scholarly journals Reduced Incidence and Delayed Onset of Diabetes in Perforin-deficient Nonobese Diabetic Mice

1997 ◽  
Vol 186 (7) ◽  
pp. 989-997 ◽  
Author(s):  
David Kägi ◽  
Bernhard Odermatt ◽  
Peter Seiler ◽  
Rolf M. Zinkernagel ◽  
Tak W. Mak ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diabetes ◽  
Cytotoxic T Cells ◽  
Disease Onset ◽  
Spontaneous Diabetes ◽  
Cell Loss ◽  
Β Cell ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice ◽  
Deficient Mice

To investigate the role of T cell–mediated, perforin-dependent cytotoxicity in autoimmune diabetes, perforin-deficient mice were backcrossed with the nonobese diabetes mouse strain. It was found that the incidence of spontaneous diabetes over a 1 yr period was reduced from 77% in perforin +/+ control to 16% in perforin-deficient mice. Also, the disease onset was markedly delayed (median onset of 39.5 versus 19 wk) in the latter. Insulitis with infiltration of CD4+ and CD8+ T cells occurred similarly in both groups of animals. Lower incidence and delayed disease onset were also evident in perforin-deficient mice when diabetes was induced by cyclophosphamide injection. Thus, perforin-dependent cytotoxicity is a crucial effector mechanism for β cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic β cell loss by less efficient secondary effector mechanisms.

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.

Induction of GAD65-specific regulatory T-cells inhibits ongoing autoimmune diabetes in nonobese diabetic mice

Diabetes ◽  
1998 ◽  
Vol 47 (6) ◽  
pp. 894-899 ◽  
Author(s):  
R. Tisch ◽  
R. S. Liblau ◽  
X. D. Yang ◽  
P. Liblau ◽  
H. O. McDevitt
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

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.

scholarly journals Androgen treatment prevents diabetes in nonobese diabetic mice.

1992 ◽  
Vol 175 (5) ◽  
pp. 1409-1412 ◽  
Author(s):  
H S Fox
Keyword(s):  
Immune Cells ◽  
Autoimmune Diabetes ◽  
Disease Model ◽  
Disease Onset ◽  
Nod Mice ◽  
Model System ◽  
Androgen Treatment ◽  
Nonobese Diabetic ◽  
Islet Inflammation ◽  
Nonobese Diabetic Mice

The nonobese diabetic (NOD) mouse strain provides a model system for human autoimmune diabetes. This disease model is extensively used not only to examine the etiology and pathogenesis of diabetes, but also as a means to evaluate therapies. In NOD mice, the disease progresses from insulitis to islet destruction and clinical diabetes in a high percentage of female mice. In this study, androgen therapy, begun after the onset of insulitis, was found to prevent islet destruction and diabetes without eliminating the islet inflammation in female NOD mice. However, diabetes can be adoptively transferred into such hormone-treated recipients. The prevention of disease onset by androgen is likely due to the hormonal alteration of the development or function of the immune cells necessary for islet destruction.

scholarly journals Reovirus Delays Diabetes Onset but Does Not Prevent Insulitis in Nonobese Diabetic Mice

2006 ◽  
Vol 80 (6) ◽  
pp. 3078-3082 ◽  
Author(s):  
J. Denise Wetzel ◽  
Erik S. Barton ◽  
James D. Chappell ◽  
Geoffrey S. Baer ◽  
Michelle Mochow-Grundy ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Autoimmune Diabetes ◽  
Primary Cultures ◽  
Systemic Infection ◽  
Nod Mice ◽  
Β Cell ◽  
Nonobese Diabetic ◽  
Strain Type ◽  
Nonobese Diabetic Mice ◽  
Type 3

ABSTRACT Mice infected with reovirus develop abnormalities in glucose homeostasis. Reovirus strain type 3 Abney (T3A) was capable of systemic infection of nonobese diabetic (NOD) mice, an experimental model of autoimmune diabetes. Reovirus antigen was detected in pancreatic islets of T3A-infected mice, and primary cultures of pancreatic islets from NOD mice supported T3A growth. Significantly fewer T3A-infected animals compared to uninfected controls developed diabetes. However, despite the alteration in diabetes penetrance, insulitis was evident in T3A-infected mice. These results suggest that viral infection of NOD mice alters autoimmune responses to β-cell antigens and thereby delays development of diabetes.

scholarly journals Exendin-4 Modulates Diabetes Onset in Nonobese Diabetic Mice

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1338-1349 ◽  
Author(s):  
Irene Hadjiyanni ◽  
Laurie L. Baggio ◽  
Philippe Poussier ◽  
Daniel J. Drucker
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Lymph Nodes ◽  
Cell Mass ◽  
Diabetic Mice ◽  
Β Cell ◽  
Diabetes Onset ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

Activation of the glucagon-like peptide-1 receptor (GLP-1R) is associated with expansion of β-cell mass due to stimulation of cell proliferation and induction of antiapoptotic pathways coupled to β-cell survival. Although the GLP-1R agonist Exenatide (exendin-4) is currently being evaluated in subjects with type 1 diabetes, there is little information available about the efficacy of GLP-1R activation for prevention of experimental type 1 diabetes. We examined the consequences of exendin-4 (Ex-4) administration (100 ng once daily and 2 μg twice daily) on diabetes onset in nonobese diabetic mice beginning at either 4 or 9 wk of age prior to the onset of diabetes. Ex-4 treatment for 26 wk (2 μg twice daily) initiated at 4 wk of age delayed the onset of diabetes (P = 0.007). Ex-4-treated mice also exhibited a significant reduction in insulitis scores, enhanced β-cell mass, and improved glucose tolerance. Although GLP-1R mRNA transcripts were detected in spleen, thymus, and lymph nodes from nonobese diabetic mice, Ex-4 treatment was not associated with significant changes in the numbers of CD4+ or CD8+ T cells or B cells in the spleen. However, Ex-4 treatment resulted in an increase in the number of CD4+ and CD8+ T cells in the lymph nodes and a reduction in the numbers of CD4+CD25+Foxp3+ regulatory T cells in the thymus but not in lymph nodes. These findings demonstrate that sustained GLP-1R activation in the absence of concomitant immune intervention may be associated with modest but significant delay in diabetes onset in a murine model of type 1 diabetes.

scholarly journals Different Modulation of Ptpn22 in Effector and Regulatory T Cells Leads to Attenuation of Autoimmune Diabetes in Transgenic Nonobese Diabetic Mice

2013 ◽  
Vol 191 (2) ◽  
pp. 594-607 ◽  
Author(s):  
Li-Tzu Yeh ◽  
Shi-Chuen Miaw ◽  
Ming-Hong Lin ◽  
Feng-Cheng Chou ◽  
Shing-Jia Shieh ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

scholarly journals The Role of Macrophages in T Cell–mediated Autoimmune Diabetes in Nonobese Diabetic Mice

1999 ◽  
Vol 189 (2) ◽  
pp. 347-358 ◽  
Author(s):  
Hee-Sook Jun ◽  
Chang-Soon Yoon ◽  
Lori Zbytnuik ◽  
Nico van Rooijen ◽  
Ji-Won Yoon
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Autoimmune Diabetes ◽  
Cytotoxic T Cells ◽  
Nod Mice ◽  
Β Cell ◽  
Prevention Of Diabetes

We have shown previously that the inactivation of macrophages in nonobese diabetic (NOD) mice results in the prevention of diabetes; however, the mechanisms involved remain unknown. In this study, we found that T cells in a macrophage-depleted environment lost their ability to differentiate into β cell–cytotoxic T cells, resulting in the prevention of autoimmune diabetes, but these T cells regained their β cell–cytotoxic potential when returned to a macrophage-containing environment. To learn why T cells in a macrophage-depleted environment lose their ability to kill β cells, we examined the islet antigen–specific immune response and T cell activation in macrophage-depleted NOD mice. There was a shift in the immune balance, a decrease in the T helper cell type 1 (Th1) immune response, and an increase in the Th2 immune response, due to the reduced expression of the macrophage-derived cytokine IL-12. As well, there was a deficit in T cell activation, evidenced by significant decreases in the expression of Fas ligand and perforin. The administration of IL-12 substantially reversed the prevention of diabetes in NOD mice conferred by macrophage depletion. We conclude that macrophages play an essential role in the development and activation of β cell–cytotoxic T cells that cause β cell destruction, resulting in autoimmune diabetes in NOD mice.

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