Acute Versus Progressive Onset of Diabetes in NOD Mice: Potential Implications for Therapeutic Interventions in Type 1 Diabetes

Mathews, Clayton E.; Xue, Song; Posgai, Amanda L.; Lightfoot, Yaíma L.; Li, Xia; Lin, Alex C.; Wasserfall, Clive; Haller, Michael J.; Schatz, Desmond; Atkinson, Mark A.

doi:10.2337/db15-0449

Cited by 44 publications

(52 citation statements)

References 27 publications

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“…We observed phosphorylated α-syn pathology in PFFs injected NOD mice (Figure 1c [36,37,48]. They also spontaneously develop type I diabetes (43%-80% by 30 weeks of age) [37,[49][50][51]. The phosphorylated α-syn load in the NOD/ ShiLtJ mice was not significantly different to that which we observed in NSG PFFs-injected mice, which supports the hypothesis that immune defects can lead to increased phosphorylated α-syn pathology.…”

Section: Increased Phosphorylated α-Syn Inclusions In Nsg Pffs Injectsupporting

confidence: 80%

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George¹,

Tyson²,

Rey

et al. 2020

Preprint

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α-Synuclein (α-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of αsynucleinopathies, such as Parkinson's disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells.These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from α-syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease.To study the role of the adaptive immune system with respect to α-syn pathology, we injected human α-syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α-syn pathology as well as microgliosis. Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α-syn pathology in the substantia nigra. We also reconstituted T and B cell populations in the NSG mice with cells isolated from a wildtype mouse spleen. Interestingly, reconstituting the T cell population decreased the accumulation of α-syn pathology and resulted in persistent microgliosis when compared to non-transplanted mice; reconstitution of B cells did not alter the nigral neuropathology. Our work provides experimental evidence that T cells play a role in the pathogenesis of α-synucleinopathies.

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Section: Increased Phosphorylated α-Syn Inclusions In Nsg Pffs Injectsupporting

confidence: 80%

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George¹,

Tyson²,

Rey

et al. 2020

Preprint

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“…Indeed, this threshold model was confirmed with the 100% incidence of diabetes in the untreated control group of 12 mice. Note that our accurate prediction of diabetes development in female NOD mice using this threshold is consistent with others who derived a normal mBG range < 170 mg/mL [16] or < 175 mg/dL [13] and used a diabetes diagnosis of two consecutive values ≥ 300 mg/dL or ≥ 400 mg/dL, respectively (almost all diabetic mice in our study were terminated at mBG ≥ 500 mg/dL). While it is difficult to translate these glycemic stages of NOD mice to those of human T1D, it is clear that ADi-100 could target treatment during clinically detectable dysglycemia (i.e., Stage 2, including hyperglycemia [25]) prior to overt clinical diabetes (Stage 3).…”

Section: Discussionsupporting

confidence: 88%

“…However, there are very few published studies demonstrating that such ASIs (as monotherapies) can "reverse hyperglycemia" (i.e., Stage 2) in NOD mice [19]. This is in contrast to several non-specific immunomodulatory agents, such as anti-CD3 mAb, that have successfully reversed hyperglycemia in NOD mice, either alone or in combination with an ASI [13,[19][20][21] and have recently been effective at delaying insulin production loss in pre-diabetic (i.e., dysglycemia, Stage 2) subjects [22]. However, unlike ASIs, these non-specific therapies may not induce durable tolerance and thus would require long-term dosing with associated safety concerns.…”

Section: Discussionmentioning

confidence: 95%

“…We derived a true hyperglycemic threshold as 4 × SD above the mean of normal mBG levels of our aged diabetes-free female mice (mean ± SD, 113 ± 17 mg/dL; n = 685 daily mBG readings from five naturally diabetes-free mice; note that 20% of our colony remain diabetes-free), which was 180 mg/dL, above which a non-diabetic mouse is highly unlikely to have a mBG reading (p = 0.00003). Indeed, Mathews et al [13] recently recommended that mBG values should be used instead of FBG to avoid any untoward influence of fasting on the course of disease progression. To determine ADi-100 efficacy when administered relatively late in the disease process during high hyperglycemia, each NOD mouse received the first ADi-100 dose when mBG was ≥ 180 mg/dL and weekly doses thereafter for a total of five injections.…”

Section: Increased Bax Plasmid Content In the Adi-100 1:2 Formulationmentioning

confidence: 99%

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Reversal of Hyperglycemia and Suppression of Type 1 Diabetes in the NOD Mouse with Apoptotic DNA Immunotherapy™ (ADi™), ADi-100

Alleva¹,

Rezaee

Yip

et al. 2020

Biomedicines

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The antigen-specific apoptotic DNA immunotherapeutic, ADi-100, is designed to suppress type 1 diabetes and consists of two DNA plasmids encoding genetic sequences of the apoptosis-inducing molecule, BAX, and the secreted form of the autoantigen, glutamic acid decarboxylase 65, that is CpG hyper-methylated to avoid inflammatory signaling (msGAD55). Upon a four-day treatment with ADi-100 of young female non-obese diabetic (NOD) mice, the frequency of various tolerogenic dendritic cell populations increased in draining lymph nodes; these cells lost the capacity to stimulate glutamic acid decarboxylase (GAD)-specific CD4+ T lymphocytes and were associated with the previously demonstrated enhancement of GAD-specific regulatory T cells. The efficacy of two ADi-100 formulations containing different proportions of BAX and msGAD55, 1:4 (10/40 µg) and 1:2 (17/33 µg), was evaluated in mildly hyperglycemic pre-diabetic NOD female mice. Both formulations suppressed the incidence of diabetes by 80% in an antigen-specific manner, while all untreated mice developed diabetes. However, treatment of pre-diabetic mice with significantly higher hyperglycemia, denoting progressive disease, showed that ADi-100 1:2 strongly suppressed diabetes incidence by 80% whereas the ADi-100 1:4 was less effective (50%). As an antigen-specific monotherapy, ADi-100 is highly efficacious in reversing elevated hyperglycemia to prevent diabetes, in which increasing apoptosis-inducing BAX content is a promising immune tolerance feature.

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“…For determining glucose tolerance, 2 to 4-month-old male and female mice were transferred to clean cages for an overnight fast before blood glucose levels were determined using a glucometer 33 . Mice were injected intraperitoneally with 1 mg glucose/g body weight, and blood glucose levels measured at 0, 30, 60, 90, and 120 min.…”

Section: Fasted Blood Glucose and Glucose Tolerance Testmentioning

confidence: 99%

Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury

et al. 2020

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Regulation of pancreas plasticity is critical for preventing injury and promoting regeneration upon tissue damage. The intricate process of pancreatic differentiation is governed by an orchestrated network of positive and negative transcription factors for appropriate gene expression. While the transcriptional repressor REST is well characterized as a silencer of neuronal genes in non-neuronal cells, the role of REST in regulating exocrine pancreas cell identity remains largely unexplored. Rest expression is increased upon injury in the mouse pancreas, such as induced acute and chronic pancreatitis and ductal adenocarcinoma. At the cellular level, Rest expression is lower in mature acinar cells compared with pancreas progenitor and ductal cells. To investigate the role of REST activity in pancreatic transdifferentiation and homeostasis, we developed a novel mouse model (Cre/REST fl/fl ) with conditional knockout (KO) of Rest expression within pancreas cells. The high Cre-mediated excision efficiency of Rest exon two KO caused decreased Rest expression and activity within the pancreas. Short-term organoid cultures of pancreatic acini to undergo acinar-to-ductal metaplasia (ADM) showed that loss of REST impedes induced ADM, while overexpression of REST increases ADM. Interestingly, REST ablation accelerated acute pancreatitis in mice treated with the cholecystokinin analog caerulein, as indicated by cellular morphology, elevated serum amylase levels and pancreatic edema. Furthermore, Cre/REST fl/fl mice were more sensitive to acute pancreatitis injury and displayed augmented tissue damage and cellular lesions. These results suggest REST has a novel protective role against pancreatic tissue damage by acting as a regulator of exocrine cell identity.

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Acute Versus Progressive Onset of Diabetes in NOD Mice: Potential Implications for Therapeutic Interventions in Type 1 Diabetes

Cited by 44 publications

References 27 publications

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

Reversal of Hyperglycemia and Suppression of Type 1 Diabetes in the NOD Mouse with Apoptotic DNA Immunotherapy™ (ADi™), ADi-100

Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury

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