scholarly journals Reversal of New-Onset Diabetes through Modulating Inflammation and Stimulating β-Cell Replication in Nonobese Diabetic Mice by a Dipeptidyl Peptidase IV Inhibitor

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3049-3060 ◽  
Author(s):  
Lei Tian ◽  
Jie Gao ◽  
Jianqiang Hao ◽  
Yu Zhang ◽  
Huimin Yi ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nod Mice ◽  
Cell Replication ◽  
Β Cell ◽  
Nonobese Diabetic ◽  
Onset Diabetes ◽  
Dpp Iv ◽  
Tgf Β1 ◽  
New Onset

Inhibition of dipeptidyl peptidase IV (DPP-IV) activity by NVP-DPP728, a DPP-IV inhibitor, improves the therapeutic efficacy of glucagon-like peptide-1 (GLP-1). CD26 is a membrane-associated glycoprotein with DPP-IV activity and is expressed on lymphocytes. We investigated the effect of NVP-DPP728 on reversing new-onset diabetes in nonobese diabetic (NOD) mice and modulating the inflammatory response and stimulating β-cell regeneration. New-onset diabetic NOD mice were treated with NVP-DPP728 for 2, 4, and 6 wk. Blood glucose level was monitored. Regulatory T cells in thymus and secondary lymph nodes, TGF-β1 and GLP-1 in plasma, and the insulin content in the pancreas were measured. Immunostaining for insulin and bromodeoxyuridine (BrdU) were performed. The correlation of β-cell replication with inflammation was determined. In NVP-DPP728-treated NOD mice, diabetes could be reversed in 57, 74, and 73% of mice after 2, 4, and 6 wk treatment, respectively. Insulitis was reduced and the percentage of CD4+CD25+FoxP3+ regulatory T cells was increased in treated NOD mice with remission. Plasma TGF-β1 and GLP-1, the insulin content, and both insulin+ and BrdU+ β-cells in pancreas were also significantly increased. No significant correlations were found between numbers of both insulin+ and BrdU+ β-cells in islets and β-cell area or islets with different insulitis score in NOD mice with remission of diabetes. In conclusion, NVP-DPP728 treatment can reverse new-onset diabetes in NOD mice by reducing insulitis, increasing CD4+CD25+FoxP3+ regulatory T cells, and stimulating β-cell replication. β-Cell replication is not associated with the degree of inflammation in NVP-DPP728-treated NOD mice.

Pro-apoptotic DNA vaccination ameliorates new onset of autoimmune diabetes in NOD mice and induces foxp3+ regulatory T cells in vitro

Vaccine ◽  
2006 ◽  
Vol 24 (23) ◽  
pp. 5036-5046 ◽  
Author(s):  
Alice Li ◽  
Okechukwu Ojogho ◽  
Edson Franco ◽  
Pedro Baron ◽  
Yuichi Iwaki ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Dna Vaccination ◽  
New Onset

scholarly journals Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice

2007 ◽  
Vol 204 (1) ◽  
pp. 191-201 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Lucine Petit ◽  
Xiaopan Zuo ◽  
Priscilla Toy ◽  
Xunrong Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Suppressor T Cells ◽  
Nonobese Diabetic ◽  
Glucose Challenge ◽  
Infiltrating Lymphocytes

Most treatments that prevent autoimmune diabetes in nonobese diabetic (NOD) mice require intervention at early pathogenic stages, when insulitis is first developing. We tested whether dendritic cell (DC)–expanded, islet antigen–specific CD4+ CD25+ suppressor T cells could treat diabetes at later stages of disease, when most of the insulin-producing islet β cells had been destroyed by infiltrating lymphocytes. CD4+ CD25+ CD62L+ regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice. A single dose of as few as 5 × 104 of these islet-specific T reg cells blocked diabetes development in prediabetic 13-wk-old NOD mice. The T reg cells also induced long-lasting reversal of hyperglycemia in 50% of mice in which overt diabetes had developed. Successfully treated diabetic mice had similar responses to glucose challenge compared with nondiabetic NOD mice. The successfully treated mice retained diabetogenic T cells, but also had substantially increased Foxp3+ cells in draining pancreatic lymph nodes. However, these Foxp3+ cells were derived from the recipient mice and not the injected T reg cells, suggesting a role for endogenous T reg cells in maintaining tolerance after treatment. Therefore, inoculation of DC-expanded, antigen-specific suppressor T cells has considerable efficacy in ameliorating ongoing diabetes in NOD mice.

scholarly journals Dendritic Cell-Targeted Pancreatic β-Cell Antigen Leads to Conversion of Self-Reactive CD4+T Cells Into Regulatory T Cells and Promotes Immunotolerance in NOD Mice

2010 ◽  
Vol 7 (1) ◽  
pp. 47-61 ◽  
Author(s):  
Cathleen Petzold ◽  
Julia Riewaldt ◽  
Tina Koenig ◽  
Sonja Schallenberg ◽  
Karsten Kretschmer
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Nod Mice ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Antigen

Su.17. Pro-Apoptotic Dna Vaccination Ameliorates New Onset of Autoimmune Diabetes in Nod Mice and Induces Foxp3 Regulatory T-Cells In Vitro

2006 ◽  
Vol 119 ◽  
pp. S165
Author(s):  
Alice Li ◽  
Okechukwu Ojogho ◽  
Edson Franco ◽  
Pedro Baron ◽  
Yuichi Iwaki ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Dna Vaccination ◽  
New Onset

scholarly journals Revealing the specificity of regulatory T cells in murine autoimmune diabetes

2018 ◽  
Vol 115 (20) ◽  
pp. 5265-5270 ◽  
Author(s):  
Allyson Spence ◽  
Whitney Purtha ◽  
Janice Tam ◽  
Shen Dong ◽  
Youmin Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Activation Markers ◽  
Nonobese Diabetic ◽  
Organ Specific ◽  
Control Organ

Regulatory T cells (Tregs) control organ-specific autoimmunity in a tissue antigen-specific manner, yet little is known about their specificity in a natural repertoire. In this study, we used the nonobese diabetic (NOD) mouse model of autoimmune diabetes to investigate the antigen specificity of Tregs present in the inflamed tissue, the islets of Langerhans. Compared with Tregs present in spleen and lymph node, Tregs in the islets showed evidence of antigen stimulation that correlated with higher proliferation and expression of activation markers CD103, ICOS, and TIGIT. T cell receptor (TCR) repertoire profiling demonstrated that islet Treg clonotypes are expanded in the islets, suggesting localized antigen-driven expansion in inflamed islets. To determine their specificity, we captured TCRαβ pairs from islet Tregs using single-cell TCR sequencing and found direct evidence that some of these TCRs were specific for islet-derived antigens including insulin B:9–23 and proinsulin. Consistently, insulin B:9–23 tetramers readily detected insulin-specific Tregs in the islets of NOD mice. Lastly, islet Tregs from prediabetic NOD mice were effective at preventing diabetes in Treg-deficient NOD.CD28−/− recipients. These results provide a glimpse into the specificities of Tregs in a natural repertoire that are crucial for opposing the progression of autoimmune diabetes.

scholarly journals A Novel Liposome Formulation Carrying Both an Insulin Peptide and a Ligand for Invariant Natural Killer T Cells Induces Accumulation of Regulatory T Cells to Islets in Nonobese Diabetic Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Hidetoshi Akimoto ◽  
Emi Fukuda-Kawaguchi ◽  
Omar Duramad ◽  
Yasuyuki Ishii ◽  
Kazunari Tanabe
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Natural Killer ◽  
Nod Mice ◽  
Liposomal Formulation ◽  
Diabetes Onset ◽  
Nonobese Diabetic ◽  
Prevention Of Diabetes ◽  
Invariant Natural Killer ◽  
Natural Killer T

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β cells by autoantigen-reactive diabetogenic cells. Antigen-specific therapies using islet autoantigens for restoring immune tolerance have emerged as promising approaches for the treatment of T1D but have been unsuccessful in humans. Herein, we report that RGI-3100-iB, a novel liposomal formulation carrying both α-galactosylceramide (α-GalCer), which is a representative ligand for invariant natural killer T (iNKT) cells, and insulin B chain 9–23 peptide, which is an epitope for CD4+ T cells, could induce the accumulation of regulatory T cells (Tregs) in islets in a peptide-dependent manner, followed by the remarkable prevention of diabetes onset in nonobese diabetic (NOD) mice. While multiple administrations of a monotherapy using either α-GalCer or insulin B peptide in a liposomal formulation was confirmed to delay/prevent T1D in NOD mice, RGI-3100-iB synergistically enhanced the prevention effect of each monotherapy and alleviated insulitis in NOD mice. Immunopathological analysis showed that Foxp3+ Tregs accumulated in the islets in RGI-3100-iB-treated mice. Cotransfer of diabetogenic T cells and splenocytes of NOD mice treated with RGI-3100-iB, but not liposomal α-GalCer encapsulating an unrelated peptide, to NOD-SCID mice resulted in the prevention of diabetes and elevation of Foxp3 mRNA expression in the islets. These data indicate that the migration of insulin B-peptide-specific Tregs to islet of NOD mice that are involved in the suppression of pathogenic T cells related to diabetes onset and progression could be enhanced by the administration of liposomes containing α-GalCer and insulin B peptide.

Regulatory T Cells in the Context of New-Onset Diabetes After Renal Transplant: A Single-Center Experience

2019 ◽  
Vol 51 (4) ◽  
pp. 1234-1238
Author(s):  
B. Biró ◽  
R.P. Szabó ◽  
L. Illésy ◽  
N. Balázsfalvi ◽  
G.J. Szőllősi ◽  
...  
Keyword(s):  
T Cells ◽  
Renal Transplant ◽  
Regulatory T Cells ◽  
Single Center ◽  
Single Center Experience ◽  
Onset Diabetes ◽  
New Onset
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