The Repertoire of Newly Developing Regulatory T Cells in the Type I Diabetes-Prone NOD Mouse is Very Diverse

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their <i>in vivo</i> activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCRa and TCRb variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRa and TCRb chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.

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The Repertoire of Newly Developing Regulatory T Cells in the Type I Diabetes-Prone NOD Mouse is Very Diverse

10.2337/figshare.14611911.v1 ◽

2021 ◽

Author(s):

Ariel Galindo-Albarrán ◽

Sarah Castan ◽

Jérémy C. Santamaria ◽

Olivier P. Joffre ◽

Bart Haegeman ◽

...

Keyword(s):

Type I Diabetes ◽

Nod Mice ◽

Vital Role ◽

Nod Mouse ◽

Type I ◽

Antigen Specificity ◽

Regulatory T Lymphocytes ◽

Winged Helix Transcription Factor ◽

Complementarity Determining Region

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Interleukin-1 effect on glycemia in the non-obese diabetic mouse at the pre-diabetic stage

Journal of Endocrinology ◽

10.1677/joe.0.1480139 ◽

1996 ◽

Vol 148 (1) ◽

pp. 139-148 ◽

Cited By ~ 25

Author(s):

A Amrani ◽

M Jafarian-Tehrani ◽

P Mormède ◽

S Durant ◽

J-M Pleau ◽

...

Keyword(s):

Insulin Resistance ◽

Type I Diabetes ◽

Interleukin 1 ◽

Nod Mice ◽

Experimental Models ◽

Nod Mouse ◽

Hypoglycemic Effect ◽

Type I ◽

Insulin Effect ◽

Corticosterone Secretion

Abstract Cytokines, particularly interleukin 1 (IL-1) and tumor necrosis factor, are known to induce hypoglycemia in normal rodents or different experimental models of type II diabetes. We investigated, at the pre-diabetic stage, the effect of short-term administration of murine recombinant interleukin-1α (mrIL-1α) on the levels of glucose, insulin and corticosterone in the non-obese diabetic (NOD) mouse, a spontaneous model of type I diabetes. Two-month-old, pre-diabetic NOD mice of both sexes were insensitive to mrIL-1α (12·5 and 50 μg/kg) 2 h after administration, the time at which the maximal decrease (around 50%) was observed in the C57BL/6 mouse strain. Kinetic studies however showed that mrIL-1α lowered glycemia in both sexes of NOD mice, but the effect was limited and delayed. In the NOD and C57BL/6 strains, mrIL-1α had no influence on insulin levels in females, but significantly increased them in males (P<0·0001). Castration of NOD males abrogated the stimulatory effect of mrIL-1α on insulin secretion. Corticosterone secretion was stimulated by mrIL-1α in both sexes of NOD and C57BL/6 mice, and this effect was faster and greater in NOD females than in C57BL/6 females. The incomplete hypoglycemic response to mrIL-1α in females may be attributed to the anti-insulin effect of glucocorticoids, an effect which can be demonstrated when mrIL-1α is administered to adrenalectomized animals or when mrIL-1α is administered together with the glucocorticoid antagonist RU38486. In NOD males, in contrast, glucocorticoids did not play a major role in the limited hypoglycemic response to mrIL-1α, since RU38486 and adrenalectomy were not able to unmask a hypoglycemic effect. Moreover, NOD mice of both sexes were less sensitive than C57BL/6 mice to the hypoglycemic effect of insulin (2·5 U/kg), which suggests some degree of insulin-resistance in NOD mice. With regard to the effect of IL-1 on NOD mouse glycemia, therefore, these results suggest that glucocorticoids and/or androgens, according to the animal's sex, may induce a state of insulin-resistance. Journal of Endocrinology (1996) 148, 139–148

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New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2

Acta Endocrinologica ◽

10.1530/eje.0.1310431 ◽

1994 ◽

Vol 131 (4) ◽

pp. 431-437 ◽

Cited By ~ 26

Author(s):

Alberto Signore ◽

Marco Chianelli ◽

Elisabetta Ferretti ◽

Anna Toscano ◽

Keith E Britton ◽

...

Keyword(s):

Gamma Camera ◽

Type I Diabetes ◽

Interleukin 2 ◽

Nod Mice ◽

Insulin Dependent Diabetes ◽

Type I ◽

New Approach ◽

In Vivo Detection ◽

Insulin Dependent

Signore A, Chianelli M, Ferretti E, Toscano A, Britton KE, Andreani D, Gale EAM, Pozzilli P. New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2. Eur J Endocrinol 1994;131:431–7. ISSN 0804–4643 Insulitis is considered the histopathological hallmark of type I (insulin-dependent) diabetes. In the nonobese diabetic (NOD) mouse, diabetes has never been observed in the absence of insulitis. The in vivo detection of insulitis could be of relevance for early prediction of diabetes. As approximately 15% of islet-infiltrating lymphocytes express interleukin 2 receptors, we have labelled recombinant interleukin 2 with 123I and used this radiopharmaceutical to detect insulitis by gamma camera imaging. We studied 71 prediabetic NOD and 27 normal Balb/c mice. Labelled α-lactalbumin was used as the control protein. In the first set of experiments we studied the tissue distribution of radiolabelled interleukin 2 in isolated organs from animals sacrificed at different time points. Higher radioactivity was detected in the pancreas of NOD mice injected with labelled interleukin 2, as compared to NOD mice receiving labelled α-lactalbumin (p < 0.003 at 20 min; p< 0.001 at 40 min; p< 0.0001 at 60 min) or Balb/c mice injected with labelled interleukin 2 (p< 0.05 at 40 min; p< 0.001 at 60 min). In another set of experiments, gamma camera images have been acquired after injection of 123I-labelled interleukin 2. Radioactivity in the pancreatic region of prediabetic NOD and Balb/c mice showed similar kinetics to those observed by single organ counting, with higher accumulation in the pancreatic region of NOD mice (p < 0.04 after 22–45 min in NOD mice vs Balb/c mice). Finally, a positive correlation was found between the radioactivity in the pancreas and the extent of lymphocytic infiltration (p < 0.01 for pancreas radioactivity counted in vitro and p< 0.004 for pancreas radioactivity counted in vivo by gamma camera). This study demonstrates that 123I-labelled interleukin 2 administered iv accumulates specifically in the inflamed pancreas of diabetes-prone NOD mice, suggesting its potential application in human insulin-dependent diabetes mellitus. A Signore, Servizio Speciale di Medicina Nucleare, II Clinica Medica, Policlinico Umberto I, 00161 Roma, Italy

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The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes

Journal of Endocrinology ◽

10.1677/joe-07-0511 ◽

2008 ◽

Vol 198 (3) ◽

pp. 581-589 ◽

Cited By ~ 5

Author(s):

Jon G Mabley ◽

Pal Pacher ◽

Kanneganti G K Murthy ◽

William Williams ◽

Garry J Southan ◽

...

Keyword(s):

Animal Models ◽

Type I Diabetes ◽

Spontaneous Diabetes ◽

Nod Mice ◽

Diabetes Incidence ◽

Type I ◽

Protective Effects ◽

Naturally Occurring ◽

Anti Inflammatory

Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic-resistant purine analogue, INO-2002, exerts anti-inflammatory effects in two animal models of type I diabetes. Type I diabetes was induced chemically with streptozotocin or genetically using the non-obese diabetic (NOD) female mouse model. Mice were treated with INO-2002 or inosine as required at 30, 100, or 200 mg/kg per day, while blood glucose and diabetes incidence were monitored. The effect of INO-2002 on the pancreatic cytokine profile was also determined. INO-2002 reduced both the hyperglycaemia and incidence of diabetes in both streptozotocin-induced and spontaneous diabetes in NOD mice. INO-2002 proved to be more effective in protecting against diabetes than the naturally occurring purine, inosine, when administered at the same dose. INO-2002 treatment decreased pancreatic levels of interleukin (IL)-12 and tumour necrosis factor-α, while increasing levels of IL-4 and IL-10. INO-2002 also reduced pancreatic levels of the chemokine MIP-1α. The inosine analogue, INO-2002, was protected more effectively than the naturally occurring purine, inosine, against development of diabetes in two separate animal models. INO-2002 exerts protective effects by changing the pancreatic cytokine expression from a destructive Th1 to a protective Th2 profile. The use of analogues of inosine such as INO-2002 should be considered as a potential preventative therapy in individuals susceptible to developing type I diabetes.

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NOD Hematopoietic Stem Cells Exhibit Autonomous Behavior and a Competitive Advantage in Allogeneic Recipients That Maps to the Idd9 Locus.

Blood ◽

10.1182/blood.v104.11.2676.2676 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2676-2676

Author(s):

Paula M. Chilton ◽

Francine Rezzoug ◽

Janina Ratajczak ◽

Mariusz Ratajczak ◽

Yiming Huang ◽

...

Keyword(s):

Bone Marrow Cells ◽

Type I Diabetes ◽

Nod Mice ◽

Cell Phenotype ◽

Type I ◽

Hematopoietic Stem ◽

Autonomous Behavior ◽

Insulin Dependent

Abstract Multiple hematopoietic defects have been defined in NOD mice and in humans with type I diabetes, including defects in myeloid cells and antigen presenting cells that correlate with diabetes progression. Since the replacement of HSC in NOD mice can eliminate the progression of autoimmunity and control on-going autoimmune responses, we characterized the function of HSC from NOD mice. We found that purified HSC from NOD mice have an autonomous behavior when transplanted in allogeneic recipient strains as reflected by significantly enhanced engraftment in allogeneic recipients. NOD HSC were able to compete for engraftment with syngeneic HSC even when the NOD and syngeneic HSC were given at a 1:1 ratio. NOD BMC produced a higher number of splenic colonies compared to B10.BR BMC in the allogeneic day 12 CFU-S assay. We also demonstrated that NOD HSC had a high resistance to irradiation, as reflected by the cell survival 20 hours after irradiation and in the in vitro CFC assay. These data suggest that NOD HSC escape alloreactivity and compete with normal HSC. The enhanced engraftment ability in allogeneic recipients of NOD HSC was not due to an increase in frequency of primitive HSC, enumerated by day 35 cobblestone area forming cells (CAFC). This finding was further confirmed by the fact that there was no difference in the long-term repopulating cell phenotype (CD49e+/CD49ddim) between HSC obtained from NOD, B10.BR or C57BL/10 mice. Notably, NOD bone marrow cells exhibit significantly enhanced chemotaxis to SDF-1 in vitro and significantly increased HSC adhesion to primary stroma. This was associated with an increase in the expression of VCAM-1, ICAM-1 and ICAM-2 on NOD HSC. Using NOD mice congenic at selected Idd loci with C57BL/10, we determined that the enhanced engraftment potential of NOD HSC mapped to the Idd9 (insulin-dependent diabetes) locus and, as such, the TNF receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSC. In conclusion, NOD HSC exhibit increased autonomy in vivo and in vitro compared to non-diabetic strains, and engraft better in allogeneic recipients, possibly due to enhanced migration and adherence to the microenvironment. This finding may be of interest for a better understanding of disease pathogenesis and in developing cell-based strategies to cure diabetes.

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Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells.

Journal of Experimental Medicine ◽

10.1084/jem.166.4.823 ◽

1987 ◽

Vol 166 (4) ◽

pp. 823-832 ◽

Cited By ~ 391

Author(s):

A Bendelac ◽

C Carnaud ◽

C Boitard ◽

J F Bach

Keyword(s):

Autoimmune Diabetes ◽

Type I Diabetes ◽

Spontaneous Diabetes ◽

Nod Mice ◽

T Cell Subsets ◽

Type I ◽

Spleen Cells ◽

Adult Mice ◽

Cellular Events

We have developed a model of syngeneic adoptive transfer for type I diabetes mellitus of NOD mice. This model consists in injecting spleen cells from diabetic adult mice into newborn NOD recipients. 50% of recipients inoculated with 20 X 10(6) cells develop diabetes within the first 10 wk of life, at a time when none of the control littermates have yet become diabetic. The earliest successful transfers are observed at 3 wk of age, at a time when controls do not even exhibit histological changes in their pancreas. In addition we have shown that: (a) both males and females can be adoptively transferred, despite the fact that males rarely develop spontaneous diabetes in our colony; (b) diabetes transfer is a dose-dependent phenomenon that provides an in vivo assay for comparing the autoimmune potential of spleen cells from mice at various stages of their natural history; (c) the susceptibility of the recipients to the transfer is limited in time and declines after 3 wk; and (d) both L3T4+ and Lyt-2+ T cell subsets are necessary for the successful transfer. The neonatal syngeneic transfer provides an effective model for studies of the cellular events involved at regulatory and effector stages of autoimmune type I diabetes.

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NOD Mice Are Defective in Proteasome Production and Activation of NF-κB

Molecular and Cellular Biology ◽

10.1128/mcb.19.12.8646 ◽

1999 ◽

Vol 19 (12) ◽

pp. 8646-8659 ◽

Cited By ~ 88

Author(s):

Takuma Hayashi ◽

Denise Faustman

Keyword(s):

Transcription Factor ◽

Inflammatory Responses ◽

Type I Diabetes ◽

Nod Mice ◽

Nod Mouse ◽

Proteolytic Processing ◽

Type I ◽

Inhibitory Protein ◽

Necrosis Factor Alpha ◽

Mouse Splenocytes

ABSTRACT The nonobese diabetic (NOD) mouse is an animal model of human type I diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) of the genome. We have identified in NOD lymphocytes a specific proteasome defect that results from the lack of the LMP2 subunit. The pronounced proteasome defect results in defective production and activation of the transcription factor NF-κB, which plays an important role in immune and inflammatory responses as well as in preventing apoptosis induced by tumor necrosis factor alpha. The defect in proteasome function in NOD mouse splenocytes was evident from impaired NF-κB subunit p50 and p52 generation by proteolytic processing and impaired degradation of the NF-κB-inhibitory protein IκBα. An obligatory role of MHC-linked proteasome subunits in transcription factor processing and activation has been established in a spontaneous-disease model and mutant cells similarly lacking the MHC-encoded subunit. These data suggest that NOD proteasome dysfunction is due to a tissue- and developmental-stage-specific defect in expression of the MHC-linkedLmp2 gene, resulting in altered transcription factor NF-κB activity, and that this defect contributes to pathogenesis in NOD mice. These observations are consistent with the diverse symptomatology of type I diabetes and demonstrate clear sex-, tissue-, and age-specific differences in the expression of this error which parallel the initiation and disease course of insulin-dependent (type I) diabetes mellitus.

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Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production

Journal of Experimental Medicine ◽

10.1084/jem.20071878 ◽

2008 ◽

Vol 205 (1) ◽

pp. 207-218 ◽

Cited By ~ 134

Author(s):

Renu Jain ◽

Danielle M. Tartar ◽

Randal K. Gregg ◽

Rohit D. Divekar ◽

J. Jeremiah Bell ◽

...

Keyword(s):

Th17 Cells ◽

Type I Diabetes ◽

Nod Mice ◽

Cell Receptor ◽

Interferon Γ ◽

Acid Decarboxylase ◽

Type I ◽

Pancreatic Cell ◽

Disease Stages ◽

Free Antigen

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells.

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