Administration of Human Derived Upper gut Commensal Prevotella histicola delays the onset of type 1 diabetes in NOD mice

Abstract Background Type 1 diabetes (T1D) is an autoimmune disease that is increasing in prevalence worldwide. One of the contributing factors to the pathogenesis of T1D is the composition of the intestinal microbiota, as has been demonstrated. in T1D patients, with some studies demonstrating a deficiency in their levels of Prevotella. We have isolated a strain of Prevotella histicola from a duodenal biopsy that has anti-inflammatory properties, and in addition, alters the development of autoimmune diseases in mouse models. Therefore, our hypothesis is that the oral administration of P. histicola might delay the development of T1D in the non-obese diabetic (NOD) mice. To assess this, we used the following materials and methods. Female NOD mice (ages 5–8 weeks) were administered every other day P. histicola that was cultured in-house. Blood glucose levels were measured every other week. Mice were sacrificed at various time points for histopathological analysis of the pancreas. Modulation of immune response by the commensal was tested by analyzing regulatory T-cells and NKp46+ cells using flow cytometry and intestinal cytokine mRNA transcript levels using quantitative RT-PCR. For microbial composition, 16 s rRNA gene analysis was conducted on stool samples collected at various time points. Results Administration of P. histicola in NOD mice delayed the onset of T1D. Beta diversity in the fecal microbiomes demonstrated that the microbial composition of the mice administered P. histicola was different from those that were not treated. Treatment with P. histicola led to a significant increase in regulatory T cells with a concomitant decrease in NKp46+ cells in the pancreatic lymph nodes as compared to the untreated group after 5 weeks of treatment. Conclusions These observations suggest that P. histicola treatment delayed onset of diabetes by increasing the levels of regulatory T cells in the pancreatic lymph nodes. This preliminary work supports the rationale that enteral exposure to a non pathogenic commensal P. histicola be tested as a future therapy for T1D.

Download Full-text

Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes

Diabetes ◽

10.2337/db21-0091 ◽

2021 ◽

pp. db210091

Author(s):

Andrea Vecchione ◽

Tatiana Jofra ◽

Jolanda Gerosa ◽

Kimberly Shankwitz ◽

Roberta Di Fonte ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Pancreatic Lymph Nodes

Download Full-text

Abnormal Cannabidiol protects pancreatic beta cells in mouse models of experimental Type 1 diabetes

10.1101/2020.12.16.423103 ◽

2020 ◽

Author(s):

Isabel Gonzalez-Mariscal ◽

Macarena Pozo Morales ◽

Silvana Yanina Romero-Zerbo ◽

Vanesa Espinosa-Jimenez ◽

Alejandro Escamilla ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Lymph Nodes ◽

Beta Cell ◽

Mouse Models ◽

Nod Mice ◽

List Type ◽

Pancreatic Lymph Nodes ◽

Islet Inflammation

ABSTRACTBackground and PurposeThe atypical cannabinoid Abn-CBD was reported to improve the inflammatory status in preclinical models of several pathologies including autoimmune diseases. However, its potential for autoimmune diabetes, i.e. type 1 diabetes (T1D), is unknown.Experimental ApproachWe used two mouse models of T1D, streptozotocin (STZ)-injected and non-obese diabetic (NOD) mice. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1mg/kg of body weight) or vehicle for 1 week, following STZ treatment, and euthanized 1 week later. Six-week-old female NOD mice were treated with Abn-CBD (0.1-1mg/kg) or vehicle for 12 weeks and then euthanized. Blood, pancreas, pancreatic lymph nodes and circulating T cells were collected and processed for analysis. Glycemia was also monitored.Key ResultsAbn-CBD decreased circulating proinflammatory cytokines, ameliorated islet inflammation and the autoimmune attack, showing a 2-fold decrease in CD8+ T cells infiltration and reduced Th1/Th2 ratio in pancreatic lymph nodes of STZ-injected mice. Mechanistically, Abn-CBD reduced intra-islet phospho-NF-κB and TXNIP. Concomitant reduction of islet cell apoptosis and intra-islet fibrosis were observed in Abn-CBD pre-treated mice compared to vehicle. In NOD mice, Abn-CBD reduced the expression of Ifng, Il21, Tnfa and Il10 while increased Il4 in circulating CD4+ T cells compared to vehicle, reducing the severity of insulitis and improving glucose tolerance.Conclusion and ImplicationsAltogether, we found that Abn-CBD reduces intra-islet inflammation and delays the progression of insulitis in mouse models of T1D, preserving healthy functional islets. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat early stages of T1D.WHAT IS ALREADY KNOWN-Phytocannabinoids such as cannabidiol (CBD) have anti-inflammatory and glucose-lowering properties-The CBD derivative Abn-CBD ameliorates inflammation in various diseases and modulates beta cell functionWHAT THIS STUDY ADDS-Abn-CBD reduces systemic and pancreatic inflammation in mice models of type 1 diabetes-Abn-CBD prevents beta cell damage and loss during type 1 diabetes onsetCLINICAL SIGNIFICANCE-Synthetic cannabinoids emerge as potential treatment for type 1 diabetes

Download Full-text

Type-I interferons inhibit interleukin-10 signaling and favor type 1 diabetes development in NOD mice

10.1101/258525 ◽

2018 ◽

Author(s):

Marcos Iglesias ◽

Anirudh Arun ◽

Maria Chicco ◽

Brandon Lam ◽

Conover Talbot ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Nod Mice ◽

Interleukin 10 ◽

Type I Interferons ◽

Type I ◽

Diabetes Development

AbstractDestruction of insulin-producing β-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in NOD mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes. IL-10 signaling inhibition is reversible and can be restored via blockade of TI-IFN/IFN-R interaction, paralleling with the resulting delay in diabetes onset and reduced severity. Overall, we propose a novel molecular link between TI-IFN and IL-10 signaling that helps better understand the complex dynamics of autoimmune diabetes development and reveals new strategies of intervention.AbbreviationsALNaxillary lymph nodesIL-10interleukin-10MFImean fluorescence intensityMLNmesentheric lymph nodesNODnonobese diabetic micePLNpancreatic lymph nodesTI-IFNtype-1 InterferonsTmemmemory T cellsTregregulatory T cells

Download Full-text

Faculty Opinions recommendation of Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1122821.580959 ◽

2008 ◽

Author(s):

Jin-Xiong She

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Nod Mice

Download Full-text

Expansion of Functional Regulatory T Cells Using Soluble RAGE Prevents Type 1 Diabetes

10.1101/2020.01.10.902627 ◽

2020 ◽

Author(s):

Sherman S. Leung ◽

Danielle J. Borg ◽

Domenica A. McCarthy ◽

Tamar E. Boursalian ◽

Justen Cracraft ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Soluble Rage ◽

Human T Cells ◽

Glycation End Products ◽

Term Administration ◽

Pancreatic Lymph Nodes ◽

And Function

AbstractType 1 diabetes (T1D) is an autoimmune disease with no cure. Therapeutic translation has been hampered by preclinical reproducibility. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent centers. Treatment with sRAGE increased regulatory T cells (Tregs) within islets, pancreatic lymph nodes and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE using knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy at multiple research centers and in human T cells.

Download Full-text