The beta cell-immune cell interface in type 1 diabetes (T1D)

James, Eddie A.; Joglekar, Alok V.; Linnemann, Amelia K.; Russ, Holger A.; Kent, Sally C.

doi:10.1016/j.molmet.2023.101809

Cited by 10 publications

(2 citation statements)

References 269 publications

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“…In recent years, significant advancements have emerged in our ability to comprehensively study the interaction between beta cells and immune cells (150). Notably, recent research has reshaped our understanding, highlighting that pancreatic beta cells play an active role rather than remaining passive during the progression of immune recognition (151). It was previously believed that T1D resulted in the complete depletion of beta cells.…”

Section: The Importance Of Beta Cell In the Interaction With Immune C...mentioning

confidence: 99%

Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge

Caldara,

Tomajer,

Monti

et al. 2023

Front. Immunol.

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Type 1 diabetes (T1D) presents a persistent medical challenge, demanding innovative strategies for sustained glycemic control and enhanced patient well-being. Beta cells are specialized cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. When beta cells are damaged or destroyed, insulin production decreases, which leads to T1D. Allo Beta Cell Transplantation has emerged as a promising therapeutic avenue, with the goal of reinstating glucose regulation and insulin production in T1D patients. However, the path to success in this approach is fraught with complex immunological hurdles that demand rigorous exploration and resolution for enduring therapeutic efficacy. This exploration focuses on the distinct immunological characteristics inherent to Allo Beta Cell Transplantation. An understanding of these unique challenges is pivotal for the development of effective therapeutic interventions. The critical role of glucose regulation and insulin in immune activation is emphasized, with an emphasis on the intricate interplay between beta cells and immune cells. The transplantation site, particularly the liver, is examined in depth, highlighting its relevance in the context of complex immunological issues. Scrutiny extends to recipient and donor matching, including the utilization of multiple islet donors, while also considering the potential risk of autoimmune recurrence. Moreover, unanswered questions and persistent gaps in knowledge within the field are identified. These include the absence of robust evidence supporting immunosuppression treatments, the need for reliable methods to assess rejection and treatment protocols, the lack of validated biomarkers for monitoring beta cell loss, and the imperative need for improved beta cell imaging techniques. In addition, attention is drawn to emerging directions and transformative strategies in the field. This encompasses alternative immunosuppressive regimens and calcineurin-free immunoprotocols, as well as a reevaluation of induction therapy and recipient preconditioning methods. Innovative approaches targeting autoimmune recurrence, such as CAR Tregs and TCR Tregs, are explored, along with the potential of stem stealth cells, tissue engineering, and encapsulation to overcome the risk of graft rejection. In summary, this review provides a comprehensive overview of the inherent immunological obstacles associated with Allo Beta Cell Transplantation. It offers valuable insights into emerging strategies and directions that hold great promise for advancing the field and ultimately improving outcomes for individuals living with diabetes.

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Section: The Importance Of Beta Cell In the Interaction With Immune C...mentioning

confidence: 99%

Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge

Caldara,

Tomajer,

Monti

et al. 2023

Front. Immunol.

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“…These culminate in the development of autoimmunity against key islet antigens and ultimately lead to β-cell loss mediated by immune cells (notably CD8+ cytotoxic T-cells) which infiltrate pancreatic islets (5)(6)(7). Although direct immune cell-endocrine cell contact may contribute to the attack, the majority of infiltrating CD8+ T-cells are found at the periphery of islets implying that cytokine secretion and remote activation of pro-apoptotic pathways are also likely to be important (5)(6)(7)(8). Interferons are among the most critical cytokines which impinge on β-cells to impair their function and viability in type 1 diabetes (9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Regulation of STAT1 signalling in human pancreatic β-cells by the lysine deacetylase, HDAC6; a new therapeutic opportunity in type 1 diabetes?

Afi Leslie,

Lekka,

J. Richardson

et al. 2024

Preprint

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<h2>Abstract</h2>Type 1 diabetes arises from the selective destruction of pancreatic β-cells by autoimmune mechanisms and intracellular pathways driven by Janus (JAK)-kinase mediated STAT isoforms (especially STAT1 & STAT2) are implicated as mediators of β-cell demise. Despite this, the molecular mechanisms that regulate JAK-STAT signalling in β-cells during the autoimmune attack remain only partially disclosed and the factors acting to antagonise pro-inflammatory STAT1 signalling are uncertain. We have recently implicated Signal Regulatory Protein (SIRP)-α in promoting β-cell viability in the face of ongoing islet autoimmunity and now reveal that this protein controls the availability of a cytosolic lysine deacetylase, HDAC6, whose activity regulates the phosphorylation and activation of STAT1. We provide evidence that STAT1 serves as a substrate for HDAC6 in β-cells and that sequestration of HDAC6 by SIRPα in response to anti-inflammatory cytokines (such as interleukin-13) leads to increased STAT1 acetylation. This then impairs the ability of STAT1 to promote gene transcription in response to pro-inflammatory cytokines including interferon-gamma (IFNγ). We further find that SIRPα is lost from the β-cells of subjects with recent-onset type 1 diabetes under conditions when HDAC6 is retained and STAT1 levels are increased. On this basis, we report a previously unrecognised role for cytokine-induced regulation of STAT1 acetylation in the control of β-cell viability and propose that targeted inhibition of HDAC6 activity may represent a novel therapeutic modality to promote β-cell viability in the face of active islet autoimmunity.Article Highlights· Signal regulatory protein-alpha (SIRPα) is present in human islet cells but its levels decline in β-cells in type 1 diabetes.· Decreases in SIRPα expression are associated with a reduction in the viability of cultured β-cells.· Immunoprecipitation of β-cell SIRPα reveals a direct interaction with the lysine deacetylase, HDAC6.· Sequestration of HDAC6 by SIRPα results in increased acetylation, reduced phosphorylation and impaired activation of STAT1 during exposure of β-cells to IFNγ.· Pharmacological targeting of HDAC6 might yield improvements in β-cell viability during progression to type 1 diabetes.

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Using GeoMx DSP Spatial Proteomics to Investigate Immune Infiltration of NOD Mouse Islet and Exocrine Compartments

Tekin,

Lindhardt,

Antvorskov

et al. 2024

Mol Imaging Biol

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Purpose Type 1 Diabetes (T1D) pathogenesis involves immune cells infiltrating pancreatic Islets of Langerhans, leading to T cell activation, beta cell destruction, and impaired insulin production. However, infiltration has a heterogenic nature that isn’t described in detail, as not all islets are infiltrated. The aim of this study was to investigate if the observed heterogeneity is coupled to differences in immune and/or dysfunctional status of islets or exocrine cells, and if specific markers could elucidate mechanistic details of T1D pathogenesis. Procedures The GeoMx platform was used to spatially quantify protein levels in pancreatic islets and exocrine tissue in Non-Obese Diabetic (NOD) mice. The protein panel included 17 immune activity markers and nine dysfunction markers. Immunohistochemical (IHC) staining and digital image analysis was used to analyze select marker proteins. Results Use of the GeoMx platform to investigate T1D was shown to be possible, as Granzyme B protein levels were found to be lower in distal islet areas when compared to proximal areas. Smooth Muscle Actin protein levels were higher in exocrine areas proximal to immune-infiltrated islets, when compared to distally located exocrine areas. Findings from GeoMx were however not observed in IHC-stained sections. Conclusions This study demonstrates that investigating T1D is possible with spatial proteomics, as the assays revealed presence of heterogenic islet areas in NOD mice, which may play a role in T1D progression and escape from immune recognition. This study highlights the potential of spatial technologies for elucidating T1D pathogenesis and future treatment strategies.

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The beta cell-immune cell interface in type 1 diabetes (T1D)

Cited by 10 publications

References 269 publications

Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge

Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge

Regulation of STAT1 signalling in human pancreatic β-cells by the lysine deacetylase, HDAC6; a new therapeutic opportunity in type 1 diabetes?

Using GeoMx DSP Spatial Proteomics to Investigate Immune Infiltration of NOD Mouse Islet and Exocrine Compartments

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