scholarly journals A new animal model signifying a decisive bridge between innate immunity and the pathognomonic morphological characteristics of Type 1 Diabetes

2021 ◽  
Author(s):  
Tegehall Angie ◽  
Ingvast Sofie ◽  
Melhus Åsa ◽  
Skog Oskar ◽  
Korsgren Olle
Keyword(s):  
Innate Immunity ◽  
Animal Model ◽  
Type 1 Diabetes ◽  
Cd8 T Cells ◽  
Morphological Characteristics ◽  
Mechanistic Studies ◽  
Normal Morphology ◽  
Recent Onset ◽  
Summary Statement

AbstractAvailable animal models for Type 1 Diabetes (T1D) show limited similarities with the human disease and have no predictive value in screening for effective intervention therapies. Heat-inactivated bacteria instilled in the ductal compartment of the pancreas in healthy rats rapidly cause periductal inflammation and accumulation of mainly granulocytes and monocytes in the exocrine pancreas and in the peri-islet area mimicking the acute pancreatic inflammation in subjects with recent onset T1D. After three weeks, the triggered exocrine inflammation had vanished and pancreases showed normal morphology. However, a distinct accumulation of both CD4+ and CD8+ T cells within and adjacent to affected islets was found in one third of the rats, mimicking the pathognomonic insulitis in T1D. As in human T1D, the insulitis affected a fraction of all islets and was observed only in certain lobes of the pancreases. The presented animal model for T1D will allow detailed mechanistic studies to unravel a previously unknown interplay between bacteria-activated innate immunity and an acquired cellular immunity forming the immunopathological events described in humans at different stages of T1D.Summary StatementThe results presented signify a previously unknown decisive bridge between innate immunity and formation of the pathognomonic immunopathological events described in subjects with recent onset T1D.

scholarly journals Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes

2022 ◽  
Vol 12 ◽  
Author(s):  
Hugo Barcenilla ◽  
Mikael Pihl ◽  
Jeanette Wahlberg ◽  
Johnny Ludvigsson ◽  
Rosaura Casas
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
B Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Helper T Cells ◽  
Follicular Helper T Cells ◽  
Recent Onset ◽  
Follicular Helper

Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.

scholarly journals One in Ten CD8+ Cells in the Pancreas of Living Individuals With Recent Onset Type 1 Diabetes Recognizes the Preproinsulin Epitope PPI15-24

2021 ◽  
Author(s):  
Ada Admin ◽  
Teresa Rodriguez-Calvo ◽  
Lars Krogvold ◽  
Natalie Amirian ◽  
Knut Dahl-Jørgensen ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cd8 T Cells ◽  
Pancreatic Tissue ◽  
Cell Reactivity ◽  
Tissue Samples ◽  
Recent Onset ◽  
Onset Type

In type 1 diabetes, 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 beta cell antigens have been detected in the periphery and in the pancreas of subjects with short and long disease duration. The Diabetes Virus Detection (DiViD) study collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset type 1 diabetes. These tissues have been extensively studied by the scientific community, but the autoreactive nature of the T cell infiltrate has remained unexplored. Our objective was to determine the number and localization of these cells in pancreas samples obtained through the DiViD study. Here, we demonstrate the presence of high frequencies of CD8+ T cells reactive against a highly relevant epitope derived from the preproinsulin signal peptide in pancreatic tissue samples from these donors. We additionally show the heterogeneity of islet distribution and CD8+ T cell infiltration. Our findings contribute to the current limited existing knowledge on T cell reactivity in the pancreas of recent onset type 1 diabetic donors, and indicate that antigen-specific therapies directed towards preproinsulin could have high clinical impact.

scholarly journals Demonstration of Tissue Resident Memory CD8 T Cells in Insulitic Lesions in Adult Patients with Recent-Onset Type 1 Diabetes

2017 ◽  
Vol 187 (3) ◽  
pp. 581-588 ◽  
Author(s):  
Enida Kuric ◽  
Peter Seiron ◽  
Lars Krogvold ◽  
Bjørn Edwin ◽  
Trond Buanes ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Cd8 T Cells ◽  
Adult Patients ◽  
Memory Cd8 T Cells ◽  
Recent Onset ◽  
Onset Type

scholarly journals One in Ten CD8+ Cells in the Pancreas of Living Individuals With Recent Onset Type 1 Diabetes Recognizes the Preproinsulin Epitope PPI15-24

2021 ◽  
Author(s):  
Ada Admin ◽  
Teresa Rodriguez-Calvo ◽  
Lars Krogvold ◽  
Natalie Amirian ◽  
Knut Dahl-Jørgensen ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cd8 T Cells ◽  
Pancreatic Tissue ◽  
Cell Reactivity ◽  
Tissue Samples ◽  
Recent Onset ◽  
Onset Type

In type 1 diabetes, 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 beta cell antigens have been detected in the periphery and in the pancreas of subjects with short and long disease duration. The Diabetes Virus Detection (DiViD) study collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset type 1 diabetes. These tissues have been extensively studied by the scientific community, but the autoreactive nature of the T cell infiltrate has remained unexplored. Our objective was to determine the number and localization of these cells in pancreas samples obtained through the DiViD study. Here, we demonstrate the presence of high frequencies of CD8+ T cells reactive against a highly relevant epitope derived from the preproinsulin signal peptide in pancreatic tissue samples from these donors. We additionally show the heterogeneity of islet distribution and CD8+ T cell infiltration. Our findings contribute to the current limited existing knowledge on T cell reactivity in the pancreas of recent onset type 1 diabetic donors, and indicate that antigen-specific therapies directed towards preproinsulin could have high clinical impact.

scholarly journals Decreased CD127 Expression on CD4+ T-Cells and Elevated Frequencies of CD4+CD25+CD127− T-Cells in Children with Long-Lasting Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Marcin Moniuszko ◽  
Barbara Glowinska-Olszewska ◽  
Malgorzata Rusak ◽  
Marta Jeznach ◽  
Kamil Grubczak ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Recent Onset ◽  
Interleukin 7 ◽  
Inflammatory Parameters ◽  
Regulatory Phenotype ◽  
Cd127 Expression

Pathobiology of type 1 diabetes (T1D) is predominantly associated with T-cell-related actions. Homeostasis of majority of T-cells is critically dependent on signals mediated by CD127 (interleukin-7 receptor, IL-7R). In contrast, regulatory T-cells express very little CD127 and thereby may be delineated by CD4+CD25+CD127− phenotype. Here we aimed to analyze CD127 expression on CD4+ and CD8+ T-cells and enumerate CD4+CD25+CD127− T-cells in long-lasting T1D. T-cells were analyzed by flow cytometry and immunologic data were correlated with vascular, metabolic, and inflammatory parameters. We demonstrated significantly decreased CD127 levels on CD4+, but not CD8+, T cells in T1D pediatric patients. Interestingly, frequencies of CD4+CD25+CD127− T-cells were significantly enhanced in T1D children and correlated well with frequencies of CD34+CD144+ endothelial progenitor cells and CD4+CD25− T-cells. Levels of CD127 on both CD4+ and CD8+ T-cells in T1D patients were not correlated to each other or HbA1C. Interestingly, however, CD127 levels on CD4+ T-cells were significantly correlated to frequencies of CD4+CD25+CD127− T-cells, whereas CD127 levels on CD8+ T-cells were significantly correlated to concentrations of VEGF and triglycerides. Our data indicate that CD127 expression is differentially modulated on CD4+ and CD8+ T-cells in the course of T1D. Moreover, we demonstrated that, in contrast to recent-onset T1D, long-lasting T1D is associated with enhancement of T-cells with regulatory phenotype.

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