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)

Cytokines have been implicated as immunological effector molecules that induce dysfunction and destruction of the pancreatic beta-cell. The mechanisms of cytokine action on the beta-cell are unknown; however, nitric oxide, resulting from cytokine-induced expression of nitric oxide synthase, has been implicated as the cellular effector molecule mediating beta-cell dysfunction. Nitric oxide is a free radical that targets intracellular iron-containing enzymes, which results in the loss of their function. The cytokine IL-1 beta induces the formation of nitric oxide in isolated rat islets and the insulinoma cell line, Rin-m5F. NMMA and NAME, both inhibitors of nitric oxide synthase, completely protect islets from the deleterious effects of IL-1 beta. These inhibitors are competitive in nature and inhibit both the cytokine-inducible and constitutive isoforms of nitric oxide synthase with nearly identical kinetics. This may preclude their use as therapeutic agents because of increases in blood pressure which result from the inhibition of constitutive nitric oxide synthase activity. Aminoguanidine, an inhibitor of nonenzymatic glycosylation of cellular and extracellular constituents associated with diabetic complications, recently has been reported to inhibit nitric oxide synthase. Aminoguanidine is approximately 40-fold more effective in inhibiting the inducible isoform of nitric oxide synthase, suggesting that aminoguanidine or analogues may serve as potential therapeutic agents to block diseases associated with nitric oxide production by the inducible isoform of nitric oxide synthase. In vivo administration of TNF IL-1 has been shown to induce anti-diabetogenic effects in the NOD mouse. This anti-diabetogenic effect of cytokines appears to conflict with evidence suggesting that cytokines mediate beta-cell dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. 137 15

IL-2 receptor positive T-cells from leukocyte-infiltrated pancreatic islets of diabetes prone or acutely diabetic NOD mice were propagated in vitro by culture in interleukin-2 containing medium. Of 13 lines obtained after limiting dilution all were positive for the T-cell marker Thy-1 and for CD8. Considerable heterogeneity in T-cell receptor usage was noted. Seven lines expressed T-cell receptors using V beta 8, one line was positive for V beta 5 and two lines expressed a non V beta 5, non V beta 8 receptor. Finally, two further lines lacked T-cell receptors. None of the cell lines were cytotoxic to islet cells although 10 lines showed non MHC restricted lysis of one or more tumour cells including rat insulinoma cells. We conclude that IL-2 receptor positive CD8+ T-lymphocytes from NOD islets are heterogenous with respect to V beta T-cell receptor usage. The majority of these cells are not cytotoxic to islet cells.
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PMID:Analysis of IL-2 receptor positive CD8(+)-T-lymphocytes grown from islets of NOD mice. 168 10

Monoclonal antibody (Mab) 1.93B7 was obtained by fusion of spleen cells from a diabetic NOD mouse with P3X63Ag8.653 myeloma cells and screening for complement mediated lysis of rat insulinoma (RIN) cells. Immunofluorescence studies revealed that this Mab binds to RIN cells but not to the rat pituitary tumour line GH3. The binding of Mab 1.93B7 to RIN cells was abolished by trypsin but not by neuraminidase treatment of the cells, suggesting that the antigen recognized is a protein. Mab 1.93B7 bound to approximately 30% of mouse (BALB/c) and rat islet cells which had been subjected to trypsin digestion and incubated as a single cell suspension for 12h to allow reexpression of trypsin sensitive antigens. Since Mab 1.93B7 is potentially pathogenic, as suggested by its reactivity to primary islet cells and its complement fixing capacity, we injected it into BALB/c and NOD mice. Cytotoxic activity against RIN cells was detected in the serum of the animals injected with Mab 1.93B7, but the Mab did not exert a diabetogenic action and failed to reverse diabetes when administered at onset in NOD mice. No modification of the course of spleen cell mediated transfer of diabetes in NOD mice was observed when the Mab was administered from the time of spleen cell inoculation to the appearance of glycosuria. The implications of the lack of an effect in vivo of Mab 1.93B7 under the conditions employed are discussed.
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PMID:A cytotoxic monoclonal islet cell surface antibody from the NOD mouse. 269 57

The authors wanted to test the long-term effectiveness of immunoisolation in the NOD mouse, an adequate model of Type I diabetes. Recipients were diabetic female NOD mice with sustained plasma glucose levels above 400 mg/100 ml. They were grafted intraperitoneally with permselective hollow fibers seeded with human insulinoma (n = 6), rodent insulinoma (n = 6), or human islets (n = 6). Controls were 15 nontreated diabetic females and 10 nondiabetic male NOD mice implanted with nonseeded macrocapsules. Electron microscopy (rectangular crystalline nucleoids characteristic of B-cells), in vitro release of insulin (during abrupt changes in glucose concentration from 40 to 400 mg/dl and return, M +/- SD insulin levels were 122 +/- 5 uu/ml and 315 +/- 17 at low and high glucose), evidence of binding hormone receptors (VIP and GIP, the binding sites being coupled with adenylyl cyclase stimulation) were used to assess the quality of the transplant. Survival was always prolonged in grafted animals. Taking complete and long-term (less than 3 months) correction of hyperglycemia as the criterion, the success rate was about 50% as observed in streptozotocin rats. Splenocytes isolated from cured and not cured recipients and injected into irradiated nondiabetic male NOD mice were always able to transfer the disease. Our bioartificial pancreas is efficient in preventing the recurrence of the disease in autoimmune diabetes.
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PMID:Bioartificial pancreas in autoimmune nonobese diabetic mice. 284 60

T cells reacting with pancreatic islet beta cell proteins play a pivotal role in the pathogenesis of type 1 diabetes in experimental animal models and man, although the islet cell autoantigens against which these T cells are directed remain to be characterized. We have previously shown the presence of disease-related antigens residing in the transplantable RIN insulinoma membranes which are recognized by T cells from diabetic NOD mice. We now report on the establishment of CD4+, T cell lines reacting with insulinoma membranes from six newly diagnosed type 1 diabetic patients. Detailed examination of T cell lines from two patients revealed that both the lines continued to react with normal islet cell proteins and, interestingly, were also stimulated by antigens present in brain microsomes. The two T cell lines showed reactivity with different molecular weight proteins of the insulinoma membranes and both the lines were histocompatibility-linked antigen (HLA)-DR restricted. Although the insulinoma membrane preparation is known to contain glutamic acid decarboxylase (GAD), none of the six T cell lines proliferates in response to purified GAD. These T cell lines will be valuable in characterizing novel islet beta cell antigens which are likely to be implicated in type 1 diabetes.
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PMID:HLA-DR-restricted T cell lines from newly diagnosed type 1 diabetic patients specific for insulinoma and normal islet beta cell proteins: lack of reactivity to glutamic acid decarboxylase. 755 82

CD4+ T cell lines were generated from the spleens of diabetic NOD mice against crude membrane preparations derived from a rat insulinoma. Adoptive transfer of these lines into neonatal mice confirms that overt diabetes is induced by gamma-IFN-secreting Th1 cells, whereas transfer of IL-4-secreting Th2 cells resulted in a nondestructive peri-islet insulitis. Analysis of the antigens recognized by individual T cell clones from the Th1 line included reactivity against an insulinoma membrane fraction enriched in proteins of approximately 38 kD. Immune responses to the same antigen preparation have been associated with T cell clones derived from human insulin-dependent diabetes mellitus. The specificity of Th2 cells includes reactivity to a fraction enriched in proteins of 30 kD. The data suggest that in insulin-dependent diabetes mellitus the balance between beta cell destruction, associated with intra-islet infiltration, and nondestructive (potential protective) peri-islet insulitis may depend on both the antigens recognized, and the prevailing cytokine environment.
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PMID:In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice. 776 40

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) by being involved in the extravasation of lymphocytes from the circulation into the inflamed pancreas. However, the mechanism of beta-cell destruction by which expression of ICAM-1 on beta-cells may facilitate adhesion of effector cells still remains to be elucidated. Several lines of evidence suggest that this adhesion molecule is involved in the destruction of pancreatic beta-cells by killer lymphocytes in the NOD mouse, which shows an autoimmune diabetic syndrome similar to that of human IDDM. Immunohistochemical study under light microscopy demonstrated that all of the mononuclear cells infiltrating the islets strongly expressed ICAM-1 and leukocyte function-associated antigen 1 (LFA-1), a counterreceptor of ICAM-1, whereas ICAM-1 expression on islet cells was not apparent. However, immunohistochemical staining under electron microscopy revealed that islet beta-cells adjacent to infiltrating lymphocytes were clearly stained by an anti-ICAM-1 monoclonal antibody (mAb). Flow cytometric analysis showed that the ICAM-1 expression on NOD islet cells and NOD-derived insulinoma cells (MIN6N8a) was inducible by interferon (IFN)-gamma or tumor necrosis factor-alpha. These cytokines had an additive effect on the ICAM-1 induction. Susceptibility of MIN6N8a cells to lysis by a NOD islet-derived CD8+ cytotoxic T-cell clone was greatly enhanced by IFN-gamma pretreatment, and this enhancement was abolished by anti-ICAM-1 and anti-LFA-1 mAbs. When both mAbs were administered into NOD mice with spontaneous or adoptively transferred diabetes, the development of diabetes was significantly prevented.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of intercellular adhesion molecule 1 on pancreatic beta-cells accelerates beta-cell destruction by cytotoxic T-cells in murine autoimmune diabetes. 778 42

We established a T-cell line and 20 CD4+ T-cell clones from the peripheral blood lymphocytes of a type I diabetic patient using a membrane preparation of a rat insulinoma cell line (beta membrane antigen [BMA]) as a source of antigen. The T-cell line and three selected clones proliferated specifically to stimulation with BMA and to membranes prepared from human islets, rat pancreas, and NOD pancreas, but not to control antigens. Proliferation-inhibition studies using human leukocyte antigen (HLA)-specific monoclonal antibodies revealed HLA-DQw1-restricted recognition of BMA. An analysis of the T-cell receptor (TCR) repertoire of the T-cell line after 8 and 40 days of culture showed a prominent usage of the V alpha 1 and V alpha 12 gene families. Although sequencing of the TCR V alpha and V beta chains of the three clones demonstrated that each used different V alpha and V beta gene segments, structural similarities were found in complementary-determining region 3 (CDR3), the region that is postulated to interact with the peptide component of the TCR ligand. When we compared these TCR sequences with published sequences of disease-inducing T-cells of NOD mice, highly related TCR V beta families were detected. Furthermore, stretches of identical amino acids within the CDR3 region were found between two pairs of human and mouse T-cells. If one considers the species differences in TCR genes and sequence differences in the restriction elements for these cells (HLA-DQ vs. H-2 I-A nod), these sequence similarities are striking and may be useful for pinpointing T-cells of primary importance in the development of disease.
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PMID:HLA-DQ-restricted, islet-specific T-cell clones of a type I diabetic patient. T-cell receptor sequence similarities to insulitis-inducing T-cells of nonobese diabetic mice. 792 6

The cytokines, interleukin 1, tumour necrosis factor, and interferon gamma are cytotoxic to islet beta cells, however, their mechanisms of beta-cell killing are not fully characterized. Since DNA damage is a mechanism of cytokine-induced cell death in some cell types, we sought evidence for cytotoxic effects of cytokines at a nuclear level in islet beta cells by measuring DNA fragmentation in rat islets and islet beta-cell lines. The individual cytokines, interleukin 1 (10 U/ml), tumour recrosis factor (10(3) U/ml) and interferon gamma (10(3) U/ml) inhibited insulin release from rat islets, but did not cause DNA fragmentation or destroy islet cells; by contrast, combination of the three cytokines induced DNA fragmentation and islet-cell death. Cytokine-induced DNA fragmentation preceded cell lysis in islet beta-cell lines (RINm5F, rat insulinoma cells; and NIT-1, NOD/Lt mouse transgenic beta cells), whereas in non-islet cell lines (GH-3, rat pituitary; and PC-12, rat adrenal) the cytokines induced cell lysis and no or late DNA fragmentation. Nicotinamide prevented both DNA fragmentation and destruction of RINm5F islet cells by the cytokines. These findings identify DNA as an early target of cytokine action in islet beta cells, and implicate DNA fragmentation as a mechanism of cytokine-induced beta-cell destruction.
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PMID:DNA fragmentation is an early event in cytokine-induced islet beta-cell destruction. 798 73

In as much as Type 1 diabetes is a T-cell mediated autoimmune disease, the valuation of cell mediated immunity would be useful for the study of its prodromal period. We have previously reported an increased binding of T splenocytes with alpha beta receptors from NOD mice to xenogeneic rat insulinoma (RIN) cells. Our present aim was to study this phenomenon in a large number of NOD mice (n = 243) of both sexes and at different ages, together with insulitis, islet cell antibodies (ICA), and insulin autoantibodies (IAA), in order to assess their respective timing of onset, prevalence, and changes during the natural history of the disease. The number of RIN-adherent splenocytes was higher (p < 0.001) in NOD mice than in several control strains and than in F1 mice (NOD x BALB/c) which did not develop diabetes or insulitis. The increased number of RIN-adherent splenocytes in NOD mice is called "diabetic rosettes", and positivity is defined as a value of RIN-adherent splenocytes higher than the mean+2SD of control mice. The prevalence of "diabetic rosettes" in NOD mice was 56%. Females displayed higher numbers of RIN-adherent splenocytes and a higher prevalence of "diabetic rosettes" (70% vs 45%) than male NOD mice (p < 0.03). Using haematoxylin-eosin staining, marked insulitis became detectable after 30 days of age, with a prevalence reaching 100% after 120 days and a severity which was higher in female than in male mice (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Splenocytes from non-obese-diabetic mice binding to xenogeneic beta-cells in vitro: an early marker of cell-mediated immunity. 802 8


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