Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) is characterized by infiltration of T-lymphocytes in the islets of Langerhans. Antigens are presented to Th-lymphocytes which can be divided into Th1- and Th2-lymphocytes, producing interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) respectively. The aim of our study was to determine the messenger-RNA (mRNA) for these cytokines by RT-PCR in antigen-stimulated lymphocytes from children with newly diagnosed IDDM. The expression of mRNA for IL-4, and to a lesser degree IFN-gamma, is increased in lymphocytes stimulated with tetanus toxoid (TT). Loss of activity after freezing and thawing could be compensated for, by increased amplification, while the use of EDTA or sodium heparin in the blood samples did not influence the results. In a pilot application, the lymphocytes from children with newly diagnosed IDDM were stimulated with a peptide of glutamic acid decarboxylase (GAD) (a.a. 247-279) known to have a similar aminoacid sequence as the Coxsackie B virus (a.a. 32-47). Increased IFN-gamma mRNA could be seen in two out of four children, whereas IL-4 showed a less pronounced mRNA expression. No increased mRNA expression for IFN-gamma and IL-4 could be seen in healthy HLA-matched controls. Further studies are needed to confirm whether increased IFN-gamma mRNA in Th1-like lymphocytes stimulated with this specific GAD-peptide play a role in the cell-mediated immune response seen in children early after the onset of IDDM.
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PMID:Determination of mRNA expression for IFN-gamma and IL-4 in lymphocytes from children with IDDM by RT-PCR technique. 969 87

Multiple sclerosis is an immune-mediated demyelinating disease of unknown etiology that presents with either a chronic-progressive or relapsing-remitting clinical course. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) and relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in the SJL/J mouse are both relevant murine CD4+ T cell-mediated demyelinating models that recapitulate the multiple sclerosis disease phenotypes. To determine the cellular and molecular basis for these observed differences in clinical course, we quantitatively analyzed the temporal expression of pro- and antiinflammatory cytokine mRNA expression in the central nervous system (CNS) and the phenotype of the inflammatory mononuclear infiltrates. TMEV-infected SJL/J mice expressed IFN-gamma, TNF-alpha, IL-10, and IL-4 mRNA during the preclinical phase, and their levels continued to increase throughout the duration of the chronic-progressive disease course. These data correlated with the continued presence of both CD4+ T cells and F4/80+ macrophages within the CNS infiltrates. In contrast, SJL/J mice with PLP(139-151)-induced R-EAE displayed a biphasic pattern of CNS expression for the proinflammatory cytokines, IFN-gamma and TNF-alpha, with expression peaking at the height of the acute phase and relapse(s). This pattern correlated with dynamic changes in the CD4+ T cell and F4/80+ macrophage populations during relapsing-remitting disease progression. Interestingly, IL-4 message was undetectable until disease remission(s), demonstrating its potential role in the intrinsic regulation of ongoing disease, whereas IL-10 was continuously expressed, arguing against a regulatory role in either disease. These data suggest that the kinetics of cytokine expression together with the nature of the persistent inflammatory infiltrates are major contributors to the differences in clinical course between TMEV-IDD and R-EAE.
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PMID:Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. 978 Feb 23

We examined the role of IL-12, a cytokine critical to the evolution of cellular responses, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment with mAbs to IL-12, especially during the effector phase, resulted in significant suppression of the development of this disease both clinically and histologically. In mice treated with these mAbs, the production of inflammatory and Th1-derived cytokines such as TNF-alpha and IFN-gamma in the spleen cells was decreased, and that of Th2-derived cytokines such as IL-4 and IL-10 was increased. The delayed type hypersensitivity and T cell proliferative response specific for TMEV were decreased by this treatment. These data suggest that IL-12 is critically involved in the pathogenesis of TMEV-IDD and that Abs to IL-12 could be a novel therapeutic approach in the clinical treatment of demyelinating diseases such as human multiple sclerosis.
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PMID:Suppressive effect on Theiler's murine encephalomyelitis virus-induced demyelinating disease by the administration of anti-IL-12 antibody. 982 May 36

At the clinical onset of insulin-dependent diabetes mellitus (type 1 diabetes), inflammation within the pancreatic islets of Langerhans causes insulitis. CD4+ or Th-lymphocytes will be activated after stimulation resulting in interferon-gamma (IFN-gamma) production by Th1-like lymphocytes and/or interleukin-4 (IL-4) secretion from Th2-like lymphocytes. The antigens responsible for this activation are unknown, but studies have suggested glutamic acid decarboxylase (GAD) to be a possible candidate. One peptide from this enzyme (amino acid 247-279) with a similar amino acid sequence to coxsackie B virus may cause lymphocyte proliferation in diabetic patients. In this study we have shown that this peptide activates Th1-like lymphocytes which produce increased amounts of IFN-gamma mRNA, but seldom mRNA for IL-4. Lymphocytes from healthy HLA-matched controls (DR3/4) did not respond with an upregulated mRNA expression for these cytokines when stimulated by the GAD-peptide (P<0.05). A low or absent expression of IFN-gamma mRNA was significantly correlated to a high fasting C-peptide at 3 months' duration (P<0.05). In conclusion, we suggest that GAD65 is involved in the development of type 1 diabetes and that the Th1-response may play a role in the destruction of beta cells.
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PMID:Peptide from glutamic acid decarboxylase similar to coxsackie B virus stimulates IFN-gamma mRNA expression in Th1-like lymphocytes from children with recent-onset insulin-dependent diabetes mellitus. 984 Apr 49

Recent evidence suggests that autoimmune animal diabetes is associated with an imbalance between the Th1 and Th2 arms of the cellular immune system. However, limited data is available regarding the Th1/Th2 imbalance in human Insulin dependent diabetes mellitus (IDDM) patients. Therefore, we examined the peak levels, secretory pattern and total cytokine production (calculated as the area under the curve, AUC) of the Th1 cytokines, IL-2 and IFN-gamma, and Th2 cytokines, IL-4 and IL-10, from stimulated peripheral blood mononuclear cells, from 17 IDDM patients and 24 normal controls. In contrast to controls, diabetic patients were characterized by an early, uniformly low secretion of Th2 cytokines, followed by a late increased secretion of Th1 cytokines. This resulted in significant differences in secretory patterns of IFN-gammaIL-2, IL-4 and IL-10 between the two groups; P<0.001, P<0.005, P<0.005 and P<0.001, respectively. No correlation was found in the diabetic patients between any profiles of the cytokines and their various clinical parameters, including age, gender, disease duration, insulin requirements or glycated hemoglobin levels. In conclusion, our data provides the first comprehensive evidence for an independent and persistent impairment of both Th1 and Th2 cytokine secretory patterns in IDDM patients.
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PMID:Decreased secretion of Th2 cytokines precedes Up-regulated and delayed secretion of Th1 cytokines in activated peripheral blood mononuclear cells from patients with insulin-dependent diabetes mellitus. 987 85

A mechanism of autoimmune destruction of islet beta-cells in type 1 diabetes has been proposed to be the binding of Fas ligand (FasL) on T-cells to Fas receptors on beta-cells. We investigated this proposal by examining the expression of FasL and Fas on islet-infiltrating T-cells and beta-cells in relation to beta-cell destruction in a syngeneic islet transplant model in NOD mice. Diabetic NOD mice were transplanted with syngeneic islets and injected with complete Freund's adjuvant, which prevented diabetes recurrence (nondestructive insulitis), and with phosphate-buffered saline, which did not (beta-cell destructive insulitis). Two-color immunohistochemical assays revealed that FasL was expressed on CD4+ T-cells, CD8+ T-cells, and beta-cells in islet grafts from both diabetic and normoglycemic mice, and the percentage of each type of cell that expressed FasL was greater in islet grafts from normoglycemic compared with diabetic mice. In contrast, Fas was expressed on CD4+ T-cells, CD8+ T-cells, and beta-cells in islet grafts from diabetic mice, but it was nearly or totally absent on these cells in islet grafts from normoglycemic mice. Similarly, polymerase chain reaction analysis of islet grafts revealed that Fas mRNA expression was significantly lower in islet grafts from normoglycemic compared with diabetic mice. Also, mRNA levels of interleukin (IL)-1alpha, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were significantly lower in islet grafts from normoglycemic mice. Finally, Fas was induced on NOD islet cells by incubation with IL-1beta, IFN-gamma, and the combination of IL-1beta, TNF-alpha, and IFN-gamma. These findings support the concept that cytokine-induced Fas receptor expression on islet beta-cells is a mechanism for their destruction by FasL-expressing CD4+ and CD8+ T-cells and, possibly, by FasL-expressing beta-cells themselves.
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PMID:Beta-cell destruction in NOD mice correlates with Fas (CD95) expression on beta-cells and proinflammatory cytokine expression in islets. 989 18

Insulin-dependent diabetes mellitus (IDDM) is not a disease of unbridled destruction. The autoimmune attack on pancreatic beta cells has two distinct stages - insulitis and diabetes - and progression of the former to the latter appears to be highly regulated. Identifying the factors controlling this transition has been difficult because it is a complex process that occurs non-universally and asynchronously. We have overcome these difficulties by coupling a simplified TCR transgenic (tg) model of IDDM and the immunosuppressive drug cyclophosphamide (CY). Young BDC2.5 TCR tg mice show insulitis but not diabetes; CY treatment provoked diabetes in 100% of animals with rapid, highly reproducible kinetics. This allowed a detailed temporal analysis of changes in cellular organization and cytokine gene expression within the lesion. The monokines IL-18, IL-12 and TNF-alpha were pivotal, their induction occurring almost immediately and their coordinate action being required for the onset of aggression. Other cytokines with direct toxicity for beta cells, including IL-1 -beta, IL-6 and IFN-gamma, were subsequently induced; in contrast, there was no cellular or molecular evidence of cell contact-mediated mechanisms of beta cell death.
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PMID:Cellular and molecular changes accompanying the progression from insulitis to diabetes. 993 6

Pancreases of untreated and nicotinamide (NIC)-treated pre-diabetic (10-week-old) and overtly diabetic (25-week-old) female NOD (non-obese diabetic) mice and of NON (non-obese non-diabetic) control mice were studied, with the following results. (1) Islets and ducts of overtly diabetic untreated NOD mice (25-week-old) were found to express low levels of MHC class I and II molecules, like NON controls, and high levels of adhesive molecules. (2) NIC was able to slightly affect glycaemia and insulitis, slowing down diabetes progression. Moreover it significantly decreased MHC class II expression (but not class I) in vivo by week 10, and significantly enhanced intercellular adhesion molecule-1 (ICAM-1) expression, mainly by week 25, within the pancreas, where 5-bromo-2'-deoxyuridine positive nuclei and insulin positive cells were present, demonstrating that a stimulation of endocrine cell proliferation occurs. (3) In addition, NIC partly counteracted the fall of superoxide dismutase levels, observed in untreated diabetic NOD animals. (4) In vitro studies demonstrated that NIC: (i) was able to significantly reduce nitrite accumulation and to increase NAD+NADH content significantly, and (ii) was able to increase the levels of interleukin-4, a T helper 2 lymphocyte (Th2) protective cytokine, and of interferon-alpha (IFN-alpha), which is known to be able to induce MHC class I and ICAM-1 but not MHC class II expression, as well as IFN-gamma, which is also known to be able to induce MHC class I and ICAM-1 expression. The latter, although known to be a proinflammatory Th1 cytokine, has also recently been found to exert an anti-diabetogenic role. This study therefore clearly shows that adhesive mechanisms are ongoing during the later periods of diabetes in pancreatic ducts of NOD mice, and suggests they may be involved in a persistence of the immune mechanisms of recognition, adhesion and cytolysis and/or endocrine regeneration or differentiation processes, as both NIC-increased ICAM-1 expression and 5-bromo-2'-deoxyuridine positivity imply. The effects of NIC on MHC class II (i.e. a reduction) but not class I, and, mainly, on ICAM-1 expression (i.e. an increase), together with the increase in Th2 protective cytokine levels are very interesting, and could help to explain its mechanism of action and the reasons for alternate success or failure in protecting against type 1 diabetes development.
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PMID:Nicotinamide decreases MHC class II but not MHC class I expression and increases intercellular adhesion molecule-1 structures in non-obese diabetic mouse pancreas. 1007 85

It is not clear if a Th1/Th2 imbalance in Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) would lead to a particular antigen-specific IgG subclass dominant as had been shown in the mouse model. In new-onset Type 1 diabetics, an autoantibody response to glutamate decarboxylase (GADab) is frequently observed but the GADab subclass repertoire is not well-established. We determined the systemic levels of representative Th1 and Th2 cytokines and the GADab IgG subclass distribution in 41 Chinese IDDM patients of whom 26 were recently diagnosed (< or = 1 year) and 32 had GADab, to ascertain a likely association of antigen-specific antibody isotype and the Th1/Th2 dichotomy. With high-sensitivity ELISA systems that measure sub-picogram cytokine concentrations, 26 of the 41 patients (63.4%) had at least one of the pro-inflammatory Th1 cytokines (TNF-alpha, IFN-gamma and IL-12) detected. Fewer patients (4/41) had the anti-inflammatory Th2 cytokine IL-4 detected. For IL-10, all subjects had measurable quantities but only three diabetics had levels above the upper limit for healthy subjects (n = 20). Grouped according to the profile of detectable cytokines, there were 24 Th1, 2 Th2 and 2 Th0 patterns. GAD-specific IgG1 antibody was more frequently expressed; 22 of 32 GADab[+] patients. The rank order for the GADab subclasses was IgG1 > 4 > 3 > 2; IgG2 was found in 11 GADab[+] patients. Recent-onset diabetics have a similar ranking of the GAD-specific IgG subclasses. In human Type 1 diabetes, a predominance of GAD-specific IgG1 antibody response is observed together with a dominant Th1 cytokine pattern.
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PMID:Systemic levels of cytokines and GAD-specific autoantibodies isotypes in Chinese IDDM patients. 1022 65

GAD65 (glutamic acid decarboxylase) is an important autoantigen in both type 1 (insulin-dependent) diabetes mellitus (IDDM) and the neurological autoimmune disease stiff-man syndrome (SMS), and is expressed in pancreatic islets as well as the nervous system. Still, only 30% of SMS patients also have type 1 diabetes. To study regulation of T cell responsiveness to GAD65, we investigated a non-diabetic SMS patient with HLA-DR3/7 (predisposing to type 1 diabetes) and high levels of type 1 diabetes-associated autoantibodies against GAD65 and islet cells, and compared the results with those of her diabetic son and two other SMS patients. T cell responses to GAD65 were repeatedly absent in primary stimulation, whereas IA-2, islet antigen and tetanus toxoid induced significant T cell proliferation. However, after in vitro restimulation, GAD65 reactive T cell lines and clones were obtained that were HLA-DR3 restricted, and cross-reactive with a homogenate of purified human pancreatic islets. These T cells produced the immunoregulatory cytokine IL-10 in combination with IFN-gamma and IL-4 (Th0). The dominant T cell epitope was mapped to the central region of GAD65. Although no primary response to whole GAD65 was detectable, the naturally processed GAD65 peptide epitope was recognized vigorously in the primary stimulation assay. The lack of detectable primary T cell responses to GAD65, together with the GAD65-specific cytokine production of restimulated T cells, suggest that GAD65-specific cellular autoimmunity in this patient is suppressed and may be related to the absence of diabetes despite humoral autoreactivity and genetic predisposition.
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PMID:GAD65-Reactive T cells in a non-diabetic stiff-man syndrome patient. 1033 Mar


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