scholarly journals Histidine Decarboxylase Deficiency Prevents Autoimmune Diabetes in NOD Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Manal Alkan ◽  
François Machavoine ◽  
Rachel Rignault ◽  
Julie Dam ◽  
Michel Dy ◽  
...  
Keyword(s):  
Histidine Decarboxylase ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Wild Type ◽  
Gene Encoding ◽  
Nonobese Diabetic ◽  
Endogenous Histamine ◽  
Wild Type Counterpart

Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC−/−mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γin HDC−/−mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC−/−mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response.

scholarly journals Development of Spontaneous Autoimmune Peripheral Polyneuropathy in B7-2–Deficient Nod Mice

2001 ◽  
Vol 194 (5) ◽  
pp. 677-684 ◽  
Author(s):  
Benoît Salomon ◽  
Lesley Rhee ◽  
Helene Bour-Jordan ◽  
Honor Hsin ◽  
Anthony Montag ◽  
...  
Keyword(s):  
T Cells ◽  
Nervous System ◽  
Autoimmune Diabetes ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Nod Mice ◽  
Nod Mouse ◽  
Nerve Tissue ◽  
Nonobese Diabetic ◽  
Peripheral Polyneuropathy

An increasing number of studies have documented the central role of T cell costimulation in autoimmunity. Here we show that the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain, deficient in B7-2 costimulation, is protected from diabetes but develops a spontaneous autoimmune peripheral polyneuropathy. All the female and one third of the male mice exhibited limb paralysis with histologic and electrophysiologic evidence of severe demyelination in the peripheral nerves beginning at 20 wk of age. No central nervous system lesions were apparent. The peripheral nerve tissue was infiltrated with dendritic cells, CD4+, and CD8+ T cells. Finally, CD4+ T cells isolated from affected animals induced the disease in NOD.SCID mice. Thus, the B7-2–deficient NOD mouse constitutes the first model of a spontaneous autoimmune disease of the peripheral nervous system, which has many similarities to the human disease, chronic inflammatory demyelinating polyneuropathy (CIDP). This model demonstrates that NOD mice have “cryptic” autoimmune defects that can polarize toward the nervous tissue after the selective disruption of CD28/B7-2 costimulatory pathway.

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 Glucagon-Like Peptide-2 Reduces Intestinal Permeability But Does Not Modify the Onset of Type 1 Diabetes in the Nonobese Diabetic Mouse

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 592-599 ◽  
Author(s):  
Irene Hadjiyanni ◽  
Kunmin Karen Li ◽  
Daniel J. Drucker
Keyword(s):  
Type 1 Diabetes ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Gut Barrier ◽  
Nonobese Diabetic ◽  
Gut Barrier Function ◽  
Glucagon Like Peptide

The development of type 1 diabetes (T1D) has been linked to environmental factors and dietary components. Increasing evidence indicates that the integrity of the gut mucosa plays a role in the development of autoimmune diseases, and evidence from both preclinical and clinical studies demonstrates that increased leakiness of the intestinal epithelium precedes the development of type 1 diabetes. However, there is limited information on modulation of gut barrier function and its relationship to diabetes development. Here we show that the nonobese diabetic (NOD) mouse, a model of T1D, exhibits enhanced intestinal transcellular permeability before the development of autoimmune diabetes. Treatment of NOD mice with a glucagon-like peptide 2 (GLP-2) analog, synthetic human [Gly2] glucagon-like peptide-2 (h[Gly2]GLP-2, increased the length and weight of the small bowel and significantly improved jejunal transepithelial resistance. However, chronic administration of once daily h[Gly2]GLP-2 failed to delay or reverse the onset of T1D when treatment was initiated in young, normoglycemic female NOD mice. Furthermore, h[Gly2]GLP-2 administration had no significant effect on lymphocyte subpopulations in NOD mice. These findings demonstrate that h[Gly2]GLP-2-mediated enhancement of gut barrier function in normoglycemic NOD mice disease is not sufficient to prevent or delay the development of experimental T1D. Increased intestinal permeability often precedes the clinical appearance of autoimmune disorders such as celiac disease or type 1 diabetes. These studies show that glucagon-like peptide 2 reduces gut permeability, but not the onset of diabetes in NOD mice.

scholarly journals Cd1-Restricted Nk T Cells Protect Nonobese Diabetic Mice from Developing Diabetes

2001 ◽  
Vol 194 (3) ◽  
pp. 313-320 ◽  
Author(s):  
Bin Wang ◽  
Yan-Biao Geng ◽  
Chyung-Ru Wang
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Dependent Manner ◽  
Nonobese Diabetic ◽  
Nk T Cells

NK T cells are a unique subset of T cells that recognize lipid antigens presented by CD1d. After activation, NK T cells promptly produce large amounts of cytokines, which may modulate the upcoming immune responses. Previous studies have documented an association between decreased numbers of NK T cells and the progression of some autoimmune diseases, suggesting that NK T cells may control the development of autoimmune diseases. To investigate the role of NK T cells in autoimmune diabetes, we crossed CD1 knockout (CD1KO) mutation onto the nonobese diabetic (NOD) genetic background. We found that male CD1KO NOD mice exhibited significantly higher incidence and earlier onset of diabetes compared with the heterozygous controls. The diabetic frequencies in female mice showed a similar pattern; however, the differences were less profound between female CD1KO and control mice. Early treatment of NOD mice with α-galactosylceramide, a potent NK T cell activator, reduced the severity of autoimmune diabetes in a CD1-dependent manner. Our results not only suggest a protective role of CD1-restricted NK T cells in autoimmune diabetes but also reveal a causative link between the deficiency of NK T cells and the induction of insulin-dependent diabetes mellitus.

scholarly journals Single cell analysis shows decreasing FoxP3 and TGFβ1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes

2005 ◽  
Vol 201 (8) ◽  
pp. 1333-1346 ◽  
Author(s):  
Shannon M. Pop ◽  
Carmen P. Wong ◽  
Donna A. Culton ◽  
Stephen H. Clarke ◽  
Roland Tisch
Keyword(s):  
T Cells ◽  
Single Cell Analysis ◽  
Autoimmune Diabetes ◽  
Single Cells ◽  
Nod Mice ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Nonobese Diabetic ◽  
Pancreatic Lymph Node

Natural CD4+CD25+ regulatory T (CD4+CD25+ T reg) cells play a key role in the immunoregulation of autoimmunity. However, little is known about the interactions between CD4+CD25+ T reg cells and autoreactive T cells. This is due, in part, to the difficulty of using cell surface markers to identify CD4+CD25+ T reg cells accurately. Using a novel real-time PCR assay, mRNA copy number of FoxP3, TGFβ1, and interleukin (IL)-10 was measured in single cells to characterize and quantify CD4+CD25+ T reg cells in the nonobese diabetic (NOD) mouse, a murine model for type 1 diabetes (T1D). The suppressor function of CD4+CD25+CD62Lhi T cells, mediated by TGFβ, declined in an age-dependent manner. This loss of function coincided with a temporal decrease in the percentage of FoxP3 and TGFβ1 coexpressing T cells within pancreatic lymph node and islet infiltrating CD4+CD25+CD62Lhi T cells, and was detected in female NOD mice but not in NOD male mice, or NOR or C57BL/6 female mice. These results demonstrate that the majority of FoxP3-positive CD4+CD25+ T reg cells in NOD mice express TGFβ1 but not IL-10, and that a defect in the maintenance and/or expansion of this pool of immunoregulatory effectors is associated with the progression of T1D.

scholarly journals Toll-Like Receptor 3 Is Critical for Coxsackievirus B4-Induced Type 1 Diabetes in Female NOD Mice

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 453-461 ◽  
Author(s):  
Kelly D. McCall ◽  
Jean R. Thuma ◽  
Maria C. Courreges ◽  
Fabian Benencia ◽  
Calvin B.L. James ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Knockout Mice ◽  
Nod Mice ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Infected Female ◽  
Coxsackievirus B4 ◽  
Nonobese Diabetic ◽  
Group B

Group B coxsackieviruses (CVBs) are involved in triggering some cases of type 1 diabetes mellitus (T1DM). However, the molecular mechanism(s) responsible for this remain elusive. Toll-like receptor 3 (TLR3), a receptor that recognizes viral double-stranded RNA, is hypothesized to play a role in virus-induced T1DM, although this hypothesis is yet to be substantiated. The objective of this study was to directly investigate the role of TLR3 in CVB-triggered T1DM in nonobese diabetic (NOD) mice, a mouse model of human T1DM that is widely used to study both spontaneous autoimmune and viral-induced T1DM. As such, we infected female wild-type (TLR3+/+) and TLR3 knockout (TLR3−/−) NOD mice with CVB4 and compared the incidence of diabetes in CVB4-infected mice with that of uninfected counterparts. We also evaluated the islets of uninfected and CVB4-infected wild-type and TLR3 knockout NOD mice by immunohistochemistry and insulitis scoring. TLR3 knockout mice were markedly protected from CVB4-induced diabetes compared with CVB4-infected wild-type mice. CVB4-induced T-lymphocyte-mediated insulitis was also significantly less severe in TLR3 knockout mice compared with wild-type mice. No differences in insulitis were observed between uninfected animals, either wild-type or TLR3 knockout mice. These data demonstrate for the first time that TLR3 is 1) critical for CVB4-induced T1DM, and 2) modulates CVB4-induced insulitis in genetically prone NOD mice.

scholarly journals CD25+ CD4+ T Cells, Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide, Suppress Autoimmune Diabetes

2004 ◽  
Vol 199 (11) ◽  
pp. 1467-1477 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Sayuri Yamazaki ◽  
Kara Olson ◽  
Priscilla Toy ◽  
Ralph M. Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Nonobese Diabetic ◽  
And Function

In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet β cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 105 polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.

scholarly journals Foxp3+Regulatory T Cells in Mouse Models of Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Cathleen Petzold ◽  
Julia Riewaldt ◽  
Deepika Watts ◽  
Tim Sparwasser ◽  
Sonja Schallenberg ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mouse Models ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Nonobese Diabetic ◽  
Human Type 1 Diabetes

Studies on human type 1 diabetes (T1D) are facilitated by the availability of animal models such as nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes, as well as a variety of genetically engineered mouse models with reduced genetic and pathogenic complexity, as compared to the spontaneous NOD model. In recent years, increasing evidence has implicated CD4+CD25+regulatory T (Treg) cells expressing the transcription factor Foxp3 in both the breakdown of self-tolerance and the restoration of immune homeostasis in T1D. In this paper, we provide an overview of currently available mouse models to study the role of Foxp3+Treg cells in the control of destructiveβcell autoimmunity, including a novel NOD model that allows specific and temporally controlled deletion of Foxp3+Treg cells.

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.

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