Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The NOD mouse is an animal model for insulin-dependent diabetes with many similarities to the human disease. NOD mice which are transgenic for the Ea gene, allowing expression of the E molecule, are protected from diabetes and rarely develop insulitis. We have constructed bone marrow chimeras between transgenic and non-transgenic NOD mice to study the correlation of E expression on bone marrow derived cells and thymic epithelium vs the production of IL-4 and IFN-gamma. We show that NOD-E-->NOD-E and NOD-E-->NOD chimeras have elevated levels of IL-4 compared to NOD-->NOD and NOD-->NOD-E chimeras in the thymus. However, in the periphery the protected NOD-E-->NOD-E show much higher IL-4 levels than any of the other chimeras. This drop in peripheral IL-4 production seen in NOD-E-->NOD, NOD-->NOD-E and NOD-->NOD chimeras correlates with the increased insulitis seen in these mice compared to NOD-E-->NOD-E. In contrast, there were no differences in IFN-gamma production between the chimeras. We suggest that the precommitted, regulatory T cells, selected in an E-expressing thymic environment, need continuous interaction with E-expressing primary antigen presenting cells in the periphery for optimal IL-4 production. Decrease in IL-4 production correlates with increased insulitis.
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PMID:E expression is needed on both bone marrow derived cells and thymic epithelium to increase IL-4 production and achieve protection in NOD bone marrow chimeras. 1052 15

Restoration of peripheral tolerance to target autoantigens during autoimmune diseases has met with several limitations because of the limited efficacy of this approach in an already immune host. To optimize the induction of tolerance, we have shown that feeding insulin conjugated to cholera toxin B-subunit (CTB), a potent mucosal adjuvant, reduced by 5,000 the amounts of antigen necessary for delaying diabetes onset in NOD mice. To analyze these protective mechanisms, we have performed cotransfer experiments using splenocytes from young females fed once with 10 microg of CTB-insulin, mixed with diabetogenic T-cells, and intravenously injected into irradiated syngeneic male recipients. We demonstrated that the delayed onset of diabetes relied on CD4+ T-cells. We studied the cytokine production from plate-bound anti-CD3-stimulated cells. Higher interleukin (IL)-4 amounts were observed in both splenocytes and pancreatic lymph node (PLN) cell cultures from CTB-insulin-fed mice as soon as 4 h after the feeding. An increase in the levels of transforming growth factor-beta was seen after 24 h only in the mesenteric lymph nodes (MLN). In both of these organs, a reduction of gamma-interferon (IFN-gamma) production occurred after CTB-insulin treatment, at 24 h in the PLN and at 7 days in the MLN. Reverse transcription-polymerase chain reaction analysis indicated an increase in the level of IL-4 and a reduction in IFN-gamma transcripts in the PLN of mice treated orally with CTB-insulin and of the recipients of regulatory T-cells. Using different strains of congenic NOD mice at the Thy1 locus, we showed that protection was associated with the accumulation of T-cells from CTB-insulin-fed mice in the lymph nodes from draining sites containing functional islets, i.e., the PLN in normal mice and the renal lymph nodes after a syngeneic islet graft under the kidney capsule of streptozotocin-treated mice. Taken together, our results clearly indicate that oral administration of CTB-insulin conjugates in NOD mice produced a shift from a T-helper type 1 to a type 2 profile with the induction of antigen-specific regulatory CD4+ T-cells in the vicinity of the mucosal barrier and close to the inflamed islets.
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PMID:Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4+ regulatory T-cells. 1053 48

We evaluated two bone marrow-derived dendritic cell (DC) populations from NOD mice, the murine model for type 1 human diabetes. DCs derived from GM-CSF [granulocyte/macrophage colony-stimulating factor] + interleukin (IL)-4 cultures expressed high levels of major histocompatibility complex (MHC) class II, CD40, CD80, and CD86 molecules and were efficient stimulators of naive allogeneic T-cells. In contrast, DCs derived from GM-CSF cultures had low levels of MHC class II costimulation/activation molecules, were able to take up mannosylated bovine serum albumin more efficiently than GM + IL-4 DCs, and were poor T-cell stimulators. The two DC populations migrated to the spleen and pancreas after intravenous injection. To determine the ability of the two DC populations to modulate diabetes development, DCs were pulsed with a mixture of three islet antigen-derived peptides or with medium before injection into prediabetic NOD mice. Despite phenotypic and functional differences in vitro, both populations prevented in vivo diabetes development. Pulsing of the DCs with peptide in vitro did not significantly improve the ability of DCs to prevent disease, which suggests that DCs may process and present antigen to T-cells in vivo. In addition, we detected GAD65 peptide-specific IgG1 antibody responses in DC-treated mice. Overall, these results suggest that a Th2 response was generated in DC-treated mice. This response was optimal when using GM + IL-4 DCs, which suggests that the balance between regulatory Th2 and effector Th1 cells may have been altered in these mice.
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PMID:Immunotherapy of NOD mice with bone marrow-derived dendritic cells. 1058 Apr 17

Cyclophosphamide (CY), an alkylating cytostatic drug, is known for its ability to accelerate a number of experimental autoimmune diseases including spontaneous diabetes in NOD mice. The mechanism(s) by which CY renders autoreactive lymphocytes more pathogenic is largely unknown, but it has been postulated that the drug preferentially depletes regulatory (suppressor) T cells. It has been suggested that in cell-mediated autoimmune diseases, Th2-like lymphocytes secreting IL-4 and/or IL-10 provide protection, while Th1-like cells secreting IFN-gamma are pathogenic. In this study, we analysed the effects of CY on autoimmune diabetes and cytokines in two mouse models: the spontaneous diabetes of NOD mice and the diabetes induced in C57BL/KsJ mice by multiple injections of low dose streptozotocin (LD-STZ). In both models, CY induced severe lymphopenia and accelerated the progression to hyperglycemia. This was associated with changes in splenic cytokine patterns indicating a shift towards the IFN-gamma-secreting phenotype. We provide here evidence that IFN-gamma producers are relatively resistant to depletion by CY and that Th0 clones can be shifted towards Th1. However, direct exposure of T lymphocytes to CY may not be a necessary condition for exacerbation of diabetes; NOD.scid mice treated with CY before adoptive transfer of NOD splenocytes developed diabetes at a higher rate than did controls. Thus, the acceleration of diabetes by CY seems to be a complex event, which includes the relatively high resistance of IFN-gamma producers to the drug, their rapid reconstitution, and a Th1 shift of surviving T cell clones.
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PMID:Acceleration of autoimmune diabetes by cyclophosphamide is associated with an enhanced IFN-gamma secretion pathway. 1058 54

Nonobese diabetic mice develop type 1 diabetes in an age-related and gender-dependent manner. Th1 (IFN-gamma and TNF-beta) and Th2 (IL-4 and IL-10) cytokine mRNA expression was analyzed in pancreatic islets isolated from female NOD mice with a high incidence of diabetes and male NOD mice with a low incidence of diabetes. The levels were measured at 5 time points from the onset of insulitis until the development of overt diabetes, using a semiquantitative reverse transcriptase PCR (RT-PCR) assay. IFN-gamma mRNA levels were significantly higher in the islets obtained from females than those of males, from 10 weeks of age. TNF-beta mRNA was expressed in both females and males between 5 and 15 weeks of age. However, TNF-beta mRNA levels were decreased in males at 20 weeks of age. In contrast, IL-4 mRNA levels were lower in females than in males. These results suggest that islet beta-cell destruction and diabetes in female NOD mice correlates with IFN-gamma and TNF-beta production in the islets, and that male NOD mice may be protected from autoimmune beta-cell destruction by down-regulation of these cytokines. Furthermore, our findings also suggest that insulitis and beta-cell destruction are independently regulated: TNF-beta is more important in forming and maintaining the insulitis, while IFN-gamma has a more important role in beta-cell destruction.
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PMID:Analysis of cytokine mRNA expression in pancreatic islets of nonobese diabetic mice. 1068 43

To evaluate the effect of antigen-pulsed dendritic cell (DC) transfer on the development of diabetes, 5-week-old female NOD mice received a single iv injection of splenic syngeneic DC from euglycemic NOD mice pulsed in vitro with human y globulin (HGG). Eleven of 12 mice were protected from the development of diabetes up to the age of 25 weeks, and the insulitis score was significantly reduced. In contrast, NOD mice receiving unpulsed splenic DCs showed histological signs of insulitis and course of type 1 diabetes similar to untreated NOD mice. Treatment with HGG-pulsed DC was associated with profound modifications of cytokine secretory capacities within the islets. Thus, supernatants of islets from these mice contained increased levels of interleukin (IL)-4, IL-10, and, to a lesser extent, interferon-gamma and diminished levels of tumor necrosis factor-a compared with controls. Because exogenous IL-4 and IL-10 exert antidiabetogenic effect in NOD mice and early blockade of endogenous tumor necrosis factor-alpha prevents NOD mouse diabetes, these phenomena may be causally related to the antidiabetogenic effect of HGG-pulsed DC treatment.
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PMID:Prevention of spontaneous autoimmune diabetes in NOD mice by transferring in vitro antigen-pulsed syngeneic dendritic cells. 1074 56

We previously found that ingestion of an extract of Ninjin-to (NJT; Ren-Shen-Tang) suppressed the development of autoimmune diabetes in C57BL/KsJ mice induced by multiple low doses of streptozotocin. To verify this effects on spontaneous autoimmune diabetes, the effects of NJT on NOD mice were investigated in the present study. NJT, provided in drinking water (0.25%, 450 mg/kg/day) from 6 weeks of age, significantly prevented the incidence of spontaneous diabetes in female NOD mice at 30 weeks of age (2/10) compared with that of the controls (7/10), with no effects on body growth or food intake. Even in non-diabetic mice, the blood glucose levels of the NOD controls gradually increased with age, while such increase in NJT-treated mice was significantly suppressed by preventing any deficiency of glucose tolerance. NJT also significantly suppressed the progression of insulitis, which causes insulin deficiency and diabetes. It is well known that NOD mice develop insulitis and diabetes because of their Th1-dominant autoimmune response. IFN-gamma production from splenic T lymphocytes stimulated with anti-CD3 monoclonal antibodies was increased, whereas IL-4 production was decreased in NOD controls compared to age- and sex-matched normal ICR mice. NJT-treatment reduced these deviations of cytokine production in NOD mice. These data all suggest that NJT can prevent spontaneous insulitis and diabetes by the modification of deviated cytokine production in NOD mice.
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PMID:Preventive effect of Ninjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulation, on spontaneous autoimmune diabetes in non-obese diabetic (NOD) mice. 1083 76

Transgenic techniques in inbred mouse strains are powerful tools to investigate the specific roles of genes in biological pathways and disease models. However, there is increasing concern over the influence of a variable genetic background in such experiments. To date there have been few investigations of the immunological differences between inbred mouse strains used in models of autoimmune diseases. Here we phenotyped lymph node cells and T-cell cytokine production in B10.Q (H2q), B10.RIII (H2r), C3H.Q (H2q), C3H. NB (H2p), NOD (H2g7), RIII/SJ (H2r) and DBA/1J (H2q) mice. We found several significant differences. The C3H strains and RIII/SJ lymph node cells had a high ratio of T cells/B cells (> 2 : 1) and a high ratio of CD4/CD8 positive cells (> 3 : 1), these strains are therefore denoted high T cell ratio (HiTR) strains. B10 strains and DBA/1, however, displayed an expansion of gammadeltaT cells after mitogen activation. T cells derived from C3H and DBA/1J strains produced more interleukin (IL)-4 than did T cells from B10 and NOD strains. DBA/1J and B10.Q showed a 10-fold increase in interferon (IFN)-gamma producing cells in the CD4+ T-cell population. Variation in the number of IL-2 and IFN-gamma producing T cells between the B10 major histocompatibility complex (MHC) congenic strains was the only difference possibly controlled by the MHC region. We conclude that non-MHC genes influence the numbers of T cells and B cells in lymph nodes, as well as IFN-gamma, IL-4 and IL-10 production by T cells.
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PMID:Non-major histocompatibility complex dependent variations in lymphocyte activity between inbred mouse strains susceptible to various autoimmune diseases. 1088 80

NKT cells are CD4(+) or CD4(-)CD8(-) CD1d-restricted lymphocytes, characterized by the property to rapidly produce IL-4 and IFN-gamma in response to TCR ligation. This IL-4 burst is lacking in autoimmunity-prone SJL and NOD strains of mice, which suggests an immunoregulatory role for NKT cells. The NKT cell status was thus investigated in the genetically selected high (H) and low (L) antibody-producer mice. The results show that (i) the frequency of cells expressing the NKT cell markers is 3- to 4-fold lower in thymus and spleen from L than H mice, (ii) L mice spleen cells did not produce IL-4 following injection of anti-TCR alpha beta antibody, and (iii) L mice thymus and spleen cells failed to produce IL-4 after in vitro stimulation by anti-TCR alpha beta antibody or alpha-galactosylceramide, a newly described NKT cell ligand. These parameters were investigated in six interval-specific congenic strains raised for the quantitative trait loci which contain the immunomodulatory genes responsible for the high/low antibody production phenotypes. IL-4 production recovery occurred only in the congenic strain in which the H origin chromosome 4 segment was introgressed on the L background. This finding was not due to increased NKT cell frequency but appeared dependent of antigen-presenting cells in co-culture experiments. This result strongly suggests the presence of gene(s) modulating NKT function on chromosome 4, close to several genes predisposing to autoimmunity.
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PMID:NKT lymphocyte ontogeny and function are impaired in low antibody-producer Biozzi mice: gene mapping in the interval-specific congenic strains raised for immunomodulatory genes. 1105 81

Studies in the NOD mouse model suggest that development of diabetes mellitus type I can be prevented and established disease cured by deviation towards a Th2-type response. To obtain insight into whether this approach may be applicable to human disease, we investigated the Th1/Th2 cytokine balance in pancreatic tissue from two patients with diabetes of recent onset (Case 1, accidental death; Case 2, ketoacidosis). Using the polymerase chain reaction to amplify reverse-transcribed cDNA, signals for actin and CD36 confirmed mRNA integrity and the presence of T cells in pancreatic tissue from both patients and from a control. IFN-gamma cDNA was also amplified from all three tissues. However, IL-4 (but not IL-10) cDNA, was amplified from the pancreas of Case 1. Conversely, IL-10 (but not IL-4) cDNA was amplified from the the pancreas of Case 2. The control pancreas yielded specific signals for both IL-4 and IL-10. Our data extend the limited database on Th1 and Th2 cytokine expression in human pancreatic tissue from recently diagnosed diabetics. Moreover, together with previous observations, our findings raise the possibility that the lack of both IL-4 and IL-10 may be associated with the development of IDDM in humans.
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PMID:Presence of interleukin 4 or interleukin 10, but not both cytokines, in pancreatic tissue of two patients with recently diagnosed diabetes mellitus type I. 1109 95


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