scholarly journals Multicomponent plasmid protects mice from spontaneous autoimmune diabetes

2021 ◽  
Author(s):  
Philippe P. Pagni ◽  
Jay Chaplin ◽  
Michael Wijaranakula ◽  
Johnna D. Wesley ◽  
Jaimie Granger ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Autoimmune Diabetes ◽  
Phase 1 ◽  
Myeloid Cell ◽  
Cell Types ◽  
Cytokine Combination

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. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).

scholarly journals Multicomponent plasmid protects mice from spontaneous autoimmune diabetes

2021 ◽  
Author(s):  
Philippe P. Pagni ◽  
Jay Chaplin ◽  
Michael Wijaranakula ◽  
Johnna D. Wesley ◽  
Jaimie Granger ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Autoimmune Diabetes ◽  
Phase 1 ◽  
Myeloid Cell ◽  
Cell Types ◽  
Cytokine Combination

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. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).

Immunotherapy: Building a bridge to a cure for type 1 diabetes

Science ◽  
2021 ◽  
Vol 373 (6554) ◽  
pp. 510-516
Author(s):  
Jeffrey A. Bluestone ◽  
Jane H. Buckner ◽  
Kevan C. Herold
Keyword(s):  
Type 1 Diabetes ◽  
Immune Cell ◽  
Cell Types ◽  
Underlying Disease ◽  
Β Cells ◽  
Current State ◽  
Islet Inflammation ◽  
Genetic And Environmental Factors ◽  
Key Events

Type 1 diabetes (T1D) is an autoimmune disease in which T cells attack and destroy the insulin-producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by compromising immune homeostasis. Although the discovery and use of insulin have transformed T1D treatment, insulin therapy does not change the underlying disease or fully prevent complications. Over the past two decades, research has identified multiple immune cell types and soluble factors that destroy insulin-producing β cells. These insights into disease pathogenesis have enabled the development of therapies to prevent and modify T1D. In this review, we highlight the key events that initiate and sustain pancreatic islet inflammation in T1D, the current state of the immunological therapies, and their advantages for the treatment of T1D.

scholarly journals Serum Concentrations of Transforming Growth Factor-Beta 1 in Predicting the Occurrence of Diabetic Retinopathy in Juvenile Patients with Type 1 Diabetes Mellitus

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Katarzyna Zorena ◽  
Ewa Malinowska ◽  
Dorota Raczyńska ◽  
Małgorzata Myśliwiec ◽  
Krystyna Raczyńska
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Type 1 Diabetes Mellitus ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Serum Concentrations ◽  
Growth Factor Beta

In the present study, we have decided to evaluate if serum transforming growth factor-beta 1 (TGF-β1) concentrations may have diagnostic value in predicting the occurrence of diabetic retinopathy (DR) in juvenile patients with type 1 diabetes mellitus (T1DM). The study included 81 children and adolescents with T1DM and 19 control subjects. All study participants had biochemical parameters examined, underwent an eye examination, and 24-hour blood pressure monitoring. Moreover, serum concentrations of TGF-β1 were measured. The group of patients with T1DM and nonproliferative diabetic retinopathy (NPDR) had statistically significant higher serum levels of TGF-β1 (P=0.001) as compared to T1DM patients without retinopathy as well as the healthy control subject. The threshold serum TGF-β1 concentrations which had a discriminative ability to predict the presence of DR were calculated using the receiver operating characteristic (ROC) curves analysis and amounted to 443 pg/ml. The area under the ROC curve (AUCROC) was 0.80, and its population value was in the range of 0.66 to 0.94. The sensitivity and specificity were calculated to be 72% and 88%, respectively. Our results suggest that TGF-β1 serum concentrations may be an additional parameter in predicting the occurrence of DR in juvenile patients with T1DM.

scholarly journals Development of early-stage type 1 diabetes in germ-free interleukin-10 deficient mice

2020 ◽  
Author(s):  
Alexandria M. Bobe ◽  
Jun Miyoshi ◽  
Patrick Moore ◽  
Suzanne Devkota ◽  
Vanessa Leone ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Immune Cell ◽  
Early Stage ◽  
Myeloid Cell ◽  
Interleukin 10 ◽  
Experimental Models ◽  
Germ Free ◽  
Early Stages

AbstractSeveral experimental models demonstrate a role for gut microbiota in the progression of type 1 diabetes (T1D) in genetically prone hosts. While the association between disturbances in gut microbiota, or microbial dysbiosis, and complex immune diseases such as inflammatory bowel diseases (IBD) are well established, less is known about its role in T1D pathogenesis. In IBD-prone interleukin-10 deficient (IL-10 KO) mice, the absence of gut microbiota under germ-free (GF) conditions prevents IBD development. However, in aged GF IL-10 KO mice (>6-months of age), polyuria and pancreatic lymphocytic infiltration resembling T1D lesions was observed. Approximately 50% of male and female mice above 6-months of age develop pancreatic immune cell infiltration, as compared to none in conventionally-raised and fecal microbiota transplanted (FMT) IL-10 KO counterparts. Immunofluorescence staining of islet infiltrates was positive for adaptive and innate immunological markers, including lymphoid and myeloid cell markers, which typically characterize autoimmune T1D lesions. A subset of GF IL-10 KO mice was also positive for insulin autoantibodies (IAA), but the majority of mice did not become diabetic. Our findings of early stage lymphocytic infiltrates in the pancreas and IAA in the absence of overt diabetes in GF IL-10 KO mice embody the early stages of T1D pathogenesis. As such, we propose that the presence of gut microbiota play a protective role against immune infiltration in the pancreas of genetically prone hosts. Moreover, our model provides an opportunity to better understand the role of the microbiota in the early stages of immune pathogenesis and perhaps conceive the development of microbe-mediated prophylactic strategies to treat or even prevent T1D.

Galectin-1 synthesis in type 1 diabetes by different immune cell types: Reduced synthesis by monocytes and Th1 cells

2011 ◽  
Vol 271 (2) ◽  
pp. 319-328 ◽  
Author(s):  
Iria Gómez-Touriño ◽  
Christian Sánchez-Espinel ◽  
Andrea Hernández-Fernández ◽  
África González-Fernández ◽  
Eduardo Pena-González ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Cell ◽  
Cell Types ◽  
Th1 Cells

scholarly journals Beneficial Effects of Hydroalcoholic Extract of Saffron in Alleviating Experimental Autoimmune Diabetes in C57bl/6 Mice

2019 ◽  
Author(s):  
Shole Faridi ◽  
Norouz Delirezh ◽  
Seyyed Meysam Abtahi Froushani
Keyword(s):  
Type 1 Diabetes ◽  
Transforming Growth Factor ◽  
Autoimmune Diabetes ◽  
Transforming Growth Factor Β ◽  
Proliferation Index ◽  
Interleukin 17 ◽  
Pancreatic Cell ◽  
Hydroalcoholic Extract ◽  
Experimental Autoimmune

Streptozocin (STZ) is a strong alkalizing agent which is capable of destroying the beta cells of the pancreatic islets. Multiple low doses (40 mg/kg, intraperitoneally for 5 consecutive days) prescription of STZ to mice can lead to the T cell-dependent immune response and induction of autoimmune diabetes (AD) with complete similarity to the human type 1 diabetes (T1D). This study has evaluated the effects of hydroalcoholic extract of saffron on the clinical and immunological profile of experimental autoimmune diabetes in C57BL/6 mice. After the establishment of the AD, mice were treated orally with hydroalcoholic extract of saffron (500 mg/kg) for 3 weeks. The results with p<0.05 were considered significant. Obtained data showed that treatment with the hydroalcoholic extract of saffron significantly reduced the incidence of hypoglycemia and restored insulin secretion and histopathological changes in pancreas sections. In addition, treatment with saffron reduced lymphocyte proliferation index in the cells isolated from the pancreas of diabetic mice. Also, the extract of saffron markedly decreased the production of pro-inflammatory interleukin-17 (IL-17) increased anti-inflammatory IL-10 and transforming growth factor-β in the pancreatic cell population. Moreover, the production of proinflammatory nitric oxide and reactive oxygen substances were down-regulated by the saffron extract. It seems that the hydroalcoholic extract of saffron can be considered as a useful strategy in the treatment of type 1 diabetes.

scholarly journals GROWTH DIFFERENTIATION FACTOR 15 IS CORRELATED TO MARKERS OF IMMUNOSENESCENCE IN MONOCYTES

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S103-S103
Author(s):  
Brandt Pence ◽  
Johnathan Yarbro
Keyword(s):  
Mitochondrial Function ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Subset ◽  
Myeloid Cell ◽  
Cytokine Gene Expression ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

Abstract Immunosenescence is an age-associated decrease in function of immune cells precipitated by a variety of mechanisms and affecting nearly every immune cell subset. In myeloid cell subsets, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we have described an aging effect on several functions indicating immunosenescence in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide (LPS). We hypothesized that circulating factors altered by the aging process underly these changes. Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-beta superfamily that has known anti-inflammatory effects in macrophages and has recently been shown to be highly differentially expressed during aging. We used biobanked serum and plasma samples to assay circulating GDF-15 levels in subjects from our previous studies and examined correlations between GDF-15 levels and monocyte mitochondrial function and inflammatory responses. Monocyte interleukin-6 production due to LPS stimulation was negatively correlated to plasma GDF-15 levels (p = 0.046). Additionally, serum GDF-15 was positively correlated to circulating CD16+ monocyte proportions (p = 0.021) and negatively correlated to monocyte mitochondrial respiratory capacity (p &lt; 0.001). Therefore, our data suggest that GDF-15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence, and thus is an attractive candidate for therapeutic intervention to ameliorate this.

scholarly journals Arrest in the Progression of Type 1 Diabetes at the Mid-Stage of Insulitic Autoimmunity Using an Autoantigen-Decorated All-trans Retinoic Acid and Transforming Growth Factor Beta-1 Single Microparticle Formulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Brett E. Phillips ◽  
Yesica Garciafigueroa ◽  
Carl Engman ◽  
Wen Liu ◽  
Yiwei Wang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Retinoic Acid ◽  
Growth Factor ◽  
Lymph Nodes ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Acute Administration ◽  
Growth Factor Beta

Type 1 diabetes (T1D) is a disorder of impaired glucoregulation due to lymphocyte-driven pancreatic autoimmunity. Mobilizing dendritic cells (DC) in vivo to acquire tolerogenic activity is an attractive therapeutic approach as it results in multiple and overlapping immunosuppressive mechanisms. Delivery of agents that can achieve this, in the form of micro/nanoparticles, has successfully prevented a number of autoimmune conditions in vivo. Most of these formulations, however, do not establish multiple layers of immunoregulation. all-trans retinoic acid (RA) together with transforming growth factor beta 1 (TGFβ1), in contrast, has been shown to promote such mechanisms. When delivered in separate nanoparticle vehicles, they successfully prevent the progression of early-onset T1D autoimmunity in vivo. Herein, we show that the approach can be simplified into a single microparticle formulation of RA + TGFβ1 with surface decoration with the T1D-relevant insulin autoantigen. We show that the onset of hyperglycemia is prevented when administered into non-obese diabetic mice that are at the mid-stage of active islet-selective autoimmunity. Unexpectedly, the preventive effects do not seem to be mediated by increased numbers of regulatory T-lymphocytes inside the pancreatic lymph nodes, at least following acute administration of microparticles. Instead, we observed a mild increase in the frequency of regulatory B-lymphocytes inside the mesenteric lymph nodes. These data suggest additional and potentially-novel mechanisms that RA and TGFβ1 could be modulating to prevent progression of mid-stage autoimmunity to overt T1D. Our data further strengthen the rationale to develop RA+TGFβ1-based micro/nanoparticle “vaccines” as possible treatments of pre-symptomatic and new-onset T1D autoimmunity.

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