scholarly journals Prevention of Autoimmune Diabetes in NOD Mice by Dimethyl Fumarate

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 193
Author(s):  
Shiri Li ◽  
Nosratola D. Vaziri ◽  
Lourdes Swentek ◽  
Chie Takasu ◽  
Kelly Vo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Islet Cells ◽  
Autoimmune Diabetes ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Dimethyl Fumarate ◽  
Control Group ◽  
Islet Isolation ◽  
Diabetes Model ◽  
Onset Of Diabetes

Oxidative stress plays critical roles in the pathogenesis of diabetes. This study tested the hypothesis that by protecting β-cells against oxidative stress and inflammation, an Nrf2 activator, dimethyl fumarate (DMF), may prevent or delay the onset of type 1 diabetes in non-obese diabetic (NOD) mice. Firstly, islet isolation was conducted to confirm the antioxidative effects of DMF oral administration on islet cells. Secondly, in a spontaneous diabetes model, DMF (25 mg/kg) was fed to mice once daily starting at the age of 8 weeks up to the age of 22 weeks. In a cyclophosphamide-induced accelerated diabetes model, DMF (25 mg/kg) was fed to mice twice daily for 2 weeks. In the islet isolation study, DMF administration improved the isolation yield, attenuated oxidative stress and enhanced GCLC and NQO1 expression in the islets. In the spontaneous model, DMF significantly reduced the onset of diabetes compared to the control group (25% vs. 54.2%). In the accelerated model, DMF reduced the onset of diabetes from 58.3% to 16.7%. The insulitis score in the islets of the DMF treatment group (1.6 ± 0.32) was significantly lower than in the control group (3.47 ± 0.21). The serum IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-12p70, IFN-γ, TNF-α, MCP-1 and CXCL16 levels in the DMF-treated group were lower than in the control group. In conclusion, DMF may protect islet cells and reduce the incidence of autoimmune diabetes in NOD mice by attenuating insulitis and proinflammatory cytokine production.

scholarly journals T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice.

1989 ◽  
Vol 169 (5) ◽  
pp. 1669-1680 ◽  
Author(s):  
C Boitard ◽  
R Yasunami ◽  
M Dardenne ◽  
J F Bach
Keyword(s):  
T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Lymphoid Cells ◽  
Dependent Diabetes Mellitus ◽  
Spleen Cells ◽  
Nonobese Diabetic ◽  
Insulin Dependent ◽  
Onset Of Diabetes

The nonobese diabetic (NOD) mouse has recently been introduced as a model for insulin-dependent diabetes mellitus. The role of regulatory T cells in the development of antipancreatic autoimmunity in this model remains unclear. To evaluate the presence of suppressive phenomena, we used disease transfer by spleen cells from diabetic NOD mice into preirradiated adult recipients as a model for accelerated disease. Suppressor phenomena were detected by testing the protection afforded by lymphoid cells from nondiabetic NOD mice against diabetes transfer in irradiated recipients. Transfer of diabetes was delayed by reconstituting recipients with spleen cells from nondiabetic NOD donors. The greatest protection against diabetes transfer was conferred by spleen cells from 8-wk-old nondiabetic female NOD mice. Depletion experiments showed that the protection was dependent on CD4+ cells. Protection was also detected within thymic cells from nondiabetic NOD mice and protection conferred by spleen cells was abrogated by thymectomy of nondiabetic female, but not male, NOD donors at 3 wk of age. These findings indicate that suppressive CD4+ T cells that are dependent on the presence of the thymus may delay the onset of diabetes in female diabetes-prone NOD mice.

Protective effect of GSK-3β/Nrf2 mediated by dimethyl fumarate in middle cerebral artery embolization reperfusion rat model

2021 ◽  
Vol 18 ◽  
Author(s):  
Yuan Li ◽  
Lan Chu ◽  
Chunfeng Liu ◽  
Zongyi Zha ◽  
Yuanlu Shu
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Sham Group ◽  
Infarct Volume ◽  
Dimethyl Fumarate ◽  
Control Group ◽  
Related Factor ◽  
Nissl Staining ◽  
Gsk 3Β ◽  
Nrf2 Expression

Aim: This study investigated the protective effect of dimethyl fumarate (DMF) in rats by mediating GSK3-β/Nrf2 using the middle cerebral artery embolization reperfusion (MCAO/R) rat model. Background: After an acute ischemic stroke (AIS), oxidative stress occurs. Dimethyl fumarate (DMF), a nuclear factor-E2-related factor 2 (Nrf2) activator, approved by the US Food and Drug Administration (FDA), was observed to regulate the Nrf2 pathway by acting as an anti-oxidative stress agent; however, whether this agent is involved in inhibiting GSK-3β remains to be established. Methods: DMF model was used to explore the effects of GSK-3β on Nrf2 expression level, Nrf2-ARE binding activity and Nrf2/ARE downstream expression level of anti-oxidant stress protein in Cerebral ischemia-reperfusion injury (CIRI). 60 rats were randomly divided into Sham group, MCAO/R group, solvent control group (DMSO group) and DMF treatment group, with 15 rats in each group. The MCAO/R, DMSO and DMF groups were considered in the MCAO/R model using the modified thread embolization method. In contrast, the Sham group was only anaesthetized and disinfected, and tissue muscle was dissected without inserting suture emboli. DMF group was gavaged with 45mg/kg per day of DMF, DMSO control group was gavaged with DMSO of equal volume, while MCAO/R group was only modeled without any intragastric treatment. The rats were treated seven days after the operation, and a neurological function Longa score was estimated. The rats were sacrificed seven days later, and the infarct volume was assessed by TTC staining. Hematoxylin-eosin (HE) staining was used to observe the pathological changes in rat brain tissue. Nissl staining was used to observe the expression of neurons in the infarcted cortex. Western blotting (WB) was used to observe the protein expression levels of glycogen synthase kinase 3β(GSK-3β), nuclear factor E2-related factor 2 (Nrf2), downstream heme oxygenase 1 (HO1) and NADPH quinone oxidoreductase 1 (NQO1) in four groups. The expression levels of GSK-3β and Nrf2 in the four groups were observed by immunohistochemistry and immunofluorescence. Results: (1) The Longa score of the MCAO/R, DMSO and DMF groups was found to be higher compared to the Sham group, indicating successful operation. The Longa score of the DMF group was lower than that of the other three groups 4-7 days after surgery (P<0.05). (2) HE and Nissl staining showed that the DMF group had lower neuron necrosis and higher gliosis compared to the control groups. (3) TTC staining results showed that the infarct volume of the DMF group was significantly smaller than the MCAO/R and DMSO groups. (4) Protein results showed that the GSK-3β expression in the DMF group was lower than that in all groups, while the expression of Nrf2, HO1 and NQO1 was higher compared to other groups. Conclusion: DMF can reduce neurological deficits and infarct size in the MCAO/R model. The protective effect may be related to decreased GSK-3β expression and increased Nrf2 expression, which may play a role in anti-oxidative stress.

scholarly journals Transient Depletion of Foxp3+ Regulatory T Cells Selectively Promotes Aggressive β Cell Autoimmunity in Genetically Susceptible DEREG Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Deepika Watts ◽  
Marthe Janßen ◽  
Mangesh Jaykar ◽  
Francesco Palmucci ◽  
Marc Weigelt ◽  
...  
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Autoimmune Diabetes ◽  
Cell Activity ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Β Cell ◽  
Cell Ablation ◽  
Tcr Repertoire

Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3+ regulatory T (Treg) cell function due to Foxp3 gene mutations, but whether the loss of Foxp3+ Treg cell activity is indeed sufficient to promote β cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, β cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutive Foxp3 deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3+ Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3+ Treg cell ablation focused on Foxp3DTR NOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4+ TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3+ Treg cell ablation on β cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3+ Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3+ Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8+ T cells in terminal β cell destruction. Despite the severity of destructive β cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced β cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3+ Treg cell activity for the control of genetically pre-installed autoimmune diabetes.

scholarly journals Long-Term Provision of Acidified Drinking Water Fails to Influence Autoimmune Diabetes and Encephalomyelitis

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Sundararajan Jayaraman ◽  
Arathi Jayaraman
Keyword(s):  
Drinking Water ◽  
Autoimmune Diseases ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Autoimmune Encephalomyelitis ◽  
Gastrointestinal Pathogen ◽  
Onset Of Diabetes ◽  
Partial Blocking

Induction of autoimmune diseases is predisposed by background genetics and influenced by environmental factors including diet and infections. Since consumption of acidified drinking water leads to eradication of gastrointestinal pathogens in animals, we tested whether it may also influence the development of autoimmune diseases. The frequency of spontaneously occurring type 1 diabetes in female NOD mice that were maintained on acidified drinking water by the vendor did not alter after switching to neutral water in our facility. In addition, experimentally induced autoimmune encephalomyelitis was also unaffected by the pH of the drinking water. Interestingly, administration of complete Freund’s adjuvant alone or emulsified with a neuronal peptide to induce neurodegenerative disease during the prediabetic stage completely prevented the onset of diabetes regardless of the pH of the drinking water. However, exposure to microbial products later in life had only a partial blocking effect on diabetes induction, which was also not influenced by the ionic content of the drinking water. Taken together, these data indicate that the onset of autoimmune diseases is not influenced by the gastrointestinal pathogen-depleting treatment, acidified drinking water. Thus, administration of acidic drinking water does not appear to be an option for treating autoimmune diseases.

scholarly journals Resident macrophages of pancreatic islets have a seminal role in the initiation of autoimmune diabetes of NOD mice

2017 ◽  
Vol 114 (48) ◽  
pp. E10418-E10427 ◽  
Author(s):  
Javier A. Carrero ◽  
Derrick P. McCarthy ◽  
Stephen T. Ferris ◽  
Xiaoxiao Wan ◽  
Hao Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Pancreatic Islets ◽  
Islet Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Diabetes Incidence ◽  
Glucose Response ◽  
Blocking Antibody ◽  
Multiple Parameters ◽  
Pancreatic Islets Of Langerhans

Treatment of C57BL/6 or NOD mice with a monoclonal antibody to the CSF-1 receptor resulted in depletion of the resident macrophages of pancreatic islets of Langerhans that lasted for several weeks. Depletion of macrophages in C57BL/6 mice did not affect multiple parameters of islet function, including glucose response, insulin content, and transcriptional profile. In NOD mice depleted of islet-resident macrophages starting at 3 wk of age, several changes occurred: (i) the early entrance of CD4 T cells and dendritic cells into pancreatic islets was reduced, (ii) presentation of insulin epitopes by dispersed islet cells to T cells was impaired, and (iii) the development of autoimmune diabetes was significantly reduced. Treatment of NOD mice starting at 10 wk of age, when the autoimmune process has progressed, also significantly reduced the incidence of diabetes. Despite the absence of diabetes, NOD mice treated with anti–CSF-1 receptor starting at 3 or 10 wk of age still contained variably elevated leukocytic infiltrates in their islets when examined at 20–40 wk of age. Diabetes occurred in the anti–CSF-1 receptor protected mice after treatment with a blocking antibody directed against PD-1. We conclude that treatment of NOD mice with an antibody against CSF-1 receptor reduced diabetes incidence and led to the development of a regulatory pathway that controlled autoimmune progression.

scholarly journals Evaluation of the cytotoxic profile of CD4 + T cells in the spontaneous autoimmune diabetes model in NOD (non obese diabetic) mice

2019 ◽  
Author(s):  
Maurílio Bonora Júnior ◽  
Alessandro dos Santos Farias ◽  
Carolina Francelin Rovarotto ◽  
Fernando Pradela
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Pancreatic Beta Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Helper T Cells ◽  
Diabetes Model ◽  
Cytotoxic Molecules ◽  
Draining Lymph Node

Type 1 Diabetes Mellitus is an autoimmune disease characterized by the destruction of the pancreatic beta cells by the action of autoreactive T cells. Using Non Obese Diabetic (NOD) mice, expression of cytotoxicity-related molecules on CD4 + helper T cells in the pancreas and peripancreatic lymph node of diabetic animals was observed. However, unlike what has been seen in the EAE model, the expression of one of the major cytotoxic molecules is similar in both organs, while two others express much more in the target organ of diabetes than in the draining lymph node.

scholarly journals Prevention and Reversal of Diabetes by All-Trans Retinoid Acid and Exendin-4 in NOD Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Jyuhn-Huarng Juang ◽  
Yang-Hau Van ◽  
Chien-Hung Kuo ◽  
Mei-Yin Lin ◽  
Ying-Hsiu Liu ◽  
...  
Keyword(s):  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Treatment Delays ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Pancreatic Insulin ◽  
Onset Of Diabetes ◽  
Retinoid Acid

It has been shown that all-trans retinoid acid (ATRA) hinders the development of autoimmune diabetes by inducing immune tolerance status. Meanwhile, exendin-4 increases beta-cell function and mass. Thus, we hypothesized that ATRA and exendin-4 combination therapy would prevent and reverse autoimmune diabetes. NOD/scid mice were intravenously transferred with splenocytes isolated from 12-week-old female NOD mice. After adoptive transfer, mice were treated with vehicle, ATRA (0.5 mg/mouse intraperitoneally every other day), exendin-4 (3 μg/kg subcutaneously twice daily), or combination for 6 weeks. Compared with vehicle, ATRA (P=0.022) and ATRA plus exendin-4 (P=0.013) treatment delayed the onset of diabetes. The pancreatic insulin content in mice treated with ATRA (P=0.013) and exendin-4 (P<0.02) was significantly higher than that of control mice. All but one spontaneous diabetic NOD mouse treated with ATRA and/or exendin-4 remained persistent hyperglycemic. ATRA and/or exendin-4 treatment did not alter their blood glucose levels and survival. Our results indicate that, before the onset of autoimmune diabetes, ATRA and exendin-4 treatment alone preserves pancreatic beta cells; ATRA and ATRA plus exendin-4 treatment delays the onset of autoimmune diabetes. However, after the onset of autoimmune diabetes, ATRA and/or exendin-4 treatment is unable to reverse hyperglycemia or improve survival.

scholarly journals Requirement of Fas for the Development of Autoimmune Diabetes in Nonobese Diabetic Mice

1997 ◽  
Vol 186 (4) ◽  
pp. 613-618 ◽  
Author(s):  
Naoto Itoh ◽  
Akihisa Imagawa ◽  
Toshiaki Hanafusa ◽  
Masako Waguri ◽  
Koji Yamamoto ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Autoimmune Diabetes ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Β Cell ◽  
Cell Destruction ◽  
Nonobese Diabetic

Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell–mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic β cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate β cell autoimmunity in NOD mice. Fas–Fas ligand system might be critical for autoimmune β cell destruction leading to IDDM.

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