scholarly journals Prevention of Type I Diabetes in Nonobese Diabetic Mice by Late Intervention with Nonhypercalcemic Analogs of 1,25-Dihydroxyvitamin D3 in Combination with a Short Induction Course of Cyclosporin A*

Endocrinology ◽  
1998 ◽  
Vol 139 (1) ◽  
pp. 95-102 ◽  
Author(s):  
Kristina M. Casteels ◽  
Chantal Mathieu ◽  
Mark Waer ◽  
Dirk Valckx ◽  
Lut Overbergh ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Disease Stage ◽  
Diabetes Incidence ◽  
Type I ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Nonobese Diabetic ◽  
Autoimmune Attack

Abstract In nonobese diabetic (NOD) mice, type I diabetes can be prevented without generalized immunosuppression by nonhypercalcemic analogs of vitamin D3 when treatment is started early, i.e. before the autoimmune attack, reflected by insulitis, occurs. The aim of this study was to investigate whether these substances can arrest progression to clinically overt diabetes when administered in a more advanced disease stage, namely when the autoimmune attack is ongoing, reflecting the situation in prediabetic subjects in whom immune intervention is being considered. We, therefore, evaluated the protective potential of MC1288 (20-epi-1,25-dihydroxyvitamin D3) a nonhypercalcemic analog of 1,25-dihydroxyvitamin D3, both alone and in combination with a short induction course of cyclosporin A, in NOD mice that already have insulitis, as demonstrated in pancreatic biopsies performed 15 days before the start of therapy. Subsequently, mice were randomized into a control group, receiving the treatment vehicle (n = 26), and three treatment groups, receiving, respectively, 7.5 mg/kg·day cyclosporin A (CyA) from days 85–105 (n = 19), 0.1μ g/kg·2 days MC1288 from days 85–200 (n = 20), or the combination of these two regimens (n = 20). At the time of the pancreatic biopsy (day 70), insulitis was evenly distributed in all groups, and 27.7% of the islets scored showed signs of destructive insulitis. Diabetes outcome by 200 days was 74% (14 of 19) in the CyA-treated group, comparable to the diabetes incidence in control mice (65%; 17 of 26; P = NS). Treatment with MC1288 alone could not reduce disease incidence (70%; 14 of 20), but the combination therapy reduced diabetes incidence to 35% (7 of 20; P < 0.05 vs. untreated; P < 0.01 vs. CyA group; P < 0.025 vs. MC1288). All treatments were well tolerated, without major side-effects on calcium or bone metabolism and without signs of generalized immunosuppression. Cotransfer experiments could not reveal the induction of suppressor cells. Reverse transcription-PCR on pancreatic tissue revealed significantly lower levels of interferon-γ and higher levels of interleukin-4 in the combination group. In conclusion, nonhypercalcemic analogs of 1,25-dihydroxyvitamin D3 administered to NOD mice when the autoimmune disease is already active can prevent clinical diabetes when this therapy is combined with a short induction course of an immunosuppressant such as CyA.

scholarly journals I-E+ nonobese diabetic mice develop insulitis and diabetes.

1993 ◽  
Vol 178 (3) ◽  
pp. 793-803 ◽  
Author(s):  
P L Podolin ◽  
A Pressey ◽  
N H DeLarato ◽  
P A Fischer ◽  
L B Peterson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mhc Class Ii ◽  
Type I Diabetes ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Large Degree ◽  
Type I ◽  
Congenic Strains ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

The development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E+ or I-E- non-NOD MHC on the NOD background, three I-E+ and three I-E- NOD MHC congenic strains (NOD.H-2i5, NOD.H-2k, and NOD.H-2h2, and NOD.H-2h4, NOD.H-2i7, and NOD.H-2b, respectively) were developed. Of these strains, both I-E+ NOD.H-2h2 and I-E- NOD.H-2h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E+ and I-E- F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E+ and I-E- F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E+ F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E+ NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E- F1 strains were no more protected from diabetes than I-E+ F1 strains, suggesting that other non-NOD MHC-linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E+ F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived cells, is not sufficient to provide protection from diabetes.

scholarly journals T Helper 2 (Th2) T Cells Induce Acute Pancreatitis and Diabetes in Immune-compromised Nonobese Diabetic (NOD) Mice

1997 ◽  
Vol 186 (2) ◽  
pp. 299-306 ◽  
Author(s):  
Syamasundar V. Pakala ◽  
Michael O. Kurrer ◽  
Jonathan D. Katz
Keyword(s):  
T Cells ◽  
Islet Cell ◽  
Autoimmune Diabetes ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Type I ◽  
T Helper ◽  
T Helper 1 ◽  
Th1 Cell ◽  
Nonobese Diabetic

Autoimmune diabetes is caused by the CD4+, T helper 1 (Th1) cell-mediated apoptosis of insulin-producing β cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.

scholarly journals 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

2008 ◽  
Vol 198 (3) ◽  
pp. 581-589 ◽  
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.

scholarly journals 1,25-Dihydroxyvitamin D3 Prevents Insulitis in NOD Mice

Diabetes ◽  
1992 ◽  
Vol 41 (11) ◽  
pp. 1491-1495 ◽  
Author(s):  
C. Mathieu ◽  
J. Laureys ◽  
H. Sobis ◽  
M. Vandeputte ◽  
M. Waer ◽  
...  
Keyword(s):  
Nod Mice ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3

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

1996 ◽  
Vol 148 (1) ◽  
pp. 139-148 ◽  
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

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

2008 ◽  
Vol 205 (1) ◽  
pp. 207-218 ◽  
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.

scholarly journals Streptococcal Preparation (OK-432) Inhibits Development of Type I Diabetes in NOD Mice

Diabetes ◽  
1986 ◽  
Vol 35 (4) ◽  
pp. 496-499 ◽  
Author(s):  
T. Toyota ◽  
J. Satoh ◽  
K. Oya ◽  
S. Shintani ◽  
T. Okano
Keyword(s):  
Type I Diabetes ◽  
Nod Mice ◽  
Type I ◽  
Streptococcal Preparation

scholarly journals Tissue-specific autoimmunity controlled by Aire in thymic and peripheral tolerance mechanisms

2019 ◽  
Vol 32 (2) ◽  
pp. 117-131
Author(s):  
Minoru Matsumoto ◽  
Koichi Tsuneyama ◽  
Junko Morimoto ◽  
Kazuyoshi Hosomichi ◽  
Mitsuru Matsumoto ◽  
...  
Keyword(s):  
T Cells ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Peripheral Tolerance ◽  
Type I ◽  
Tolerance Mechanisms ◽  
Thymic Function ◽  
Tissue Specific ◽  
Thymic Stroma ◽  
Antigen Presenting

Abstract Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms.

scholarly journals Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse.

1987 ◽  
Vol 165 (6) ◽  
pp. 1639-1654 ◽  
Author(s):  
L S Wicker ◽  
B J Miller ◽  
L Z Coker ◽  
S E McNally ◽  
S Scott ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Dominant Gene ◽  
Nod Mouse ◽  
Autoimmune Response ◽  
Type I ◽  
Diabetes In Animals ◽  
Nonobese Diabetic ◽  
Control Of Diabetes ◽  
Insulin Dependent ◽  
Or Gene

Genetic analysis of the development of diabetes and insulitis has been performed in the nonobese diabetic (NOD) mouse strain, a model of insulin-dependent (type I) diabetes mellitus. (NOD X C57BL/10)F1, F2, and (F1 X NOD) first-, second-, and third-backcross generations were studied. The data obtained were consistent with the hypothesis that diabetes is controlled by at least three functionally recessive diabetogenic genes, or gene complexes, one of which is linked to the MHC of the NOD. In contrast, pancreatic inflammation leading to insulitis was found to be controlled by a single incompletely dominant gene. One of the two diabetogenic loci that is not linked to the MHC appears to be essential for the development of severe insulitis. This diabetogenic gene may be identical to the gene that controls the initiation of the autoimmune response that progresses to insulitis. Although this gene appears to be functionally recessive in its control of diabetes, it is incompletely dominant in its control of insulitis. The MHC-linked diabetogenic gene, although not required for the development of insulitis, apparently influences the progression of the autoimmune response since NOD MHC homozygotes in the backcross generations displayed the highest incidence and most severe cases of insulitis. Interestingly, we have found two MHC heterozygous backcross females that have become diabetic, suggesting that either the MHC-linked diabetogenic gene is not strictly recessive or that a recombination event has occurred between the diabetogenic gene and the K or I-A regions of the MHC. The third diabetogenic locus appears to influence the progression of severe insulitis to overt diabetes. In animals homozygous at this locus, diabetes may result from a decreased ability to develop a protective suppressor response to the autoimmune process.

Sign in / Sign up

Export Citation Format

Share Document