Type 1 diabetes: immune pathology and novel therapeutic approaches.

Type 1 diabetes (T1D) is characterized by the progressive destruction of insulin-producing beta cells in the pancreas. Despite improvements in insulin monitoring techniques, there remains no cure for T1D. Individuals with T1D require lifelong insulin therapy and some develop life-threatening complications.

Assisting the implementation of screening for type 1 diabetes by using artificial intelligence on publicly available data.

The type 1 diabetes community is coalescing around the benefits and advantages of early screening for disease risk. To be accepted by healthcare providers, regulatory authorities and payers, screening programmes need to show that the testing variables allow accurate risk prediction and that individualised risk-informed monitoring plans are established, as well as operational feasibility, cost-effectiveness and acceptance at population level. Artificial intelligence (AI) has the potential to contribute to solving these issues, starting with the identification and stratification of at-risk individuals.

Immunological and virological triggers of type 1 diabetes: insights and implications.

Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease.

Liraglutide protects β-cells in novel human islet spheroid models of type 1 diabetes.

To enable accurate, high-throughput and longer-term studies of the immunopathogenesis of type 1 diabetes (T1D), we established three in-vitro islet-immune injury models by culturing spheroids derived from primary human islets with proinflammatory cytokines, activated peripheral blood mononuclear cells or HLA-A2-restricted preproinsulin-specific cytotoxic T lymphocytes. In all models, β-cell function declined as manifested by increased basal and decreased glucose-stimulated insulin release (GSIS), and decreased intracellular insulin content. Additional hallmarks of T1D progression such as loss of the first-phase insulin response (FFIR), increased proinsulin-to-insulin ratios, HLA-class I expression, and inflammatory cytokine release were also observed.

Effect of IL4 and IL10 on a human in vitro type 1 diabetes model.

We defined the effect of the anti-inflammatory cytokines IL4 and IL10 on an in vitro model of human T1D. After preincubation with IL4 or IL10, human islet microtissues were co-cultured with PBMC and proinflammatory cytokines for a few hours or for multiple days to assess acute and chronic effects. This resulted in an immune attack with infiltration of T cells into the islet, a loss of beta cell endocrine function, and an upregulation of HLA-I on the beta cells.

Induction of antigenic immune tolerance to delay type 1 diabetes - challenges for clinical translation.

Purpose Of Review: Dissect the field of antigen-specific immunotherapy (ASIT) in type 1 diabetes (T1D), highlighting the major barriers currently blocking clinical translation.

Recent Findings: ASIT remains a promising approach in T1D to re-establish the proper balance in the immune system to avoid the autoimmune-mediated attack or destruction of beta-cells in the pancreas. Despite some encouraging preclinical results, ASIT has not yet successfully translated into clinical utility, predominantly due to the lack of validated and clinically useful biomarkers.

Interleukin 6 in diabetes, chronic kidney disease, and cardiovascular disease: mechanisms and therapeutic perspectives.

Introduction: Diabetes, chronic kidney disease (CKD) and cardiovascular disease (CVD) are cardiometabolic diseases that remain amongst the leading causes of morbidity and premature mortality. Here, we review the current understanding of how anti-inflammatory intervention via inhibition of the pro-inflammatory but pleiotropic cytokine interleukin (IL) 6 may benefit patients with these or related diseases or complications.

Areas Covered: Based on a PubMed literature search, this review integrates and contextualizes evidence regarding the clinical utility of anti-IL-6 intervention in the treatment of cardiometabolic diseases, as well as of the associated condition nonalcoholic hepatosteatosis.

Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes.

Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice.

Upregulation of HLA class II in pancreatic beta cells from organ donors with type 1 diabetes.

Aims/hypothesis: We aimed to characterise and quantify the expression of HLA class II (HLA-II) in human pancreatic tissue sections and to analyse its induction in human islets.

Methods: We immunostained human pancreatic tissue sections from non-diabetic (n = 5), autoantibody positive (Aab+; n = 5), and type 1 diabetic (n = 5) donors, obtained from the Network of Pancreatic Organ Donors (nPOD), with HLA-II, CD68 and insulin. Each tissue section was acquired with a widefield slide scanner and then analysed with QuPath software.

Efficacy and safety of liraglutide in type 1 diabetes by baseline characteristics in the ADJUNCT ONE and ADJUNCT TWO randomized controlled trials.

Aim: To evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJUNCT ONE and ADJUNCT TWO trials.

Materials And Methods: ADJUNCT ONE and ADJUNCT TWO were randomized controlled phase 3 trials in 1398 and 835 participants with T1D treated with liraglutide (1.8, 1.

Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes.

Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice.

IL-17 is expressed on beta and alpha cells of donors with type 1 and type 2 diabetes.

Purpose: IL-17 is an important effector cytokine driving immune-mediated destruction in autoimmune diseases such as psoriasis. Blockade of the IL-17 pathway after the initiation of insulitis was effective in delaying or preventing the onset of type 1 diabetes (T1D) in rodent models. Expression of IL-17 transcripts in islets from a donor with recent-onset T1D has been reported, however, studies regarding IL-17 protein expression are lacking.

Peripheral autoreactive CD8 T-cell frequencies are too variable to be a reliable predictor of disease progression of human type 1 diabetes.

Objectives: The detection of a peripheral immune cell signature that specifically reflects autoimmunity in type 1 diabetes would enable the prediction and staging of disease on an individual basis. However, defining such a signature is technically challenging. Reliable interpretation of immune cell-related biomarkers depends on their inherent variability and, to understand this variability, longitudinal analyses are required.

Means, Motive, and Opportunity: Do Non-Islet-Reactive Infiltrating T Cells Contribute to Autoimmunity in Type 1 Diabetes?

In human type 1 diabetes and animal models of the disease, a diverse assortment of immune cells infiltrates the pancreatic islets. CD8 T cells are well represented within infiltrates and HLA multimer staining of pancreas sections provides clear evidence that islet epitope reactive T cells are present within autoimmune lesions. These effectors have been a key research focus because these cells represent an intellectually attractive culprit for β cell destruction.

Current state of antigen-specific immunotherapy for type 1 diabetes.

Purpose Of Review: Update on antigen-specific immunotherapy (ASIT) in type 1 diabetes (T1D) with focus on deoxyribonucleic acid (DNA)-induced immunization and the current obstacles to further research and clinical realization.

Recent Findings: In T1D, immune system imbalances together with malfunctioning islet-specific processes cause autoreactive immune cells to destroy beta cells in the islets. ASIT may restore self-tolerance; however, the approach has yet to fully meet its promise and may require co-administration of antigen (preproinsulin) and suitable immune response modifiers.

HLA class I hyper-expression unmasks beta cells but not alpha cells to the immune system in pre-diabetes.

Human leukocyte antigens of class-I (HLA-I) molecules are hyper-expressed in insulin-containing islets (ICI) of type 1 diabetic (T1D) donors. This study investigated the HLA-I expression in autoantibody positive (AAB+) donors and defined its intra-islet and intracellular localization as well as proximity to infiltrating CD8 T cells with high-resolution confocal microscopy. We found HLA-I hyper-expression had already occurred prior to clinical diagnosis of T1D in islets of AAB+ donors.

Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial.

Background: Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation.

Methods: This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries.

Current and future therapies for type 1 diabetes.

In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia.

New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes.

Since the establishment of the network for pancreatic organ donors with diabetes (nPOD), we have gained unprecedented insight into the pathology of human type 1 diabetes. Many of the pre-existing "dogmas", mostly derived from studies of animal models and sometimes limited human samples, have to be revised now. For example, we have learned that autoreactive CD8 T cells are present even in healthy individuals within the exocrine pancreas.

One in Ten CD8 Cells in the Pancreas of Living Individuals With Recent-Onset Type 1 Diabetes Recognizes the Preproinsulin Epitope PPI.

In type 1 diabetes (T1D), a lifelong autoimmune disease, T cells infiltrate the islets and the exocrine pancreas in high numbers. CD8 T cells are the main cell type found in the insulitic lesion, and CD8 T cells reactive against β-cell antigens have been detected in peripheral blood and in the pancreas of patients with short- or long-term disease. In the Diabetes Virus Detection (DiViD) study, researchers collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset T1D.

The effect of Toll-like receptor stimulation on the motility of regulatory T cells.

Regulatory T cells (Tregs) have suppressive functions and play an important role in controlling inflammation and autoimmunity. The migratory capacity of Tregs determines their location and their location determines whether they inhibit the priming of naïve lymphocytes in lymphoid tissues or the effector phase of immune responses at inflamed sites. Tregs generated or expanded in vitro are currently being tested in clinics for the treatment of autoimmune disorders, however, little is known about the factors controlling their migration towards therapeutically relevant locations.

The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes.

Preproinsulin (PPI) is presumably a crucial islet autoantigen found in patients with type 1 diabetes (T1D) but is also recognized by CD8 T cells from healthy individuals. We quantified PPI-specific CD8 T cells within different areas of the human pancreas from nondiabetic controls, autoantibody-positive donors, and donors with T1D to investigate their role in diabetes development. This spatial cellular quantitation revealed unusually high frequencies of autoreactive CD8 T cells supporting the hypothesis that PPI is indeed a key autoantigen.

Interference with pancreatic sympathetic signaling halts the onset of diabetes in mice.

The notably lobular distribution of immune lesions in type 1 diabetes (T1D) has been hypothesized to be the result of innervation within the pancreas. To investigate whether neuroimmune interactions could explain this phenomenon, we explored the impact of sympathetic signaling in the RIP-LCMV-GP mouse model of autoimmune diabetes. In this model, the CD8 T cell attack on β cells replicates a key pathogenic feature of human T1D.