Aug 2026· Expert Opinion on Biological Therapy· 0 citations· 83 references
Medicine
TL;DR
Current preclinical and clinical evidence from 2019 to 2026 for gene-edited hypoimmune islets is critically evaluated, highlighting key immunological vulnerabilities that may emerge over time and whether these long-term challenges can be overcome.
Abstract
INTRODUCTION
Islet transplantation has long been considered a potential long-term treatment for type 1 diabetes mellitus (T1DM); however, the need for systemic immunosuppression has limited its clinical utility due to associated toxicity. Gene-edited hypoimmune islets represent a promising immunosuppression-free alternative. Recent first-in-human data demonstrating short-term engraftment and C-peptide production without immunosuppression, with 12-week immune monitoring and extended 14-month follow-up, provide an important proof-of-concept. However, whether short-term immune evasion can translate into durable long-term graft survival remains unclear.
AREAS COVERED
We critically evaluate current preclinical and clinical evidence from 2019 to 2026 for gene-edited hypoimmune islets, highlighting key immunological vulnerabilities that may emerge over time.
EXPERT OPINION
The central question is no longer whether these islets can evade acute rejection, but whether they can sustain this evasion and efficacy long-term against the human immune system. Several theoretical mechanisms may contribute to delayed graft injury: indirect allorecognition (particularly non-HLA antibody formation), persistence of autoreactive immune memory, β-cell stress-induced neoantigen formation, and susceptibility to viral infection. Durable graft survival will likely require multimodal approaches combining gene-edited islets with adjunct immunomodulation (e.g. teplizumab, low-dose ATG, tegoprubart) and metabolic support. If these long-term challenges can be overcome, gene-edited hypoimmune islets could transform T1DM treatment paradigms.
Type 1 diabetes (T1D) impacts more than 9 million individuals globally. Despite a century since the isolation and clinical introduction of insulin, exogenous insulin injections remain the primary form of treatment for T1D. While continuous glucose monitoring systems and optimized insulin delivery reduce life-threatening hypoglycemic events, they do not provide a permanent cure. Transplantation of pancreatic islets offers a potential long-term solution. Recent advances in stem cell–derived islets (SC-islets) have shown remarkable promise in both clinical and research settings. This article highlights recent clinical reports in the use of SC-islets to restore islet function and their versatility as a platform for disease modeling and drug screening while emphasizing current strategies aimed at overcoming their limitations and enhancing their therapeutic potential. We also discuss exciting emerging approaches that expand investigations beyond pancreatic endocrine cells to encompass nonendocrine cell types in the pancreas, offering a unique bird’s-eye view into pancreatic biology and insights into cellular cross talk in health and disease. Our aim is for this article to serve as a resource for up-to-date advances in SC-islet research and to highlight novel platforms for studying diabetes pathogenesis in unprecedented ways, accelerating progress toward a permanent cure. Article Highlights Stem cell–derived islets provide a renewable source of insulin-producing cells for studying diabetes and developing regenerative therapies. Stem cell–derived islets are still functionally immature in comparison with primary human islets, underscoring the need for deeper insights into β-cell biology to improve their fidelity. Nonetheless, they serve as a powerful platform for diabetes disease modeling. Emerging technological advances, including spatial multiomics and multicellular organoid development, are revealing key roles for non–β-cell and nonislet cell types in pancreatic diseases. Integrating these emerging tools is critical for broadening our understanding of diabetes pathophysiology and may enable us to view the disease from previously unexplored perspectives.
Noyonika Mukherjee, J. Millman· Diabetes· 0 citations
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of β-cells in the pancreatic islets, resulting in insulin deficiency. Currently the best treatment option for T1D is exogenous insulin, which regulates blood glucose levels, but does not change the underlying disease. The increasing number of T1D diagnoses highlight the need for novel therapies. An area of growing interest is the use of regulatory T cells (Tregs) to suppress autoreactive T cells. Clinical trials involving the transfer of autologous ex vivo expanded polyclonal CD4+ Tregs have shown this approach to be safe; however, it has limitations. These include challenges with ex vivo Treg expansion, antigen specificity, loss of immunosuppressive activity, and inherent Treg functional defects due to genetic deficiencies in autoimmune patients.
Our group has developed a patented protocol for generating engineered Tregs (eTregs) by expressing two transcription factors critical for Treg function, FOXP3 and Helios in conventional T cells. We hypothesize that our FOXP3+Helios+ eTregs can suppress the islet-specific reactivity of cytotoxic CD8+ T cells (CTLs). To test this hypothesis, we have generated CTLs specific for an islet-specific antigen and FOXP3+Helios+ eTregs, as well as isolated natural Tregs (nTregs), all from the same donor. We then compared the ability of the eTregs with that of nTregs to suppress CTL reactivity against the human β cell line βlox5.
Preliminary experiments revealed that both the nTregs and eTregs can suppress the cytotoxic function and cytokine secretion of the islet-specific CTLs. Separating the Tregs and CTLs using transwell inserts abrogated the suppressive effect, indicating that suppression is mediated by a cell contact-dependent mechanism.
These data indicate that FOXP3+Helios+ engineered Tregs can effectively suppress islet specific CTL responses in vitro and support the continued investigation of eTregs as a potential cell-based immunotherapy for T1D.
Breakthrough T1D (1-INO-2025-1709-A-N), NIH/NIGMS (P20GM130423), Children’s Mercy Hospital
Therapeutic Approaches to Autoimmunity (THER)
Elly Puckett, Sofia Colon Guzman, M. Markiewicz· Journal of Immunology· 0 citations
ABSTRACT Introduction Type 1 diabetes (T1D) has long been viewed as an immune-driven disease characterized by the destruction of otherwise healthy pancreatic beta cells. However, growing evidence indicates that beta cells may actively contribute to disease initiation. Intrinsic dysfunction – such as impaired protein processing, endoplasmic reticulum stress, neoantigen formation, and early upregulation of major histocompatibility complex (MHC) class I – could increase beta-cell immunogenicity and promote autoimmune recognition. This emerging paradigm has significant implications for prevention and therapeutic strategies. Areas covered This review synthesizes experimental, translational, and clinical evidence supporting beta cell stress and dysfunction as central components of T1D pathogenesis. It examines intrinsic beta cell pathways, mechanisms of immune recognition, and therapeutic approaches aimed at preserving beta-cell integrity. These findings challenge the traditional immune-centric model and support a more integrated view of disease progression, emphasizing the interplay between beta cell vulnerability and immune activation. Expert opinion Effective prevention will likely require combination strategies that address both beta cell stress and autoimmunity. Approaches integrating beta cell protective agents with antigen-specific tolerance therapies may delay or prevent progression when applied early. Stage-adapted interventions targeting both beta cell resilience and immune modulation may redefine T1D prevention and improve management of pre-symptomatic individuals.
M. von Herrath, Joana R. N. Lemos, Filip Krag Knop· Expert Review of Clinical Im...· 0 citations
Antibody-mediated rejection (AMR) is the primary immunological obstacle limiting long-term survival in heart transplant recipients. Driven by donor-specific antibodies (DSA), AMR damages graft microvasculature through multiple pathways, including complement activation, antibody-dependent cellular cytotoxicity, and sustained endothelial activation. It may present as acute hemodynamic collapse or progress insidiously in a subclinical manner, ultimately culminating in cardiac allograft vasculopathy (CAV) and graft failure. Over the past two decades, with successive updates to the ISHLT pathological diagnostic system, AMR has evolved from a vague clinical concept into a distinct entity defined by explicit histopathological and immunopathological criteria. However, therapeutic advances have markedly lagged behind the deepening understanding of its diagnosis. For a long time, the first−line regimen has consisted of plasma exchange combined with intravenous immunoglobulin (IVIG). Nevertheless, its mechanism—clearance of circulating antibodies plus broad−spectrum immunomodulation—neither targets the source of antibody production (long−lived plasma cells) nor selectively blocks terminal effector pathways. Approximately 30–50% of refractory AMR cases respond poorly to this regimen. Over the past decade, agents targeting plasma cells (proteasome inhibitor bortezomib), the terminal complement component (C5 monoclonal antibody eculizumab), the IL−6 pathway (tocilizumab, clazakizumab), and the more recent anti−CD38 monoclonal antibody (daratumumab) have entered clinical practice, shifting AMR treatment from having no actionable targets to enabling multi−node intervention. This review delineates the rationale underlying this evolution: the treatment paradigm is transitioning from empirical combination therapy to biomarker−driven, multi−target precision intervention covering the entire sequence of “production–circulation–effector pathways.” However, the field remains in a distinct transitional phase characterized by “weapons available but tactics lacking”—the vast majority of evidence derives from single−center, retrospective, small−sample observational studies, with no randomized controlled trial (RCT) specifically designed for AMR in heart transplantation. Consensus is lacking on how to select, combine, and sequence these agents based on individual immune phenotypes. Stratified therapy, dynamic biomarker monitoring, and rational multi−target combination will be the core directions for solving this challenge in the coming decade.
Ning Xu, Yaqin Dong, Yehong Yue et al.· Frontiers in Immunology· 0 citations
Type 1 diabetes (T1D) is a chronic disease characterized by the relentless autoimmune destruction of insulin producing pancreatic beta cells (β cells). About 9.5 million people worldwide live with T1D. 1.9 million are under 20 years old. There is no cure and few effective treatments, making novel therapies desperately needed. All-trans retinoic acid (ATRA) has shown promise in preventing and even ameliorating T1D, particularly in various rodent T1D models. Benefits are thought to be mediated by influences on T cells, particularly regulatory (Treg) and autoreactive effector T cells. Intriguingly, ATRA may also directly contribute to the differentiation and maintenance of pancreatic β cells. This mini review will focus on experiences with ATRA in rodent models of T1D, including measures of efficacy, Treg cell expansion, reduction of autoreactive effector T cell activity and oxidative stress, and perhaps most promisingly, preservation and stimulation of pancreatic β cells. We will then discuss the clinical potential of ATRA in T1D, including targeted drug delivery strategies to deliver ATRA locally to the relevant immune microenvironment, limiting its systemic exposure, reducing toxic side effects and enhancing efficacy.
Benjamin L. Green, D. Auci· Canadian Journal of Diabetes· 0 citations
For decades, autoimmune disease treatment depended on long-term immunosuppression, which seldom yields lasting immune tolerance and carries cumulative toxic risks. Recent cell therapies, including chimeric antigen receptor (CAR) T cells, regulatory T cells, and mesenchymal stromal cells, have induced deep remission in refractory diseases, often persisting after treatment withdrawal and indicating benefits beyond short-term inflammation suppression. However, traditional dose-exposure-response pharmacokinetic/pharmacodynamic frameworks are insufficient to account for the in vivo expansion, trafficking, and phenotypic evolution of living cellular products. Here we propose that, in autoimmune diseases, cell-based therapies exemplified by CAR T cells should be reframed from exposure-control pharmacology to state-transition pharmacology. Through endogenous expansion and immune networks, therapeutic cells may shift the immune system from a pathological toward a tolerant steady state. Because toxicities may reflect the amplification or persistence of intended mechanisms, future work requires quantitative metrics of immune state transitions and programmable strategies for precise functional control.
Juliang Qin, Guangyu Zhang, Ning Zhao et al.· Annual Review of Pharmacolog...· 0 citations
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
