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.
Abstract
Type 1 Diabetes (T1D) is an autoimmune disease-causing selective destruction of pancreatic β-cells, requiring lifelong insulin. Current treatments cannot prevent β-cells loss or restore immune tolerance, highlighting the need for diseasemodifying therapies. Alpha-1 antitrypsin (AAT) has attracted attention due to its multiple mechanisms of action in T1D. It can regulate NKDC interactions, boost Treg function, and inhibit Th1 and CD8+ T cells. It also suppresses the NFκB/IL-1β pathway and upregulates IL1Ra. These actions reduce β-cell apoptosis and increase β-cell mass. Clinical studies show safety of AAT in new-onset T1D and islet autotransplantation, but efficacy outcomes have not been consistently met, partly due to insufficient dosing (90 mg/kg/week) and compensatory endogenous AAT elevation. Different reactions related to gender have been observed in female patients. Future larger-dose, placebo-controlled trials with gender are needed. 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
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
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.
Benjamin L. Green, D. Auci· Canadian Journal of Diabetes· 0 citations
Type 1 diabetes (T1D) is an autoimmune disorder caused by T cell-mediated destruction of pancreatic β cells. There is a critical need to develop novel therapies for this disease, which requires further understanding of T1D pathogenesis. One pathway that is implicated is signaling through the immune receptor NKG2D. However, NKG2D’s role has remained unclear due to conflicting reports in the literature.
We generated multiple novel mouse strains on the non-obese diabetic (NOD) background to better define the role of NKG2D in autoimmune diabetes. We compared diabetes incidence, insulitis, including digital spatial profiling, and islet-specific CD8+ CTL generation between mice genetically deficient in NKG2D (NKG2D KO) and wild-type (WT) mice housed in both specific-pathogen-free (SPF) and germ-free (GF) conditions.
NKG2D KO mice had delayed diabetes, insulitis, and CD8+ T cell pancreatic infiltration, with the most significant effect in GF and male mice. Further, we found that NKG2D signaling did not occur in the pancreas, that NKG2D ligands were expressed in the pancreatic lymph node, that deletion of NKG2D in CD8+ T cells was required to delay diabetes, that there was reduced differentiation of CTL from islet-specific naive NKG2D KO CD8+ T cells, and that the transcriptome of NKG2D KO CTL was altered. Additionally, we found that blocking NKG2D signaling similarly reduced human CTL differentiation.
The results of our studies definitively demonstrate that NKG2D in CD8+ T cells plays a critical role in autoimmune diabetes. We show this role is to enhance CTL generation rather than the CTL effector response in islets as previously proposed. Further, our data explain the conflicting reports surrounding NKG2D’s role, as we reveal the existence of redundant, compensatory signaling that is influenced by the microbiome and sex. This inherent redundancy strongly suggests that signaling through NKG2D or its compensatory pathway is critical for islet-specific CTL generation.
Breakthrough T1D (3-SRA-2023-1412-S-B and 1-INO-2022-1118-A-N), NIH P20GM104936
Basic Autoimmunity (BA)
M. Markiewicz, Zoe K Bedrosian, Allison Manning et al.· Journal of Immunology· 0 citations
Abstract Introduction Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell–mediated destruction of pancreatic β cells. Current insulin therapy does not address autoimmune pathology or restore endogenous β-cell function, highlighting the need for disease-modifying strategies. Methods We developed a combination therapy integrating a proton pump inhibitor (PPI; omeprazole) with a non–Fc-binding anti-CD3 F(ab’)2 antibody fragment (anti-CD3 F(ab’)2) to concurrently promote β-cell neogenesis and modulate autoimmune T-cell responses. T1D was induced in nonobese diabetic (NOD) mice using a cyclophosphamide-accelerated protocol (CY-NOD). Following hyperglycemia onset, mice received combination treatment and were evaluated by blood glucose monitoring, flow cytometric analysis of T-cell populations, and assessment of pancreatic β-cell function. Therapeutic efficacy was further examined in spontaneous-onset NOD mice. Results Combination therapy restored normoglycemia without exogenous insulin, reduced lymphocytic infiltration in pancreatic islets, and preserved endogenous insulin secretion. Treatment decreased pathogenic CD4+ and CD8+ T cells, increased regulatory T cells, and enhanced transforming growth factor-β expression. Comparable and durable glycemic control was observed in spontaneous-onset NOD mice. Conclusions Concurrent modulation of β-cell function and autoimmune immunity achieved sustained glycemic control in T1D models. The use of clinically approved agents supports the translational potential of this non–insulin-dependent therapeutic strategy.
Tung-Yun Wu, Che-Yi Chen, Michael Chen et al.· Immunotherapy Advances· 0 citations
Type 1 diabetes mellitus (T1DM) is regarded as an autoimmune disorder characterized by a progressive loss of β-cells, culminating in insulin deficiency and hyperglycemia. Currently, T1DM is managed through exogenous insulin administration. Continued efforts to decipher T1DM pathogenesis have yielded significant progress, which can be harnessed to develop disease-modifying therapeutic modalities. Immunological and genetic studies have demonstrated pathogenetic mechanisms that underpin the sensitivity and risk of developing autoimmunity, ultimately leading to the destruction of β-cells. Genetic and immunological studies, therefore, suggest that certain individuals are at risk of developing T1DM; and that autoantibodies against β-cells develop and circulate years before the onset of symptomatic T1DM. Furthermore, the onset of autoimmunity has been associated with specific triggers in genetically susceptible individuals. Recent developments have revealed how viral infections, gut dysbiosis, dietary factors, and obesity trigger autoimmunity and β-cell damage. In this review, we present the current, consolidated understanding of T1DM pathogenesis, informed by recent research. We further identify opportunities for early-detection strategies and drug development targeting the asymptomatic phase of T1DM to slow disease progression. Currently, immunomodulatory strategies have yielded promising outcomes in clinical trials. These strategies seek to target immune cells and inflammatory mediators implicated in the pathogenesis of T1DM. Other strategies include tolerogenic strategies against autoimmune cells, whilst others employ β-cell protection. The emergence of regenerative therapies also offers promising avenues toward T1DM.
N. Ngcobo, N. Sibiya· Pathophysiology· 0 citations
