeric antigen receptor (CAR) Tregs. The authors generated CAR Treg cells that targeted human leukocyte antigen (HLA)–A2 (A2-CAR Treg cells) and cotransferred them with pathogenic, islet-reactive effector T cells into mice transplanted with HLA-A2–expressing islets. When the A2-CAR Treg cells were included in the transplantation setup, the islets were protected from killing by the cotransferred effector cells.
Thus, A2-CAR Treg cells can induce linked suppression and long-lasting tolerance to a distinct autoimmune antigen. Tolerance to the autoantigen does not require A2-CAR Treg persistence, indicating the presence of infectious tolerance. Overall, these data demonstrate that A2-CAR Treg cells have potential therapeutic use to simultaneously control both allo- and autoimmunity in islet transplantation. This phenomenon of infectious tolerance, where CAR Tregs induce long-lasting protection even after they are no longer present, represents a paradigm shift in transplantation immunology and suggests that a single, potentially transient dose of CAR Tregs could provide durable graft protection.
CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. These preclinical findings have generated considerable excitement about the potential for CAR Treg therapy to eliminate the need for chronic immunosuppression in clinical islet transplantation.
Clinical Translation of Treg Therapy
Clinical trials of Treg therapy to date have primarily tested autologous polyclonal, ex vivo-expanded Tregs showing excellent safety and tolerability. Early-phase clinical trials have demonstrated that Treg infusion is safe and well-tolerated in transplant recipients and patients with autoimmune diseases. However, achieving consistent clinical efficacy has proven more challenging, likely due to the use of polyclonal rather than antigen-specific Tregs and the need to optimize dosing and timing of Treg administration.
Several clinical trials are currently underway to evaluate the safety and efficacy of Treg therapy in islet transplantation. These studies are exploring various approaches, including the co-transplantation of Tregs with islets, the use of donor-specific Tregs, and strategies to expand Tregs in vivo after transplantation. The results of these trials will be crucial in determining whether Treg therapy can become a standard component of clinical islet transplantation protocols.
Costimulation Blockade: Interrupting T Cell Activation
T cell activation requires two signals: recognition of antigen presented on MHC molecules (signal 1) and engagement of costimulatory molecules (signal 2). Blocking costimulatory pathways represents an attractive strategy for preventing T cell activation and promoting transplant tolerance without the broad immunosuppression associated with conventional drugs.
CD28-B7 Pathway Blockade
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. CTLA4-Ig (belatacept) has been approved for use in kidney transplantation and has shown promise in preclinical islet transplantation studies. By blocking the interaction between CD28 on T cells and B7 molecules on antigen-presenting cells, CTLA4-Ig prevents the delivery of costimulatory signals necessary for full T cell activation.
Others reported that in the presence of B7:CD28 and CD40:CD40L co-stimulatory blockade, the suppressive function of CD4+CD25+ Tregs was activated, suppressing the proliferation of CD4+ effector cells. Experiments in vitro found that co-stimulatory blockade primed Foxp3+ Tregs to be more suppressive than naïve Foxp3+ Tregs. This synergy between costimulation blockade and Treg function suggests that combination approaches may be particularly effective in promoting transplant tolerance.
PD-1/PD-L1 Pathway Modulation
Targeting the PD-1/PD-L1 pathway was shown to regulate and delay immune destruction of allograft in cardiac, islet, and corneal transplantation. The PD-1/PD-L1 pathway represents an important immune checkpoint that normally functions to limit excessive immune responses and prevent autoimmunity. In transplantation, upregulation of PD-L1 on transplanted cells or delivery of PD-L1 to the graft site can engage PD-1 on T cells, delivering inhibitory signals that suppress their activation and effector functions.
In addition, PD-L1 and CTLA4-Ig have been demonstrated to inhibit T cell activity in a nonredundant way. Despite these promising developments, the PD-L1 or CTLA4-Ig was often administered systemically and cause nonspecific immune responses and immune-related toxicity. Thus, there is great interest in targeted delivery of immunomodulatory molecules and localized regulation of immune responses within the graft microenvironment.
Engineered Mesenchymal Stromal Cells for Local Immunomodulation
Here, we 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. This approach represents an elegant solution to the problem of systemic toxicity associated with costimulation blockade, as the engineered MSCs deliver immunomodulatory molecules locally at the graft site.
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. 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.
Genetic Engineering of Islets for Immune Evasion
Recent advances in gene editing technologies have opened new possibilities for creating “hypoimmunogenic” islets that can evade immune recognition and destruction. This approach aims to modify islets at the genetic level to reduce their immunogenicity while preserving their insulin-secreting function.
HLA Modification Strategies
Hypoimmunogenic islets can be generated with ablation of HLA expression while maintaining HLA-G and E, and overexpression of PD-L1, or CD47. By deleting genes encoding classical HLA class I and class II molecules (B2M and CIITA, respectively), researchers can create islets that are less visible to the recipient’s immune system. However, complete absence of HLA molecules can trigger natural killer (NK) cell-mediated rejection, as NK cells normally recognize and kill cells lacking HLA expression.
To address this challenge, scientists have developed strategies to maintain expression of non-classical HLA molecules such as HLA-E and HLA-G, which can inhibit NK cell activation while not triggering T cell responses. More recently, Hu et al. reported that 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.
Clinical Breakthrough: Hypoimmune Islets Without Immunosuppression
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. This landmark achievement represents a major milestone in the field of islet transplantation and demonstrates the feasibility of the hypoimmune approach in humans.
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. While this is early data from a single patient, it provides crucial proof of concept that gene-edited, immune-evasive islets can survive and function in humans without the need for immunosuppressive drugs.
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.
Localized Immunomodulation Through Cytokine Secretion
To enhance immune evasion, the 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 leverages the natural immunoregulatory properties of these cytokines to create a protective microenvironment around the transplanted islets.
On the other hand, anti-inflammatory cytokine IL-10 can promote graft survival by modulating the innate immune response, as demonstrated by administration of an IL-1 receptor antagonist (anakinra) alongside a TNF inhibitor (etanercept) at the time of transplantation. By engineering islets to continuously secrete these protective factors, researchers can achieve sustained local immunomodulation without the need for repeated drug administration.
Encapsulation Technologies: Physical Barriers to Immune Attack
Encapsulation represents a fundamentally different approach to protecting transplanted islets from immune rejection. Rather than modulating the immune response, encapsulation creates a physical barrier that prevents immune cells and antibodies from reaching the islets while allowing the passage of nutrients, oxygen, and insulin.
Principles of Islet Encapsulation
To address these challenges, 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. This review outlines the contemporary challenges in pancreatic β cell therapy, particularly immune rejection, and recent progress in immune-isolation devices, hypoimmunogenic stem cells, and immune regulation of transplants. The ideal encapsulation material must be biocompatible, mechanically stable, and have precisely controlled permeability to allow insulin secretion and nutrient exchange while excluding immune cells and antibodies.
Various materials have been explored for islet encapsulation, including alginate, agarose, and synthetic polymers. Alginate, a naturally derived polysaccharide, has been the most widely studied material due to its biocompatibility, ease of gelation, and ability to form stable capsules. However, challenges remain in achieving optimal capsule size, preventing fibrotic overgrowth, and ensuring adequate oxygen and nutrient supply to encapsulated islets.
Macroencapsulation Devices
Macroencapsulation devices contain multiple islets within a single, larger chamber that can be surgically implanted and retrieved if necessary. 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.
Macroencapsulation devices offer several advantages, including the ability to retrieve the device if complications arise and the potential for prevascularization to improve oxygen and nutrient supply. However, they also face challenges related to device biocompatibility, fibrotic overgrowth that can impair function, and the need for surgical implantation and potential removal.
Microencapsulation Approaches
Microencapsulation involves coating individual islets or small clusters of islets with a thin layer of biocompatible material, typically alginate. This approach offers a higher surface area-to-volume ratio compared to macroencapsulation, potentially improving oxygen and nutrient diffusion. Microencapsulated islets can be transplanted via minimally invasive procedures, such as injection into the peritoneal cavity.
Despite these advantages, microencapsulation faces significant challenges. The capsules can trigger foreign body responses leading to fibrotic overgrowth, which impairs islet function and survival. Additionally, ensuring long-term capsule stability and preventing capsule rupture that would expose islets to the immune system remain ongoing concerns. Researchers are actively working to develop next-generation encapsulation materials with improved biocompatibility and anti-fibrotic properties.
Biomaterial-Based Immunomodulation Strategies
Beyond simple physical barriers, advanced biomaterials are being developed to actively modulate the immune response at the transplant site. These materials can deliver immunomodulatory drugs, present tolerogenic signals, or create microenvironments that promote immune tolerance.
Controlled Release of Immunomodulatory Agents
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. 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 scaffolds can be loaded with various immunomodulatory agents, including anti-inflammatory drugs, tolerogenic cytokines, or costimulation blocking antibodies. By controlling the degradation rate of the polymer, researchers can achieve sustained, localized release of these agents at the transplant site, providing prolonged immunoprotection without the need for systemic drug administration.
In summary, PLG scaffolds can serve as an alternative delivery system for islet transplantation that allows for the co-localization of immunomodulatory cells within islet grafts and induces long-term graft survival in an autoimmune diabetes model. This method of co-localizing immunomodulatory cells with islets in a clinically translatable transplant site to affect the immune system on a local and systemic level has potential therapeutic implications for human islet transplantation.
Immunomodulatory Nanoparticles
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 strategy demonstrates how biomaterials can be used not only to protect islets but also to actively remodel the transplant site to create a more favorable environment for graft survival.
Nanoparticles offer unique advantages for immunomodulation due to their ability to target specific immune cells and deliver payloads with high efficiency. Researchers have developed nanoparticles that can selectively target antigen-presenting cells in lymph nodes, delivering tolerogenic signals that promote the development of regulatory immune responses. Other nanoparticle formulations can encapsulate donor antigens along with immunomodulatory drugs, inducing antigen-specific tolerance without broad immunosuppression.
Surface Modification with Immunomodulatory Ligands
Another biomaterial strategy involves modifying the surface of scaffolds or encapsulation materials with immunomodulatory ligands. These ligands can include PD-L1, FasL, or other molecules that deliver inhibitory signals to immune cells upon contact. By presenting these signals directly at the graft site, researchers can create a local immunosuppressive microenvironment that protects transplanted islets while preserving systemic immunity.
Surface modification can also be used to promote vascularization of the transplant site, which is crucial for long-term islet survival and function. Incorporating vascularization strategies is proven to promote graft survival, accelerate cell maturation, and overall enhance and sustain function, which could be a beneficial next step. Materials can be functionalized with pro-angiogenic factors or designed with specific topographies that promote blood vessel ingrowth, ensuring adequate oxygen and nutrient supply to transplanted islets.
Alternative Transplantation Sites and Their Immunological Implications
The choice of transplantation site can significantly impact islet survival and function. While the portal vein has been the standard site for clinical islet transplantation, alternative sites are being explored that may offer immunological and functional advantages.
Limitations of Portal Vein Transplantation
Replacement of β cells by allogeneic islet transplantation via portal vein has been established in clinics all over the world and shown to improve glycemic control among patients. However, portal vein transplantation has several drawbacks. The instant blood-mediated inflammatory reaction (IBMIR) causes significant early islet loss. Additionally, islets transplanted into the liver are exposed to high concentrations of immunosuppressive drugs, which can be toxic, and to absorbed nutrients and drugs from the gastrointestinal tract, which may affect their function.
The liver environment also makes it difficult to monitor transplanted islets or retrieve them if complications arise. These limitations have motivated the search for alternative transplantation sites that might provide better conditions for islet survival and function while potentially offering immunological advantages.
The Omentum and Subcutaneous Sites
The omentum, a fold of peritoneum that hangs from the stomach, has been explored as an alternative transplantation site. It offers good vascularization and accessibility for monitoring and potential retrieval. However, achieving adequate engraftment and function in the omentum has proven challenging, often requiring prevascularization strategies or the use of scaffolds to support islet survival.
Subcutaneous sites offer the advantage of easy accessibility for implantation, monitoring, and potential retrieval. However, the subcutaneous space typically has poor vascularization, which can limit islet survival. Researchers have developed various strategies to overcome this limitation, including prevascularization devices, angiogenic factor delivery, and the use of scaffolds that promote blood vessel ingrowth.
The Spleen as an Immunomodulatory Transplant Site
Islet transplants growing in tissue-remodeled spleens restore normoglycemia in diabetic mice and macaques. The spleen represents a particularly intriguing transplantation site due to its unique immunological properties. As a secondary lymphoid organ, the spleen contains high concentrations of immune cells, which might initially seem disadvantageous. However, when properly conditioned with immunomodulatory nanoparticles, the spleen can be transformed into a tolerogenic environment that supports islet survival.
This study supports further safety and efficacy testing of the remodeled spleen as an islet transplant site for ameliorating insulin-deficient diabetes. The ability to leverage the spleen’s immunological properties to promote tolerance rather than rejection represents a paradigm shift in thinking about transplantation sites and highlights the potential for site-specific immunomodulation strategies.
Stem Cell-Derived Islets: Addressing the Donor Shortage
One of the major limitations of islet transplantation has been the shortage of donor pancreata. However, 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 development of protocols to generate functional islets from human pluripotent stem cells represents a major breakthrough that could make islet transplantation available to many more patients.
Advances in Stem Cell Differentiation Protocols
Research over the past decade yielded an enriched pancreatic progenitor population and promoted their developmental potential towards beta cell fate. The protocols generated vary depending on the stem cell line and culture conditions. The most prominent protocols are optimized for hESC lines H1, HUES8, MEL1, and CyT49, and their derivative reporter lines, as monolayers or suspension aggregates. These protocols can now generate islet-like clusters that respond to glucose stimulation and secrete insulin in a physiologically appropriate manner.
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. This clinical success demonstrates that stem cell-derived islets can function effectively in humans, providing a proof of concept for this approach.
Immunological Considerations for Stem Cell-Derived Islets
Nevertheless, implementing this cell replacement therapy still requires chronic immune suppression, which may result in life-long side effects. To address these challenges, 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. Stem cell-derived islets face the same immunological challenges as cadaveric islets, including both alloimmune and autoimmune rejection in type 1 diabetes patients.
However, stem cell-derived islets also offer unique opportunities for immunomodulation. Because they are generated in vitro, they can be genetically modified before transplantation to enhance their immune evasion properties. 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.
Universal Donor Cells
The concept of “universal donor” cells that could be transplanted into any recipient without triggering immune rejection represents the ultimate goal of cell therapy. By combining multiple genetic modifications—including deletion of HLA class I and II molecules, expression of non-classical HLA molecules, and overexpression of immunomodulatory proteins like PD-L1 and CD47—researchers are working to create stem cell-derived islets that can evade immune recognition.
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. This hypoimmune technology moves us closer to the possibility of having enough immune-evading cells for everyone with T1D.
Combination Strategies: Synergistic Approaches to Immune Protection
Increasingly, researchers recognize that no single immunomodulatory strategy may be sufficient to achieve long-term islet graft survival without immunosuppression. Instead, combination approaches that address multiple aspects of the immune response simultaneously may be necessary.
Integrating Cell Engineering with Biomaterials
Importantly, mitigating immunosuppression without blocking vascularization is an essential next step, which could be achieved via the generation of hypoimmunogenic SC-islets or engineering an immunomodulatory transplantation microenvironment. Combining genetically modified islets with immunomodulatory biomaterials could provide multiple layers of protection. For example, hypoimmunogenic islets could be transplanted on scaffolds that deliver tolerogenic cytokines and promote vascularization, creating an optimal microenvironment for graft survival.
This multi-pronged approach addresses different aspects of the rejection process: genetic modification reduces the initial immune recognition of islets, biomaterial-delivered immunomodulatory agents suppress local immune responses, and vascularization strategies ensure adequate oxygen and nutrient supply for long-term islet function.
Combining Cellular Therapies
The co-transplantation of islets with immunomodulatory cells represents another promising combination strategy. More recent advances in islet transplantation derive from islet encapsulation devices, biomaterial platforms releasing immunomodulatory compounds or surface-modified with immune regulating ligands, islet engineering and co-transplantation with accessory cells. Below, we compare the recent preclinical research in immunomodulation via biomaterials-based approaches to islet engineering and cellular co-transplantation strategies, which allow islet cells to protect themselves against the host’s immune system.
Mesenchymal stromal cells, regulatory T cells, or tolerogenic dendritic cells could be co-transplanted with islets to provide local immunosuppression and promote tolerance. These accessory cells can secrete anti-inflammatory cytokines, suppress effector T cell activation, and promote the development of regulatory immune responses. The challenge lies in optimizing the ratio of islets to immunomodulatory cells and ensuring that both cell types survive and function effectively after transplantation.
Temporal Sequencing of Interventions
The timing of different immunomodulatory interventions may be crucial for achieving optimal outcomes. For example, aggressive immunosuppression or T cell depletion at the time of transplantation could create a window of opportunity for tolerance induction, followed by the administration of regulatory T cells or tolerogenic vaccines to establish long-term tolerance. This approach aims to prevent the initial priming of alloreactive T cells while simultaneously promoting the development of regulatory mechanisms that can maintain tolerance after immunosuppression is withdrawn.
Furthermore, rATG treatment has been shown to promote expansion of peripheral Tregs which likely contributed to the faster kinetics of Treg reconstitution in rATG-treated patients over basiliximab-treated patients. In a comparative study of islet allograft transplant recipients receiving either αCD25 or rATG induction therapies, ATG recipients maintained a stable frequency of CD25+CD4+ T cells, whereas the frequency of these Tregs decreased significantly in αCD25 induction therapy recipients. Of note, both groups had similar rates of insulin independence 1 year after islet transplantation. Understanding how different induction therapies affect regulatory T cell populations could help optimize protocols for tolerance induction.
Monitoring and Biomarkers for Transplant Outcomes
As immunomodulatory strategies become more sophisticated, the ability to monitor immune responses and predict transplant outcomes becomes increasingly important. Developing reliable biomarkers could enable personalized immunosuppression, where treatment is tailored to each patient’s individual immune response.
Immune Monitoring Technologies
The phenotypic characterization of T-cell subpopulations in the context of islet transplantation has revealed potential targets for immunomodulatory therapies, indicating the potential of these cell types for improving transplantation outcomes to dissect the molecular mechanisms, gene expression profiles, biological pathway alterations, and intercellular communication patterns among T-cell subgroups in both allogeneic and syngeneic islet transplantation models. This approach provided a high-resolution view of the cellular heterogeneity and dynamic changes within the T-cell community, essential for pinpointing the critical factors influencing transplantation outcomes.
Advanced technologies such as single-cell RNA sequencing, mass cytometry, and T cell receptor sequencing are providing unprecedented insights into the immune responses to transplanted islets. These tools can identify specific T cell populations associated with rejection or tolerance, track the evolution of immune responses over time, and potentially predict which patients are at risk for graft loss.
Non-Invasive Graft Monitoring
Developing methods to monitor the grafts in vivo and conducting head-to-head comparisons of transplant outcomes across various sites in research settings could also help identify optimal conditions for long-term efficacy with potential for clinical translation. The ability to non-invasively monitor islet graft function and detect early signs of rejection would be invaluable for clinical management. Researchers are exploring various approaches, including imaging techniques, circulating biomarkers, and donor-derived cell-free DNA as indicators of graft health.
C-peptide levels remain the gold standard for assessing islet function, but they provide limited information about the mechanisms underlying graft dysfunction. More sophisticated biomarkers that can distinguish between different causes of graft failure—such as immune rejection, recurrent autoimmunity, or metabolic exhaustion—would enable more targeted interventions to preserve graft function.
Clinical Trials and Regulatory Considerations
Translating innovative immunomodulatory strategies from the laboratory to the clinic requires navigating complex regulatory pathways and conducting rigorous clinical trials to demonstrate safety and efficacy.
Current Clinical Trial Landscape
We trace the progress up to 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, while highlighting the remaining challenges that must still be addressed for widespread clinical adoption. The FDA approval of Lantidra marked a watershed moment for the field, establishing islet transplantation as a recognized therapy for type 1 diabetes. However, this approval came with the requirement for continued immunosuppression, highlighting the need for further advances in immunomodulation.
Numerous clinical trials are currently underway testing various immunomodulatory approaches, including Treg therapy, encapsulation devices, and stem cell-derived islets. These trials face unique challenges, including the need for long-term follow-up to assess durability of graft function, the difficulty of comparing outcomes across different protocols and patient populations, and the high costs associated with cell therapy manufacturing and quality control.
Regulatory Pathways for Cell and Gene Therapies
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.
Genetically modified islets and CAR Treg therapies face additional regulatory scrutiny as gene therapy products. Demonstrating the safety of genetic modifications, ensuring the absence of off-target effects, and establishing long-term safety monitoring protocols are all essential requirements for regulatory approval. The complexity of these requirements can slow the translation of promising therapies from preclinical studies to clinical application.
Manufacturing and Scalability Challenges
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. Manufacturing cell therapies at clinical scale while maintaining consistent quality and function represents a major challenge for the field.
For autologous therapies like patient-specific CAR Tregs, the manufacturing process must be repeated for each individual patient, which is time-consuming and expensive. Allogeneic approaches using universal donor cells could potentially overcome these limitations by enabling off-the-shelf availability, but they require more extensive genetic modifications to prevent rejection. Developing automated, closed-system manufacturing platforms and establishing rigorous quality control standards will be essential for making these therapies widely accessible.
Future Directions and Emerging Technologies
The field of immunomodulation for islet transplantation continues to evolve rapidly, with new technologies and approaches emerging that promise to further improve outcomes.
Artificial Intelligence and Machine Learning
Artificial intelligence and machine learning are beginning to be applied to transplantation immunology, with the potential to predict rejection risk, optimize immunosuppression protocols, and identify novel therapeutic targets. By analyzing large datasets from clinical trials and patient registries, machine learning algorithms could identify patterns and biomarkers that are not apparent through traditional statistical approaches.
AI could also be used to design optimal combination immunomodulatory strategies, predicting which combinations of genetic modifications, biomaterials, and cellular therapies are most likely to succeed for individual patients based on their immune profiles and clinical characteristics. This personalized medicine approach could maximize the chances of achieving long-term graft survival while minimizing the risks of immunosuppression.
CRISPR and Advanced Gene Editing
CRISPR-Cas9 and other advanced gene editing technologies are enabling increasingly sophisticated modifications of islets and immune cells. Beyond simple gene knockouts, researchers are now using base editing and prime editing to make precise changes to individual nucleotides, potentially correcting disease-causing mutations or optimizing gene expression levels.
Multiplexed gene editing, where multiple genes are modified simultaneously, is enabling the creation of islets with comprehensive immune evasion properties. Future iterations might include not only HLA modifications and immunomodulatory protein expression but also enhanced resistance to inflammatory cytokines, improved glucose sensing, and increased insulin secretion capacity.
Organoid and Bioprinting Technologies
Three-dimensional bioprinting and organoid technologies are opening new possibilities for creating more physiologically relevant islet constructs. Rather than transplanting dispersed islets, researchers are exploring the creation of pancreatic organoids that more closely mimic the native pancreatic architecture, potentially improving function and survival.
Bioprinting could enable the precise spatial arrangement of islets, vascular cells, and immunomodulatory cells within engineered tissue constructs, creating optimal microenvironments for graft survival and function. These constructs could be designed with built-in vascular networks to ensure adequate oxygen and nutrient supply from the moment of transplantation.
Xenotransplantation Advances
Porcine islets represent another potential solution to the donor shortage problem. Recent advances in pig genetic engineering, including the knockout of genes encoding xenoantigens and the expression of human complement regulatory proteins, have significantly improved the survival of porcine islets in preclinical models. While xenotransplantation faces unique immunological challenges, including the need to overcome both cellular and antibody-mediated rejection, continued progress in this area could eventually provide an unlimited supply of islets for transplantation.
In Vivo Reprogramming
An emerging frontier in diabetes treatment is the direct reprogramming of other pancreatic cell types into insulin-producing beta cells within the patient’s own pancreas. This approach would eliminate the need for transplantation altogether, avoiding both the donor shortage problem and the challenges of immune rejection. While still in early stages of development, in vivo reprogramming represents a potentially transformative approach that could benefit from many of the immunomodulatory insights gained from islet transplantation research.
Challenges and Barriers to Clinical Translation
Despite the remarkable progress in immunomodulation for islet transplantation, significant challenges remain before these advances can be widely implemented in clinical practice.
Cost and Accessibility
Advanced cell and gene therapies are extremely expensive to develop and manufacture, raising concerns about accessibility and health equity. The cost of CAR Treg therapy, genetically modified islets, or sophisticated encapsulation devices may be prohibitive for many patients and healthcare systems. Developing strategies to reduce manufacturing costs and demonstrating cost-effectiveness compared to lifelong insulin therapy and management of diabetes complications will be essential for widespread adoption.
Long-Term Safety Concerns
The long-term safety of genetically modified cells remains a concern, particularly regarding the potential for insertional mutagenesis, off-target gene editing effects, or uncontrolled cell proliferation. Establishing comprehensive long-term safety monitoring protocols and developing safety switches that allow for the selective elimination of transplanted cells if problems arise will be important for regulatory approval and patient acceptance.
Standardization and Reproducibility
The complexity of many immunomodulatory strategies makes standardization and reproducibility challenging. Protocols for cell isolation, expansion, genetic modification, and transplantation must be rigorously standardized to ensure consistent outcomes across different centers and patient populations. Establishing international registries and collaborative networks to share protocols and compare outcomes will be important for advancing the field.
Patient Selection and Risk-Benefit Assessment
However, systemic immunosuppression, required to prevent allograft rejection, may be toxic to islets and, more importantly, has deleterious side effects to patients. Of note, for most T1D patients, the systemic immunosuppression is riskier than long-term standard management with exogenous insulin supplementation, which makes eliminating systemic immunosuppression critical to β cell replacement therapies. Determining which patients are most likely to benefit from islet transplantation and which immunomodulatory approaches are most appropriate for individual patients remains challenging.
Patients with severe hypoglycemia unawareness and those who have already received kidney transplants (and are therefore already on immunosuppression) are clear candidates for islet transplantation. However, as immunomodulatory strategies improve and the need for systemic immunosuppression decreases, islet transplantation may become appropriate for a broader range of patients. Developing tools to assess individual risk-benefit profiles and predict which patients are most likely to achieve long-term success will be important for optimizing patient selection.
The Path Forward: Integrating Research and Clinical Practice
Recent efforts can be broadly categorized into: (1) improving the cell product as surrogates of native beta cells, (2) promoting engraftment post-transplant to support cell survival, integration into the host, and endocrine function, and (3) developing immunomodulation strategies to reduce or circumvent immunosuppression regimen. In this review, we discuss recent and emerging advances in these three areas and the potential, risk, and scalability of experimental models to the clinic.
The ultimate goal of immunomodulation research in islet transplantation is to achieve durable insulin independence without the need for chronic immunosuppression. While this goal has not yet been fully realized in clinical practice, the rapid pace of scientific progress suggests that it may be achievable in the foreseeable future.
Collaborative Research Networks
Advancing the field will require close collaboration between basic scientists, clinicians, bioengineers, and industry partners. Establishing collaborative research networks that can conduct multi-center clinical trials, share data and biological samples, and coordinate translational research efforts will be essential for accelerating progress. International consortia focused on islet transplantation and diabetes cure research are already playing important roles in facilitating these collaborations.
Patient Engagement and Advocacy
Engaging patients and advocacy organizations in research priority-setting and clinical trial design is crucial for ensuring that research efforts align with patient needs and preferences. Patient input can help identify the most important outcomes to measure, acceptable risk-benefit tradeoffs, and barriers to clinical trial participation. Organizations focused on diabetes research and cure advocacy are playing increasingly important roles in funding research, raising awareness, and connecting patients with clinical trials.
Regulatory Innovation
Regulatory agencies are increasingly recognizing the need for innovative approaches to evaluating complex cell and gene therapies. Adaptive trial designs, surrogate endpoints, and accelerated approval pathways may help speed the translation of promising therapies while maintaining appropriate safety standards. Continued dialogue between researchers, clinicians, and regulators will be important for developing regulatory frameworks that balance innovation with patient safety.
Conclusion: A New Era in Diabetes Treatment
This highlights the urgent need for novel interventions to prevent autoimmune attack on β-cells and delay disease progression. In parallel, innovative strategies must be developed to support the long-term survival of transplanted islets in advanced-stage patients without systemic immunosuppression. The field of immunomodulation for islet transplantation has made remarkable progress in recent years, moving from broad, non-specific immunosuppression toward increasingly sophisticated strategies that promote specific immune tolerance.
The convergence of multiple technological advances—including gene editing, biomaterial engineering, cell therapy, and advanced immunology—is creating unprecedented opportunities to overcome the immunological barriers that have limited islet transplantation. 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.
Recent clinical successes, including the FDA approval of Lantidra and the demonstration that gene-edited islets can function without immunosuppression in humans, provide proof of concept that these approaches can work in clinical practice. While challenges remain in terms of scalability, cost, long-term safety, and accessibility, the trajectory of the field is clearly toward more effective and less toxic approaches to protecting transplanted islets.
For patients with type 1 diabetes, these advances offer hope for a future where insulin independence can be achieved without the burden of chronic immunosuppression. As immunomodulatory strategies continue to improve, islet transplantation may transition from a treatment reserved for a small subset of patients to a widely available option for achieving diabetes cure. The integration of stem cell-derived islets with advanced immunomodulation approaches could eventually make functional cure accessible to the millions of people worldwide living with type 1 diabetes.
The next decade will be critical for translating the wealth of preclinical findings into clinical practice. Success will require continued investment in basic and translational research, collaborative clinical trials, innovative regulatory approaches, and sustained commitment from the scientific community, healthcare providers, industry partners, and patient advocates. With these elements in place, the goal of achieving long-term islet graft survival without immunosuppression—and ultimately, a functional cure for type 1 diabetes—is within reach.
For more information on diabetes research and clinical trials, visit the JDRF (Juvenile Diabetes Research Foundation) and the National Institute of Diabetes and Digestive and Kidney Diseases. Additional resources on islet transplantation can be found through the Clinical Islet Transplantation Consortium, American Diabetes Association, and Cell and Gene Therapy Catapult.