scholarly journals Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope

2011 ◽  
Vol 208 (7) ◽  
pp. 1501-1510 ◽  
Author(s):  
Carolin Daniel ◽  
Benno Weigmann ◽  
Roderick Bronson ◽  
Harald von Boehmer
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Nonobese Diabetic ◽  
Cell Clones ◽  
Autoimmune Attack ◽  
Agonistic Activity ◽  
Novel Strategy

Type 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic β cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-Ag7 molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3+ regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease.

scholarly journals Helminth Infection Can Reduce Insulitis and Type 1 Diabetes through CD25- and IL-10-Independent Mechanisms

2009 ◽  
Vol 77 (12) ◽  
pp. 5347-5358 ◽  
Author(s):  
Qian Liu ◽  
Krishnan Sundar ◽  
Pankaj K. Mishra ◽  
Gity Mousavi ◽  
Zhugong Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Helminth Infection ◽  
Inflammatory Responses ◽  
Nod Mice ◽  
Interleukin 4 ◽  
Heligmosomoides Polygyrus ◽  
Nonobese Diabetic

ABSTRACT Parasitic helminth infection has been shown to modulate pathological inflammatory responses in allergy and autoimmune disease. The aim of this study was to examine the effects of infection with a helminth parasite, Heligmosomoides polygyrus, on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice and to elucidate the mechanisms involved in this protection. H. polygyrus inoculation at 5 weeks of age protected NOD mice from T1D until 40 weeks of age and also inhibited the more aggressive cyclophosphamide-induced T1D. Moreover, H. polygyrus inoculation as late as 12 weeks of age reduced the onset of T1D in NOD mice. Following H. polygyrus inoculation of NOD mice, pancreatic insulitis was markedly inhibited. Interleukin-4 (IL-4), IL-10, and IL-13 expression and the frequency of CD4+ CD25+ FoxP3+ regulatory T cells were elevated in mesenteric and pancreatic lymph nodes. Depletion of CD4+ CD25+ T cells in vivo did not abrogate H. polygyrus-induced T1D protection, nor did anti-IL-10 receptor blocking antibody. These findings suggest that infection with H. polygyrus significantly inhibits T1D in NOD mice through CD25- and IL-10-independent mechanisms and also reduces the severity of T1D when administered late after the onset of insulitis.

scholarly journals C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes

2017 ◽  
Vol 115 (1) ◽  
pp. 162-167 ◽  
Author(s):  
Yang Wang ◽  
Tomasz Sosinowski ◽  
Andrey Novikov ◽  
Frances Crawford ◽  
David B. Neau ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell Activation ◽  
Posttranslational Modifications ◽  
Cell Activation ◽  
Nod Mice ◽  
Side Chain ◽  
C Terminus

A polymorphism at β57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9–23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg7 and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the β57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.

scholarly journals Regulatory T Cells Prevent Transfer of Type 1 Diabetes in NOD Mice Only When Their Antigen Is Present In Vivo

2008 ◽  
Vol 181 (7) ◽  
pp. 4516-4522 ◽  
Author(s):  
Daniel R. Tonkin ◽  
Jing He ◽  
Gene Barbour ◽  
Kathryn Haskins
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Nod Mice

scholarly journals Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5638-5646 ◽  
Author(s):  
Soojeong Kang ◽  
Eun-Jin Park ◽  
Yeonsoo Joe ◽  
Eunhui Seo ◽  
Mi-Kyoung Park ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Gelatin Zymography ◽  
Nod Mice ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Nonobese Diabetic ◽  
Induced Apoptosis

Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or β-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control β-galactosidase animals. Pancreatic tissue isolated from Ad.hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic β-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D.

scholarly journals CD25+ CD4+ T Cells, Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide, Suppress Autoimmune Diabetes

2004 ◽  
Vol 199 (11) ◽  
pp. 1467-1477 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Sayuri Yamazaki ◽  
Kara Olson ◽  
Priscilla Toy ◽  
Ralph M. Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Nonobese Diabetic ◽  
And Function

In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet β cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 105 polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.

scholarly journals Correction to: In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice

Diabetologia ◽  
2019 ◽  
Vol 62 (8) ◽  
pp. 1517-1517
Author(s):  
Midhat H. Abdulreda ◽  
R. Damaris Molano ◽  
Gaetano Faleo ◽  
Maite Lopez-Cabezas ◽  
Alexander Shishido ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Vivo Imaging ◽  
Nod Mice

scholarly journals Rodent Models for Investigating the Dysregulation of Immune Responses in Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Feng-Cheng Chou ◽  
Heng-Yi Chen ◽  
Shyi-Jou Chen ◽  
Mei-Cho Fang ◽  
Huey-Kang Sytwu
Keyword(s):  
Type 1 Diabetes ◽  
Animal Studies ◽  
Genetic Manipulation ◽  
Nod Mice ◽  
Environmental Parameters ◽  
Conditional Knockout ◽  
Therapeutic Approaches ◽  
Nonobese Diabetic ◽  
Genetically Manipulated

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producingβcells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches.

Sign in / Sign up

Export Citation Format

Share Document