UMLS:C0011854 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0011854 (type 1 diabetes)
20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pentoxifylline (PTX) has been recently shown to have a variety of immunomodulatory effects. PTX suppresses the production of tumor necrosis factor-alpha (TNF-alpha) and T helper type 1 (Th1) cytokine, interferon-gamma (IFN-gamma), whereas it increases the production of Th2 cytokines, such as interleukin-4 (IL-4) and IL-10. In the pathogenesis of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD), encephalitogenic Th1 cells may play a major role. We examined the effect of PTX treatment on TMEV-IDD. We treated SJL/J mice, inoculated TMEV intracerebrally, with either PTX or saline from days -2 to 12 and days 14 to 27 postintracerebral infection. In the group of mice treated with PTX from days -2 to 12, the onset of TMEV-IDD was suppressed. On the other hand, in the group of mice treated with PTX from days 14 to 27 or saline, the onset of TMEV-IDD was not inhibited. The results of enzyme-linked immunospot (ELISPOT) assay of spleen cells of mice showed that the production of TNF-alpha and IFN-gamma was significantly inhibited (TNF-alpha and IFN-gamma, p < 0.001) and IL-4 and IL-10 production was significantly increased (IL-4, P < 0.001; and IL-10, P < 0.05, respectively) in the group of mice treated with PTX from days -2 to 12. These findings suggest that PTX suppresses the onset of TMEV-IDD by suppressing the production of TNF-alpha and modulating Th1-dominant immune responses into Th2-dominant ones.
...
PMID:The effect of pentoxifylline (PTX) on Theiler's murine encephalomyelitis (TMEV)-induced demyelinating disease. 966 56

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.
...
PMID:Determination of mRNA expression for IFN-gamma and IL-4 in lymphocytes from children with IDDM by RT-PCR technique. 969 87

Spontaneously diabetic nonobese diabetic (NOD/Lt) mice were treated with anti-T-cell monoclonal antibodies (mAbs) at the time of grafting with vascularized segmental pancreas isografts. Recipients were either untreated or given anti-CD4 and/or anti-CD8 mAbs (0.5 mg/20-g mouse on each of 4 consecutive days), which reduced target cell levels to <5% of normal. Graft function was monitored by measuring blood glucose (BG) levels. Transplants were removed for histological examination when BG returned to >20 mmol/l for two consecutive readings. Isografts from 3- to 4-week-old prediabetic mice placed in untreated diabetic NOD mice ceased functioning in 9-13 days with a mean survival time (MST) +/- SD of 10 +/- 2. Treatment with anti-CD4 prolonged survival significantly (MST = 61 +/- 35 days, P < 0.05 compared with untreated control mice). Anti-CD8 treatment was less effective, but it still significantly improved graft survival (MST = 24 +/- 9 days, P < 0.05 compared with untreated control mice). Anti-CD8 plus anti-CD4 treatment was highly effective in inhibiting autoimmune destruction of the grafts (MST = 97 +/- 8 days). This clearly demonstrates that transient inactivation of most T-cells with anti-CD4 plus anti-CD8 mAbs effectively controls autoimmune disease in the isograft, despite recovery of CD4 and CD8 T-cells to normal levels. Although insulitis developed in the long-term grafts, insulitis scores did not increase between 33 and 100 days, and none of the mice progressed to IDDM in 100 days. Histology showed a predominantly peri-islet T-cell and macrophage infiltrate with ductal expression of the cytokines interleukin (IL)-4, IL-2, and interferon-gamma. There was little infiltrate or expression of cytokines within the islets. Thus, mAb treatment at the time of grafting allowed isograft survival and prevented progression from insulitis to beta-cell destruction.
...
PMID:Long-term survival of segmental pancreas isografts in NOD/Lt mice treated with anti-CD4 and anti-CD8 monoclonal antibodies. 972 27

Cytokines could contribute to beta-cell damage in Type I diabetes mellitus. The radical nitric oxide, generated by the inducible form of nitric oxide synthase (iNOS), is a potential mediator of cytokine-induced beta-cell dysfunction. In rat pancreatic islets and insulin-producing cell lines, interleukin-1beta (IL-1beta) induces expression of iNOS mRNA and increases NO production, an effect potentiated by interferon-gamma (IFN-gamma). In human islet cells both IL-1beta and IFN-gamma are required for iNOS expression. We have shown previously that both the transcription factors nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor-1 (IRF-1) are activated by cytokines in rodent and human islets but there is no direct information on the regulation of the iNOS promoter in insulin-producing cells. We presently investigated the effects of cytokines on iNOS transcriptional regulation in both rat insulin-producing RINm5F cells and in primary FACS-purified rat beta cells. Transient transfection experiments with the 1.5-kb rat promoter region and 5' deletants of it showed that a distal region extending up to -1002 bp, and containing a distal and a proximal nuclear factor-kappaB (NF-kappaB) binding site, a gamma-interferon activated site (GAS) and two adjacent IFN-stimulated response elements (ISRE), is required for IL-1beta induction and IFN-gamma potentiation of iNOS activation. Site-mutation analysis showed that both the distal and proximal NF-kappaB and GAS are necessary for IL-1beta-induced iNOS expression in RINm5F cells. In these cells IFN-gamma potentiation is mostly mediated by GAS and ISRE, suggesting a role for the IFN-gamma-induced transcription factors Stat1alpha (which binds GAS) and IRF-1 (which binds ISRE), which may cooperate with NF-kappaB induced by IL-1beta for iNOS activation. In primary beta cells both NF-kappaB binding sites are required for IL-1beta-induced iNOS promoter activation. In these cells IFN-gamma neither increased IL-1beta-induced iNOS promoter activity nor iNOS mRNA expression but it induced a twofold increase in NO production. The present results unveiled the nature of the promoter binding sites necessary for iNOS expression in rodent beta cells. This information could be relevant for the development of new strategies aimed at preventing cytokine-induced iNOS expression and consequent beta-cell damage.
...
PMID:Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. 975 30

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.
...
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

In type 1 diabetes, autoimmune destruction of pancreatic beta-cells has been attributed to cytokines released from infiltrating immunocytes. Exposure of isolated islets to cytokines leads to nitric oxide (NO) production, which can damage beta-cells. Because ductal cells are closely associated with human beta-cells, we examined whether they can contribute to this process. Isolated human ductal cells were cultured for 48 h with various cytokines. The combination of interleukin-1beta (IL-1beta) plus interferon-gamma (IFN-gamma) increased nitric oxide production 12-fold while stimulating mRNA expression of inducible nitric oxide synthase (iNOS). In this condition, 10-20% of cells positive for the cytokeratin-19 duct marker also stained positive for iNOS protein, whereas no positive cells were found in control preparations. Comparison of the magnitude of iNOS mRNA expression and nitric oxide production in these cells with that in isolated human islets suggests that >50% of total islet nitric oxide production might originate from associated ductal cells. It is concluded that ductal cells are a potential source of nitric oxide production in human islets infiltrated by cytokine-releasing immunocytes.
...
PMID:Contribution of ductal cells to cytokine responses by human pancreatic islets. 989 19

Type I (insulin-dependent) diabetes mellitus (IDDM) is an autoimmune disease that results from the destruction of insulin-secreting pancreatic islet beta-cells by autoreactive cells and their mediators. Although its exact cause is not completely understood, it is well established that IDDM is associated with dysregulated humoral and cellular immunity, exemplified by altered production of and response to macrophage- and T cell-derived cytokines and a shift in T helper (Th) cell differentiation in favor of a pathogenic Th1 pathway. Th1 cytokines, including interleukin-2 and interferon-gamma, induced islet beta-cell destruction directly by accelerating activation-induced cell death (apoptosis) and by up-regulating the expression of select adhesion molecules, Th1 cytokines facilitated the pancreatic homing of autoreactive leukocytes, hence enhancing beta-cell destruction. More recently, a role for Th2 cytokines in IDDM pathogenesis was described. Accordingly, local production of Th2 cytokines, in particular interleukin-10, accelerated beta-cell destruction by enhancing autoreactive cell infiltration of the pancreas (insulitis) through modulation of the release of other cytokines and by modulating the microvasculature. Whereas both Th1 and Th2 cytokines are present in peripheral T cells and in the pancreas in IDDM, the mechanism of action and the kinetics of a cell damage induced by Th1 and Th2 cytokines appeared to be distinct. Collectively, this supports the idea that IDDM is not an exclusive Th1-mediated disorder as was suggested, and that both Th1 and Th2 cells and their respective mediators participate and cooperate in inducing and sustaining pancreatic islet beta-cell destruction in IDDM.
...
PMID:Clinical review 103: T helper type 1 and 2 cytokines mediate the onset and progression of type I (insulin-dependent) diabetes. 1032 67

Environmental factors contribute to the pathogenesis of type 1 diabetes (insulin-dependent diabetes mellitus). Multiple low doses of streptozotocin (MLDS) induce hyperglycaemia and insulitis in mice. Previously we demonstrated that adhesion of lymphocytes to endothelium of islets is only increased when donor animals were diabetic and recipient mice had received 5 mg/kg streptozotocin (STZ). Therefore we used streptozotocin to evaluate the immunological relevance of such an irritation of islets. Lymphocytes, separated from diabetic mice (MLDS), were fluorescently labelled and injected to recipient mice that had received 5 mg/kg STZ. With in vivo microscopy we measured lymphocyte flow and adherence in islets. Expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in the pancreas was assessed using immunohistochemistry. Very late antigen-4 (VLA-4) and leucocyte function-associated antigen-1 (LFA-1) expression on transferred lymphocytes was measured with flow cytometry. Pretreatment of recipients with antibodies to cytokines or silica reduced lymphocyte adherence to islet endothelium from 2.04% (goat immunoglobulin G; IgG) or 1.82% (rat IgG) to 0.47, 0.58, 0.39 or 0. 19% for monoclonal antibody (mAb) interferon-gamma (IFN-gamma), polyclonal antibody (pAb) tumour necrosis factor-alpha (TNF-alpha), pAb interleukin (IL)-1alpha or silica, respectively. Reduced adhesion was associated with a decreased expression of VCAM-1 and ICAM-1 in islets of treated recipients compared with mice treated with 5 mg/kg STZ alone. In conclusion, pretreatment of recipients with 5 mg/kg STZ leads to an increased expression of adhesion molecules in the islets and lymphocyte adhesion to islet endothelium in vivo, demonstrating an immune response of the islets. Prevention of increased expression of ICAM-1 or VCAM-1 and reduction of lymphocyte adhesion in islets by silica or antibody indicate an involvement of macrophages and macrophage derived cytokines in the generation of this immune response.
...
PMID:In vivo microscopy of murine islets of Langerhans: increased adhesion of transferred lymphocytes to islets depends on macrophage-derived cytokines in a model of organ-specific insulitis. 1046 41

Type 1 diabetes is a disease characterized by progressive loss of beta-cell function due to an autoimmune reaction affecting the islets of Langerhans. It is now generally accepted that cytokines are implicated in the pathogenesis of autoimmune diseases. Animal studies have shown that interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma affect type 1 diabetes development profoundly. It has been suggested that beta-cells are destroyed by cytokine-induced free radical formation before cytotoxic T-helper (Th)-lymphocytes and/or autoantibody-mediated cytolysis. This hypothesis is known as the "Copenhagen model." We introduce a mathematical model encompassing the various processes within this framework. The model is expressed in rate equations describing the changes in numbers of beta-cells, macrophages, and Th-lymphocytes. Being concerned with the earliest events, we explore the conditions necessary to maintain self-sustained beta-cell elimination based on the feedback between immune cells and insulin-producing cells. The motivation for this type of analysis becomes clear when we consider the multifactorial and complicated nature of the disease. Indeed, recent research has provided detailed information about the different factors that contribute to the development of the disease, stressing the importance of incorporating these findings into a more general picture. A mathematical formalism allows for a more comprehensive description of the biological problem and can reveal nonintuitive properties of the dynamics. Despite the rather complicated structure of the equations, our main conclusion is simple: onset of type 1 diabetes is due to a collective, dynamical instability, rather than being caused by a single etiological factor.
...
PMID:Onset of type 1 diabetes: a dynamical instability. 1048 May 94

Two rodent models of autoimmune type 1 diabetes have been used to investigate the role of insulin as an autoantigen in this disease. In lymphopoenia-induced diabetes in the PVG.RT1u rat, neonatal tolerization with insulin B-chain peptides, but not A-chain peptides, conferred significant protection from disease. After rechallenge of adult rats, neonatally B-chain-tolerized animals showed diminished B-chain-specific T-cell proliferation, interleukin (IL)-2 production, and interferon-gamma (IFN-gamma) production, as compared with control animals. The epitope recognized by the PVG.RT1u rat was mapped to residues 1-18 of the B-chain; T-cell lines specific for this epitope were generated, and these conferred diabetes upon adoptive transfer to irradiated syngeneic recipients. In adult nonobese diabetic (NOD) mice, subcutaneous immunization with B-chain peptide 9-23 emulsified in incomplete Freund's adjuvant (IFA) was also potent at preventing onset of diabetes. In contrast to PVG.RT1u rats, NOD mice recognized an epitope within residues 10-29 of the insulin B-chain. The data implicate insulin as a target autoantigen in type 1 diabetes but do not support a role for molecular mimicry to insulin in the pathogenesis of this disease.
...
PMID:Peptides derived from murine insulin are diabetogenic in both rats and mice, but the disease-inducing epitopes are different: evidence against a common environmental cross-reactivity in the pathogenicity of type 1 diabetes. 1053 49

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>