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.
Abstract
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.
Preliminary experiments revealed that both the nTregs and eTregs can suppress the cytotoxic function and cytokine secretion of the islet-specific CTLs, indicating that suppression is mediated by a cell contact-dependent mechanism.
Elly Puckett, Sofia Colon Guzman, M. Markiewicz· Journal of Immunology· 0 citations
Engineered mesenchymal stem cells overexpressing AAT and gene delivery strategies provide an effective way to achieve sustained and localized AAT expression, and are expected to overcome the current challenges in clinical translation.
Type 1 diabetes (T1D) continues to be a complex, multifactorial autoimmune condition characterized by targeted destruction of pancreatic β-cells and permanent insulin dependence. How tremendous the change has been since the advent of insulin therapy, yet T1D patients remain at catastrophic risk from acute complications and chronic vascular injury, calling for more potent disease-modifying therapies. Developments in immunology and genetics have unraveled the interaction of environmental trigger events, including viral infection and gut microbiota, with genetic susceptibility, i.e., HLA class II alleles, on the aberration of immune tolerance and induction of β- cell autoimmunity. The last few decades have seen remarkable advances in the pathogenesis of T1D, including the discovery of β-cell autoantibodies and the pivotal role of autoreactive T cells. However, therapeutic trials in humans of immunomodulatory interventions, such as cyclosporine, anti-CD3 antibodies, and tolerogenic dendritic cells, have, to date, shown only temporary preservation of native insulin secretion, with safety limitations or failure to sustain efficacy being significant limitation. In parallel, efforts at inducing antigen-specific tolerance and microbiota modification have been promising in preclinical models but are still to be validated in humans. Technological advances, including continuous glucose monitoring and artificial pancreas systems, have enhanced glycemic management and quality of life without influencing causative autoimmunity. New strategies, β-cell replacement by transplant or xenograft, genetic engineering to favor immune evasion, and gene therapy for insulin production promise more definitive cures, but much remains in the path of safety, immune rejection, and long-term efficacy. Finally, in the years to come, the management of T1D will be a blend of early diagnosis, customized immunomodulation, improved sensing of glucose, and regeneration. Research on the genetic, immunologic, and environmental determinants for T1D and the creation of safer and more potent therapies will continue to be needed to advance beyond disease symptomatology management to disease modification and prevention.
Jasvinder Saini, Dushyant, Jagdeep Singh et al.· Current Topics in Medicinal...· 0 citations
Type 1 diabetes (T1D) is a selective autoimmune loss of insulin-secreting pancreatic β-cells and lifelong replacement with exogenous insulin. The disease remains incurable despite extensive research. New therapies, such as stem cell replacement, have been developed as the leading β-cell replacement modality. Pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) have been established as insulin-secreting cells, a theoretically unlimited reservoir for transplantation. Defective β-cell function, immune rejection, and ethical issues still exist. New immunosuppressive measures such as costimulation blockade therapy or regulatory T cell (Treg)-based therapy have been proposed to optimize graft survival with fewer side effects. Bioengineered islet grafting, xenograft transplantations, and gene editing tools are also analyzed in order to improve the effectiveness of β-cell replacement. Therapeutic advances in target immunomodulation and islet encapsulation are also enhancing survival and functionality of transplanted cells. This article provides a pharmaceutical review of emerging β-cell replacement therapies including stem cell-derived therapy, immunotherapy, and innovative biotechnologybased solutions. Breaking through current limitations of these therapies is crucial to achieving long-term insulin independence for T1D patients. Refining differentiation protocols, improving immune evasion strategies, and merging paradigms of personalized medicine are essential to achieving maximal therapeutic benefit in future studies.
Dushyant, Smita Narwal, Gurvirender Singh et al.· Recent advances in inflammat...· 0 citations
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.
Ahmed Hassanein, F. Cyprian, Saghir Akhtar· Expert Opinion on Biological...· 0 citations
In autoimmune diseases, cell-based therapies exemplified by CAR T cells should be reframed from exposure-control pharmacology to state-transition pharmacology, and through endogenous expansion and immune networks, therapeutic cells may shift the immune system from a pathological toward a tolerant steady state.
Juliang Qin, Guang-Yu Zhang, Ning Zhao et al.· Annual Review of Pharmacolog...· 0 citations
