scholarly journals GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 43
Author(s):  
Jide Tian ◽  
Blake Middleton ◽  
Victoria Seunghee Lee ◽  
Hye Won Park ◽  
Zhixuan Zhang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gabab Receptor ◽  
Combined Treatment ◽  
Nod Mice ◽  
Rna Seq ◽  
Gaba Production ◽  
Insulin Cells ◽  
Suboptimal Dose ◽  
Clinical Potential

Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit β-cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.

scholarly journals Recombinant Lactococcus lactis Carrying IL-4 and IL-10 Coding Vectors Protects against Type 1 Diabetes in NOD Mice and Attenuates Insulitis in the STZ-Induced Model

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Tatiane M. Preisser ◽  
Vanessa P. da Cunha ◽  
Mariana P. Santana ◽  
Vanessa B. Pereira ◽  
Denise C. Cara ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Pancreatic Islets ◽  
Lactococcus Lactis ◽  
Combined Treatment ◽  
Nod Mice ◽  
Eukaryotic Expression ◽  
Expression Vectors ◽  
Bacterial Strains ◽  
Long Term Treatment

Type 1 diabetes (T1D) is an autoimmune disease that culminates in beta cell destruction in the pancreas and, subsequently, deficiency in insulin production. Cytokines play a crucial role in the development of diabetes, orchestrating the recruitment and action of immune cells, to not only destroy insulin-producing cells but also preserve them. Therefore, the aim of this study was to investigate the effect of orally administered Lactococcus lactis MG1363 FnBPA+ strains carrying plasmids encoding IL-4 and IL-10 in the streptozotocin- (STZ-) induced diabetes model and in nonobese diabetic (NOD) mice. The STZ-induced mice that were treated with combined bacterial strains carrying plasmids encoding IL-4 and IL-10 showed lower incidence of diabetes and more preserved pancreatic islets than the mice that received the individual bacterial strains. Combined administration of L. lactis MG1363 FnBPA+ (pValac::dts::IL-4) and L. lactis MG1363 FnBPA+ (pValac::IL-10) resulted in protection against diabetes in NOD mice. It was shown that the combined treatment with recombinant bacterial by oral route prevented hyperglycemia and reduced the pancreatic islets-destruction in NOD mice. In addition, increased levels of IL-4 and IL-10 in serum and pancreatic tissue revealed a systemic effect of the treatment and also favored an anti-inflammatory microenvironment. Reduced concentrations of IL-12 in pancreas were essential to the regulation of inflammation, resulting in no incidence of diabetes in treated NOD mice. Normal levels of intestinal sIgA after long-term treatment with the L. lactis strains carrying plasmids encoding IL-4 and IL-10 indicate the development of oral tolerance and corroborate the use of this potent tool of mucosal delivery. For the first time, L. lactis MG1363 FnBPA+ strains carrying eukaryotic expression vectors encoding IL-4 and IL-10 are tested in STZ-induced and NOD mouse models. Therefore, our study demonstrates this innovative strategy provides immunomodulatory potential for further investigations in T1D and other autoimmune diseases.

scholarly journals 173. Insulin B9-23 LV-Driven Expression in Hepatocytes Combined With Suboptimal Dose of Anti-CD3 mAb Cures Type 1 Diabetes in NOD Mice

2015 ◽  
Vol 23 ◽  
pp. S69
Author(s):  
Andrea Annoni ◽  
Fabio Russo ◽  
Alessio Cantore ◽  
Luigi Naldini ◽  
Maria Grazia Roncarolo
Keyword(s):  
Type 1 Diabetes ◽  
Nod Mice ◽  
Suboptimal Dose

1190-P: IFN-Alpha Kinoid: A Promising Vaccine against Type 1 Diabetes Targeting IFN-alpha in NOD Mice

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1190-P
Author(s):  
NOÉMIE CAILLOT ◽  
FABIEN COLAONE ◽  
ROMAIN BERTRAND ◽  
JENNIFER DA SILVA ◽  
SAMIR HAMDI ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Nod Mice ◽  
Ifn Alpha

PBI-4547 Prevents Progression of Prediabetic Condition to Type 1 Diabetes in NOD Mice

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1817-P
Author(s):  
FRANÇOIS A. LEBLOND ◽  
KATHY HINCE ◽  
FRANÇOIS SARRA-BOURNET ◽  
WILLIAM GAGNON ◽  
MIKAËL TREMBLAY ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Nod Mice

A Novel Dual-Function GLP-1 Analogue Prevents Type 1 Diabetes Onset in NOD Mice by Controlling the Balance of Treg/Th17 and Th2/Th1

2019 ◽  
Author(s):  
Fujian Qin ◽  
Yanfeng Zhang ◽  
Kaiying Li ◽  
Huashan Gao ◽  
Qian Zhao ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Nod Mice ◽  
Dual Function ◽  
Diabetes Onset

Natural Cures for Type 1 Diabetes: A Review of Phytochemicals, Biological Actions, and Clinical Potential

2013 ◽  
Vol 20 (7) ◽  
pp. 899-907
Author(s):  
C.L.T. Chang ◽  
Yi-Ching Chen ◽  
Hui-Ming Chen ◽  
Ning-Sun Yang ◽  
Wen-Chin Yang
Keyword(s):  
Type 1 Diabetes ◽  
Clinical Potential ◽  
Biological Actions

scholarly journals MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis

2021 ◽  
Author(s):  
Tiantian Yue ◽  
Fei Sun ◽  
Faxi Wang ◽  
Chunliang Yang ◽  
Jiahui Luo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Type 1 Diabetes ◽  
Adoptive Transfer ◽  
Nod Mice ◽  
Transcriptional Level ◽  
Clinical Settings ◽  
Cpg Dna ◽  
Ifn Γ

AbstractThe methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2−/− CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings.

scholarly journals IRAK-M Deficiency Promotes the Development of Type 1 Diabetes in NOD Mice

Diabetes ◽  
2014 ◽  
Vol 63 (8) ◽  
pp. 2761-2775 ◽  
Author(s):  
Q. Tan ◽  
M. Majewska-Szczepanik ◽  
X. Zhang ◽  
M. Szczepanik ◽  
Z. Zhou ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Nod Mice
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