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)

The ABBOS-peptide from bovine serum albumin (BSA) in cow's milk has been suggested to initiate the autoimmune process against the beta-cells leading to type 1 diabetes. The aim of this study was to elucidate if the ABBOS-peptide is a possible trigger of type I diabetes. The cytokines IL-4 and IFN-gamma were determined at the level of transcription as mRNA in lymphocytes, stimulated with the ABBOS-peptide. Sixteen children with newly diagnosed type 1 diabetes were compared with 10 healthy controls matched for the diabetes associated HLA-type DR3/4. Antibodies to bovine serum albumin (BSA), insulin antibodies (IA), and antibodies against islet cells (ICA) were determined, as well as serum C-peptide. Increased mRNA expression for IFN-gamma and/or IL-4 could be observed in lymphocytes from 13/16 children with recent onset of diabetes after in vitro stimulation with the ABBOS-peptide. Low expression of IFN-gamma mRNA was associated with high secretion of C-peptide, whereas a positive relationship could be observed between expression of IL-4 mRNA and insulin antibodies. Expression of IFN-gamma and/or IL-4 mRNA was also detected in lymphocytes from 6/10 healthy controls. ABBOS may have a role as a reactive epitope in the upregulation of the autoimmune process against the beta-cells but ABBOS does not seem to cause any specific Th1 response. An increased mRNA expression could also be seen in lymphocytes from healthy controls. Thus, the ABBOS-peptide might just cause or reflect an unspecific immune activity.
...
PMID:The ABBOS-peptide from bovine serum albumin causes an IFN-gamma and IL-4 mRNA response in lymphocytes from children with recent onset of type 1 diabetes. 1074 69

Engineered insulinoma cell lines may represent an alternative to isolated islets for transplantation therapy of type 1 diabetes. Success of this approach may require development of cell lines that can withstand cytokine-mediated damage. To this end, we have cultured INS-1 insulinoma cells in increasing concentrations of interleukin-1beta (IL-1beta) + gamma-interferon (IFN-gamma), with approximate weekly iterations over an 8-week period. Based on the C,N diphenyl-N'-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium+ ++ bromide (MTT) viability assay, the selected cells, termed INS-1res, were 100% viable after 5 days of treatment with 10 ng/ml of IL-1beta. These cells were also 78 +/- 1.2% viable after 5 days of exposure to the combination of 10 ng/ml IL-1beta and 100 U/ml IFN-gamma, whereas parental INS-1 cells treated in the same manner were only 0.3 +/- 0.03% viable. INS-1res cells were also resistant to treatment with supernatants from activated rat peripheral blood mononuclear cells, whereas only 20% of parental INS-1 cells survived such treatment. The resistance to IL-1beta conferred by this procedure was stable, whereas the partial resistance to IFN-gamma was transient but reinducible by culture in the presence of cytokines. Stable transfection of INS-1res cells with a plasmid containing the human insulin cDNA and expansion of the transfected colonies in the absence of cytokines produced cell lines that were on average more resistant to IL-1beta + IFN-gamma (53 +/- 11%) than similarly transfected clones derived from parental INS-1 cells (15 +/- 7%). Importantly, several INS-1res-derived clones retained the capacity to secrete insulin in response to glucose concentrations over the normal physiological range. With regard to the mechanism by which selection was conferred, we found normal levels of IFN-gamma receptor mRNA, but a 60% reduction in expression of the IL-1 receptor type I (IL-1RI) in INS-1res cells compared with parental INS-1 cells. IL-1beta signaling through p38 MAP kinase was found to be normal in INS-1res cells, suggesting that their expression of IL-1RI is sufficient to maintain cytokine action. However, normal IL-1beta-mediated translocation of NF-kappaB and induction of inducible nitric oxide synthase expression and nitric oxide production was severely impaired in the INS-1res cell lines, suggesting a mechanism for the IL-1beta resistance. In sum, this study defines a strategy for isolation of cytokine-resistant beta-cell lines and provides a new system for studying the mechanisms by which such resistance can be achieved.
...
PMID:Selection of insulinoma cell lines with resistance to interleukin-1beta- and gamma-interferon-induced cytotoxicity. 1087 Nov 93

Insulin-dependent diabetes mellitus is an autoimmune disease in which pancreatic islet beta cells are destroyed by a combination of immunological and inflammatory mechanisms. In particular, cytokine-induced production of nitric oxide has been shown to correlate with beta cell apoptosis and/or inhibition of insulin secretion. In the present study, we investigated whether the interleukin (IL)-1beta intracellular signal transduction pathway could be blocked by overexpression of dominant negative forms of the IL-1 receptor interacting protein MyD88. We show that overexpression of the Toll domain or the lpr mutant of MyD88 in betaTc-Tet cells decreased nuclear factor kappaB (NF-kappaB) activation upon IL-1beta and IL-1beta/interferon (IFN)-gamma stimulation. Inducible nitric oxide synthase mRNA accumulation and nitrite production, which required the simultaneous presence of IL-1beta and IFN-gamma, were also suppressed by approximately 70%, and these cells were more resistant to cytokine-induced apoptosis as compared with parental cells. The decrease in glucose-stimulated insulin secretion induced by IL-1beta and IFN-gamma was however not prevented. This was because these dysfunctions were induced by IFN-gamma alone, which decreased cellular insulin content and stimulated insulin exocytosis. These results demonstrate that IL-1beta is involved in inducible nitric oxide synthase gene expression and induction of apoptosis in mouse beta cells but does not contribute to impaired glucose-stimulated insulin secretion. Furthermore, our data show that IL-1beta cellular actions can be blocked by expression of MyD88 dominant negative proteins and, finally, that cytokine-induced beta cell secretory dysfunctions are due to the action of IFN-gamma.
...
PMID:Dominant negative MyD88 proteins inhibit interleukin-1beta /interferon-gamma -mediated induction of nuclear factor kappa B-dependent nitrite production and apoptosis in beta cells. 1096 6

Destruction of pancreatic islet beta-cells in type 1 diabetes appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as interferon (IFN)-gamma, interleukin (IL)-1 beta, and tumor necrosis factor TNF-alpha that such cells produce. We recently reported on a method for selection of insulinoma cells that are resistant to the cytotoxic effects of inflammatory cytokines (INS-1(res)), involving their growth in progressively increasing concentrations of IL-1 beta plus IFN-gamma, and selection of surviving cells. In the current study, we have investigated the molecular mechanism of cytokine resistance in INS-1(res) cells. By focusing on the known components of the IFN-gamma receptor signaling pathway, we have discovered that expression levels of signal transducer and activator of transcription (STAT)-1 alpha are closely correlated with the cytokine-resistant and -sensitive phenotypes. That STAT-1 alpha is directly involved in development of cytokine resistance is demonstrated by an increase of viability from 10 +/- 2% in control cells to 50 +/- 6% in cells with adenovirus-mediated overexpression of STAT-1 alpha (p < 0.001) after culture of both cell groups in the presence of 100 units/ml IFN-gamma plus 10 ng/ml IL-1 beta for 48 h. The resistance to IL-1 beta plus IFN-gamma in STAT-1 alpha-expressing cells is due in part to interference with IL-1 beta-mediated stimulation of inducible nitric-oxide synthase expression and nitric oxide production. Furthermore, overexpression of STAT-1 alpha does not impair robust glucose-stimulated insulin secretion in the INS-1-derived cell line 832/13. We conclude that expression of STAT-1 alpha may be a means of protecting insulin-producing cell lines from cytokine damage, which, in conjunction with appropriate cell-impermeant macroencapsulation devices, may allow such cells to be used for insulin replacement in type 1 diabetes.
...
PMID:Expression of the transcription factor STAT-1 alpha in insulinoma cells protects against cytotoxic effects of multiple cytokines. 1102 34

Autoimmune diabetes is caused by selective loss of insulin-producing pancreatic beta-cells. The main factors directly implicated in beta-cell death are autoreactive, cytotoxic (islet-antigen specific) T-lymphocytes (CTL), and inflammatory cytokines. In this study, we have used an antigen-specific model of virally induced autoimmune diabetes to demonstrate that even high numbers of autoreactive CTL are unable to lyse beta-cells by perforin unless major histocompatibility complex class I is upregulated on islets. This requires the presence of inflammatory cytokines induced by viral infection of the exocrine pancreas but not of the beta-cells. Unexpectedly, we found that the resulting perforin-mediated killing of beta-cells by autoreactive CTL is not sufficient to lead to clinically overt diabetes in vivo, and it is not an absolute prerequisite for the development of insulitis, as shown by studies in perforin-deficient transgenic mice. In turn, destruction of beta-cells also requires a direct effect of gamma-interferon (IFN-gamma), which is likely to be in synergy with other cytokines, as shown in double transgenic mice that express a mutated IFN-gamma receptor on their beta-cells in addition to the viral (target) antigen and do not develop diabetes. Thus, destruction of most beta-cells occurs as cytokine-mediated death and requires IFN-gama in addition to perforin. Understanding these kinetics could be of high conceptual importance for the design of suitable interventions in prediabetic individuals at risk to develop type 1 diabetes.
...
PMID:Virus-induced autoimmune diabetes: most beta-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. 1107 46

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.
...
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

There have been two previous conflicting reports that the development of T-cell-mediated autoimmune diabetes (type 1 diabetes) was respectively unaffected or inhibited in NOD mice genetically deficient in the T-helper (Th) 1 cytokine interferon (IFN)-gamma or the alpha-chain subunit of its receptor. Our goal was to resolve this conundrum by congenically transferring, from a 129 donor strain to the NOD background, a functionally inactivated gene for the beta-chain signaling (located on chromosome 16) rather than the alpha-chain ligand binding domain (located on chromosome 10) of the IFN-gamma receptor. These NOD.IFNgammaRBnull mice were characterized by normal patterns of leukocyte development and T-cells that produced greatly enhanced levels of the putatively type 1 diabetes-protective Th2 cytokine interleukin (IL)-4. However, despite being unable to respond to the primary Thl cytokine IFN-gamma and having T-cells that produce greatly enhanced levels of IL-4, NOD.IFNgammaRBnull mice remained highly susceptible to type 1 diabetes. This result indicated that the previously reported inhibition of type 1 diabetes in NOD mice carrying a functionally inactivated IFN-gamma receptor alpha-chain gene may have been due to a closely linked and previously unidentified diabetes resistance allele. Furthermore, our results indicate that the pathogenicity of diabetogenic T-cells in NOD mice is not dampened by an inability to respond to IFN-gamma and a concurrent shift to greatly enhanced Th2 cytokine production. This finding calls into question whether clinical protocols designed to shift beta-cell autoreactive T-cells from a Thl to Th2 cytokine production profile will truly be safe and efficacious in blocking the development of type 1 diabetes in humans.
...
PMID:Interferon-gamma receptor signaling is dispensable in the development of autoimmune type 1 diabetes in NOD mice. 1111 1

The 9-23 amino acid region of the insulin B chain (B9-23) is a dominant epitope recognized by pathogenic T lymphocytes in nonobese diabetic mice, the animal model for type 1 diabetes. We describe herein similar (B9-23)-specific T-cell responses in peripheral lymphocytes obtained from patients with recent-onset type 1 diabetes and from prediabetic subjects at high risk for disease. Short-term T-cell lines generated from patient peripheral lymphocytes showed significant proliferative responses to (B9-23), whereas lymphocytes isolated from HLA and/or age-matched nondiabetic normal controls were unresponsive. Antibody-mediated blockade demonstrated that the response was HLA class II restricted. Use of the highly sensitive cytokine-detection ELISPOT assay revealed that these (B9-23)-specific cells were present in freshly isolated lymphocytes from only the type 1 diabetics and prediabetics and produced the proinflammatory cytokine IFN-gamma. This study is, to our knowledge, the first demonstration of a cellular response to the (B9-23) insulin epitope in human type 1 diabetes and suggests that the mouse and human diseases have strikingly similar autoantigenic targets, a feature that should facilitate development of antigen-based therapeutics.
...
PMID:A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin. 1116 Jan 33

Cytokines may participate in islet destruction during the development of type 1 diabetes. Expression of inducible nitric oxide synthase (iNOS) and subsequent NO formation induced by IL-1 beta or (IL-1 beta + IFN-gamma) may impair islet function in rodent islets. Inhibition of iNOS or a deletion of the iNOS gene (iNOS -/- mice) protects against cytokine-induced beta-cell suppression, although cytokines might also induce NO-independent impairment. Presently, we exposed wild-type (wt, C57BL/6 x 129SvEv) and iNOS -/- islets to IL-1 beta (25 U/ml) and (IL-1 beta (25 U/ml) + IFN-gamma (1000 U/ml)) for 48 h. IL-1 beta and (IL-1 beta + IFN-gamma) induced a significant increase in NO formation in wt but not in iNOS -/- islets. Both IL-1 beta and (IL-1 beta + IFN-gamma) impaired glucose-stimulated insulin release and reduced the insulin content of wt islets, while (IL-1 beta + IFN-gamma) reduced glucose oxidation rates and cell viability. IL-1 beta exposure to iNOS -/- islets impaired glucose-stimulated insulin release, increased insulin accumulation and reduced the insulin content, without any increase in cell death. Exposure to (IL-1 beta + IFN-gamma) had no effect on iNOS -/- islets except reducing the insulin content. Our data suggest that IL-1 beta may inhibit glucose-stimulated insulin release by pathways that are not NO-dependent and not related to glucose metabolism or cell death.
...
PMID:Cytokine-induced inhibition of insulin release from mouse pancreatic beta-cells deficient in inducible nitric oxide synthase. 1118 Oct 61

The aim of this study was to evaluate possible changes in the circulating levels of interferon (IFN)-gamma, interleukin (IL)-4 and transforming growth factor (TGF)-beta in association with the autoimmune process leading to type 1 diabetes. Expression levels of mRNAs specific for each cytokine were determined in peripheral blood mononuclear cells (PBMC) by a multiplex reverse transcription-polymerase chain reaction (RT-PCR) followed by hybridization reactions with lanthanide-labelled probes and detection by time-resolved fluorometry. Newly diagnosed diabetic children had lower levels of IFN-gamma, IL-4 and TGF-beta 1 signals compared to their age- and sex-matched controls (P < 0.02, P < 0.005 and P < 0.005, respectively) and also the autoantibody-positive subjects had significantly lower levels of IL-4 and TGF-beta 1 in comparison with their matched controls (P = 0.0013 and P = 0.012). No significant differences were observed when comparing matched pairs of diabetic children and autoantibody-positive subjects. Our results suggest a systemic bias towards reduced production of T-helper cell type 2 cytokines (IL-4 and TGF-beta 1) during the autoimmune process, but there was also a reduced level of IFN-gamma expression in the periphery at the onset of clinical diabetes.
...
PMID:Cytokine expression in unstimulated PBMC of children with type 1 diabetes and subjects positive for diabetes-associated autoantibodies. 1130 60

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