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)

We have recently reported that systemic and chronic administration of recombinant tumour necrosis factor alpha (TNF-alpha), as well as streptococcal preparation (OK-432), inhibits development of insulin-dependent diabetes mellitus (IDDM) in NOD mice and BB rats, models of IDDM. In this study we examined whether serum containing endogenous TNF induced by OK-432 injection could inhibit IDDM in NOD mice. Treatment twice a week from 4 weeks of age with OK-432-injected mouse serum, which contained endogenous TNF (75U), but not IL-1, IL-2 and interferon-gamma (IFN-gamma) activity, reduced the intensity of insulitis and significantly inhibited the cumulative incidence of diabetes by 28 weeks of age in NOD mice, as compared with the incidence in non-treated mice (P less than 0.01) and in mice treated with control serum (P less than 0.02). This inhibitory effect of the serum was diminished, although not significantly, by neutralization of serum TNF activity with anti-mouse TNF antibody. In the mice treated with the serum from OK-432-injected mice, Thy-1.2+ or CD8+ spleen cells decreased (P less than 0.01) and surface-Ig+ (S-Ig+) cells increased (P less than 0.05), whereas the proliferative response of spleen cells to concanavalin A (P less than 0.01) and lipopolysaccharide (P less than 0.05) increased. The results indicate that the inhibition by OK-432 treatment of IDDM in NOD mice was partially mediated by serum factors including endogenous TNF.
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PMID:Inhibition of autoimmune diabetes in NOD mice with serum from streptococcal preparation (OK-432)-injected mice. 174 49

Normal mouse islet cells express low levels of MHC class I molecules and undetectable or extremely low levels of MHC class II molecules. Class I expression was dose-dependently augmented by incubation with interferon-gamma (IFN-gamma) or tumor necrosis factor (TNF). Although neither IFN-gamma nor TNF alone induce class II molecules on islet cells, synergistic interaction of IFN-gamma (200 U/ml) and TNF (200 U/ml) may induce class II expression on approximately 50% of islet cells. Niacinamide and 3-aminobenzamide, both inhibitors of ADP ribosylation and scavengers of free radicals, attenuated the class II expression induced by IFN-gamma and TNF. Twenty millimolar niacinamide and 10 mM 3-aminobenzamide reduced the rates of class II antigen-positive cells to mean +/- SD 3.6 +/- 0.3 and 6.1 +/- 1.9%, respectively. The agents did not affect the cytokine-induced augmentation of class I antigens. The inhibition of class II molecule expression may at least partly account for the preventive effect of niacinamide on autoimmune-associated beta-cell damage in NOD mice.
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PMID:Inhibition of cytokine-induced MHC class II but not class I molecule expression on mouse islet cells by niacinamide and 3-aminobenzamide. 214 88

Polyinosinic:polycytidylic acid (poly I:C) is a synthetic double-stranded polyribonucleotide that elicits immune responses analogous to those observed during viral infection. It is also known to modulate the expression of certain autoimmune disorders including diabetes mellitus in the BB rat and NOD mouse. The mechanism underlying these immunomodulatory effects is not known, but it could involve activation of vascular endothelium. We now report that parenteral poly I:C induces rat pancreatic endothelium to hyperexpress intercellular adhesion molecule 1 (CD54). This is accompanied by a perivascular recruitment of mononuclear cells to the exocrine pancreas. Corollary in vitro studies demonstrated that poly I:C is a potent activator of both rat and human endothelial cells in culture. It upregulates endothelial expression of several leukocyte adhesion molecules, stimulates the release of interleukin-6 and interleukin-8, and antagonizes interferon-gamma induction of major histocompatibility complex class II expression. We conclude that poly I:C activates endothelial cells to express surface molecules and cytokines in a pattern classically associated with leukocyte recruitment. These effects may in part contribute to the immunomodulatory effects of poly I:C in animal models of autoimmunity.
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PMID:Polyinosinic:polycytidylic acid is a potent activator of endothelial cells. 751 92

It has been reported that the level of Tap-1 (transporter associated with antigen processing) mRNA and the expression of class I on splenocytes are low in NOD mice. Class I expression at 37 degrees C depends on an adequate supply of peptides, so a decrease in Tap could lead to lower class I levels. Since hypoexpression of class I correlated uniformly with the development of diabetes, it has also been suggested that Tap-1nod is diabetogenic. However, others report normal Tap-1 and class I levels in NOD mice. We examined Tap-1 and Tap-2 mRNA levels in NOD/Smrf mice using a reverse transcriptase-polymerase chain reaction method that detects > or = 25% changes in mRNA. We also assessed class I expression with three monoclonal antibodies. No difference in Tap-1 or Tap-2 mRNA levels for females of different ages or between diabetic and nondiabetic animals was observed. Tap-1 mRNA levels were identical between NOD/Smrf and BALB/cJ mice. Kd expression was significantly lower on NOD lymphocytes than in BALB/cJ cells, but the difference was due to the smaller size of the NOD splenic lymphocyte. When cells of the same size were analyzed, no difference in class I levels was observed. Class I levels were also identical in diabetic and age-matched nondiabetic NOD and BALB/c females. Both NOD Tap-1 mRNA and class I were increased by interferon-gamma. We find no evidence for impaired NOD Tap gene activity or class I expression, as previously reported for this strain.
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PMID:Levels of Tap-1 and Tap-2 mRNA and expression of Kd and Db on splenic lymphocytes are normal in NOD mice. 772 18

The autoimmune response that leads to destruction of pancreatic islet beta-cells and insulin-dependent diabetes mellitus (IDDM) has a genetic basis; however, environmental factors can exert profound modulating effects on the genetic predisposition to this autoimmune response. Recent studies in animal models for human IDDM, the genetically diabetes-prone NOD mouse and BB rat, have revealed that microbial agents--including certain viruses and extracts of bacteria, fungi, and mycobacteria--often have a protective action against diabetes development. Many of these microbial preparations are immune adjuvants, which are agents that stimulate the immune system. The protective effects of these agents against diabetes appear to involve perturbations in the production of cytokines, which are polypeptides produced by and acting on cells of the immune system. Thus, recent studies in NOD mice suggest that the islet beta-cell-directed autoimmune response may be mediated by a T-helper 1 (Th1) subset of T-cells producing the cytokines interleukin-2 (IL-2) and interferon-gamma. These studies also suggest that the diabetes-protective effects of administering microbial agents, adjuvants, and a beta-cell autoantigen (GAD65 [glutamic acid decarboxylase]) may result from activation of a Th2 subset of T-cells that produce the cytokines IL-4 and IL-10 and consequently downregulate the Th1-cell-mediated autoimmune response. The clinical implication of these findings is that the autoimmune response leading to islet beta-cell destruction and IDDM may be amenable to prevention or suppression by therapeutic interventions aimed at stimulating the host's own immunoregulatory mechanisms.
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PMID:Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation? 778 55

Ten out of 20 (50%) 17-week-old female NOD/WEHI mice developed an acute form of autoimmune diabetes when injected with two large doses of cyclophosphamide (CY), given at 14-day intervals. If these mice were treated under a prophylactic regimen with 2.5 mg/kg body weight per day of the novel immunosuppressant deoxyspergualin (DSP) the onset of diabetes was completely prevented. Moreover, DSP-treated animals showed reduced signs of pancreatic insulitis, had lower percentages of splenic lymphoid cells (SLC) expressing IL-2 receptors and Ly-6C antigens on their surfaces, and these cells released lower amounts of interferon-gamma (IFN) when stimulated in vitro. These data, providing evidence for the capacity of DSP to protect NOD/WEHI mice from experimental autoimmune diabetes and to modulate histo-immunological pathogenic pathways, indicate DSP as a drug of potential interest in the treatment of human insulin-dependent diabetes mellitus.
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PMID:Prevention of cyclophosphamide-induced diabetes in the NOD/WEHI mouse with deoxyspergualin. 842 90

Transfer of an interleukin 2/interferon-gamma-secreting islet-specific CD4+ T-cell clone, BDC-6.9, in the immunodeficient NOD-scid mouse induces destruction of pancreatic beta-cells without help from host B-cells, CD4+ T-cells, or CD8+ T-cells. However, a second islet-specific T-cell clone, BDC-2.5, showing the same cytokine profile and T-cell receptor Vbeta expression as BDC-6.9 was not capable of inducing diabetes or insulitis in NOD-scid mice. Even though BDC-2.5 by itself readily induces diabetes in young unmanipulated NOD mice, cotransfer of CD8-enriched T-cells was required to induce disease in NOD-scid mice. Immunohistochemical staining of pancreatic lesions in young NOD mice receiving either BDC-2.5 or BDC-6.9 showed the presence of CD4+, CD8+, Vbeta4+, and MAC-1+ cells within the infiltrate, similar to infiltrates in lesions of spontaneously diabetic female NOD mice. In contrast, NOD- scid mice that received BDC-6.9 showed only the presence of CD4+Vb4+ T-cells and a large population of MAC-1+ cells in islet lesions. NOD-scid recipients of cotransferred BDC- 2.5/CD8+ splenic T-cells showed a small population of CD4+ T-cells and a larger population of CD8+ T-cells within the infiltrated islets, whereas no infiltrate was detectable in recipients of CD8+ splenocytes or BDC-2.5 alone. Our results suggest that at least two types of islet-specific CD4+ T-cell clones play a role in diabetes pathogenesis.
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PMID:Transfer of diabetes in the NOD-scid mouse by CD4 T-cell clones. Differential requirement for CD8 T-cells. 859 38

The NOD mouse is an animal model of IDDM that shows many of the characteristics of human IDDM. It has been proposed that beta-cell destruction in IDDM progresses over time in a linear manner. Recently, we and others have demonstrated that T helper type 1 (Th1) cells have pathogenic roles in the NOD model and proposed that cytokine balances change as the disease progresses. However, it has not been demonstrated how or when the cytokine balances change or how the beta-cell destruction progresses. We have recently demonstrated that the cytokine profiles of CD45RB(low) CD4+ cells correlate either with their pathogenic or with their protective roles in the NOD mouse. To further analyze this apparent correlation between the shift in cytokine level and IDDM, we examined the anti-CD3-induced cytokine profiles of this subset from NOD mice of various ages compared with that from age-matched I-Ak transgenic NOD and BALB/c mice as controls. A significantly higher ratio of anti-CD3-induced interferon-gamma/interleukin-4 was found in diabetic NOD mice (P < 0.0001) but not in age-matched nondiabetic NOD mice. This cytokine ratio did not change significantly until the onset of diabetes in NOD mice. Based upon these results, we propose that IDDM in the NOD mouse progresses as a predominant inflammatory beta-cell dysfunction without actual beta-cell destruction until late in the disease process. This supports the possibility that late-stage immunotherapy may preserve islet beta-cell mass.
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PMID:Beta-cell destruction may be a late consequence of the autoimmune process in nonobese diabetic mice. 869 Jan 53

NOD mice constitute a model for studying the prevention of human autoimmune type 1 diabetes. Glutamic acid decarboxylase (GAD) could be a key antigen involved in this disease, and GAD65 peptide 524-543 has been implicated in early T cell response in young NOD mice. We performed two i.p. injections of GAD peptide 524-543 (100 micrograms at each injection), together with Freund's incomplete adjuvant (FIA), into female NOD mice at 30 and 45 days old. Diabetes was accelerated 2 weeks later by a single injection of cyclophosphamide (CY), which acts against suppressive mechanisms. Treatment with GAD 524-543 peptide delayed the onset of diabetes and reduced its incidence (28% versus 60%; P < 0.001) compared with control mice injected with FIA alone, or GAD peptide 534-553, or an irrelevant peptide. In the same group, the severity of lymphocytic inflammation of pancreatic islets was reduced (P < 0.03). Up to 3 months after peptide injections, a strong splenocytic proliferative response occurred in immunized NOD mice against the immunizing peptide alone (but not against a panel of seven other GAD65-derived peptides). After peptide challenge of splenocytes in vitro, protection against CY-accelerated diabetes was associated with higher peptide-specific production of T helper type 2 (Th2)-associated interleukins 4 and 10, whereas Th1-associated interferon-gamma and IL-2 were proportionally less represented. During contransfer, T splenocytes from GAD 524-543-immunized mice were able to reduce the capacity of T cells from diabetic donors to transfer the disease adoptively (P < 0.01), demonstrating the generation of cellular mechanisms that actively suppress the disease. It is concluded that immunization of NOD mice with GAD65 peptide 524-543 can counteract CY-accelerated diabetes, possibly through active cellular suppression linked to a shift of Th1/Th2 balance toward the production of Th2 cytokines such as IL-4 and IL-10. This study provides additional support for the notion that GAD, and more precisely its epitope 524-543, could be one of the key targets for the pathogenesis of type 1 diabetes in NOD mice, as well as for the efficacy of disease-specific peptide therapy in type 1 diabetes.
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PMID:Immunization of non-obese diabetic (NOD) mice with glutamic acid decarboxylase-derived peptide 524-543 reduces cyclophosphamide-accelerated diabetes. 870 42

Cytokines are thought to contribute to the induction of pancreatic beta-cell destruction in insulin-dependent diabetes mellitus. The molecular mechanisms that underlie beta-cell death were investigated by studying cytokine-induced cell death in beta-cell lines. A combination of three cytokines (interleukin-1 beta, tumour necrosis factor-alpha, and interferon-gamma) induced apoptotic cell death in the mouse pancreatic beta-cell line beta TC1, as judged from the appearance of cells with hypodiploid nuclei and oligonucleosomal DNA fragmentation. The same treatment also induced apoptosis in the mouse pancreatic alpha-cell line alpha TC1 and the NOD/Lt mouse beta-cell line NIT-1, although to a lesser extent than in beta TC1 cells. The abundance of endogenous Bcl-2 in beta TC1 cells was lower than that in the other two cell lines. Overexpression of human Bcl-2 in beta TC1 cells partially protected them from cytokine-induced cell death. These results suggest that apoptosis may be responsible, at least in part, for cytokine-induced beta-cell destruction and that Bcl-2 prevents apoptosis in pancreatic islet cells.
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PMID:Cytokine-induced apoptotic cell death in a mouse pancreatic beta-cell line: inhibition by Bcl-2. 873 12


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