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)

Most of the evidence linking enterovirus (EV) infection with the development and/or acceleration of type 1 diabetes is indirect. Few studies have examined T-cell responses to these viruses, and therefore the nature of the viral targets and the immune cells involved in antiviral responses remain unclear. In the present study, we examined the characteristics of the T-cell response to the EV Coxsackievirus B4 (CVB4) in patients with type 1 diabetes and healthy control subjects. We find that CVB4-specific T-cells preferentially target the envelope proteins VP1, VP2, and VP3, and that the response to these and other CVB4 proteins differs markedly in type 1 diabetic patients compared with nondiabetic control subjects. The frequency of T-cell proliferative responses against VP2 was significantly reduced in type 1 diabetic patients compared with control subjects, especially in patients tested near to diagnosis (P < 0.001). In contrast, median levels of gamma-interferon (IFN-gamma) production by T-cells in response to the CVB4 antigens tested were generally high in new-onset type 1 diabetic patients, who produced significantly higher levels in response to VP3 compared with healthy subjects (P < 0.05) and patients with long-standing disease (P < 0.05). New-onset type 1 diabetic patients also had higher levels in response to P2C compared with healthy subjects (P < 0.005) and to VP2 compared with patients with long-standing disease (P < 0.05). These results suggest that the quality of the immune response to CVB4 antigens differs significantly between type 1 diabetic patients and control subjects, with a predominance of primed effector (IFN-gamma-producing) memory cells near to disease diagnosis. The data are consistent with the notion that the diagnosis of type 1 diabetes is associated with recent or persistent exposure to EV antigens.
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PMID:Characterization of the T-cell response to coxsackievirus B4: evidence that effector memory cells predominate in patients with type 1 diabetes. 1203 61

The nonobese diabetic (NOD) mouse is a good model for human type 1 diabetes, which is characterized by autoreactive T-cell-mediated destruction of insulin-producing islet beta-cells of the pancreas. The 9-23 amino acid region of the insulin B-chain [B((9-23))] is an immunodominant T-cell target antigen in the NOD mouse that plays a critical role in the disease process. By testing a series of B((9-23)) peptide analogs with single or double alanine substitutions, we identified a set of altered peptide ligands (APLs) capable of inhibiting B((9-23))-induced proliferative responses of NOD pathogenic T-cell clones. These APLs were unable to induce proliferation of these clones. However, vaccinations with the APLs induced strong cellular responses, as measured by in vitro lymphocyte proliferation and Th2 cytokine production (i.e., interleukin [IL]-4 and IL-10, but not gamma-interferon [IFN-gamma]). These responses were cross-reactive with the native antigen, B((9-23)), suggesting that the APL-induced Th2 responses may provide protection by controlling endogenous B((9-23))-specific Th1 (i.e., IFN-gamma-producing) pathogenic responses. One of these APLs that contained alanine substitutions at residues 16 and 19 (16Y-->A, 19C-->A; NBI-6024) was further characterized for its therapeutic activity because it consistently induced T-cell responses (e.g., T-cell lines and clones) that were of the Th2 type and that were cross-reactive with B((9-23)). Subcutaneous injections of NBI-6024 to NOD mice administered either before or after the onset of disease substantially delayed the onset and reduced the incidence of diabetes. This study is the first to report therapeutic activity of an APL derived from an islet beta-cell-specific antigen in type 1 diabetes.
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PMID:Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9-23) peptide. 1208 42

We investigated the expression of Th1- and Th2-associated chemokine receptors on peripheral blood lymphocytes at diagnosis and in the first phase of type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) of 25 patients with newly diagnosed type 1 diabetes, 10 patients with longstanding type 1 diabetes, and 35 healthy control subjects were examined for expression of the chemokine receptors CXCR4 (naive T-cells), CCR5 and CXCR3 (Th1 associated), and CCR3 and CCR4 (Th2 associated) on CD3+ lymphocytes. Furthermore, we analyzed chemokine serum levels (monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and RANTES [regulated on activation, normal T-cell expressed and secreted]) and phytohemagglutinin (PHA)-stimulated cytokine secretion of Th1- (gamma-interferon [IFN-gamma] and tumor necrosis factor-alpha [TNF-alpha]) and Th2 (interleukin [IL]-4 and -10)-associated cytokines by PBMC. The patients with newly diagnosed type 1 diabetes were followed for these parameters at 6-12 months after diagnosis. The PBMCs of patients with newly diagnosed but not with longstanding type 1 diabetes showed reduced expression of the Th1-associated chemokine receptors CCR5 (P < 0.001 vs. control subjects) and CXCR3 (P < 0.002 vs. control subjects). This reduction correlated with reduced IFN-gamma and TNF-alpha production of PBMCs after PHA stimulation and reversed 6-12 months after diagnosis to normal levels. CCR4 cells were reduced in both newly diagnosed and longstanding type 1 diabetic patients, which correlated to reduced PHA-stimulated IL-4 production. MIP-1alpha and MIP-1beta levels were considerably elevated in a subgroup of patients with newly diagnosed diabetes. We assume that Th1-associated peripheral T-cells are reduced in a narrow time window at the time of diagnosis of diabetes, possibly due to extravasation in the inflamed pancreas. Thus, chemokine receptor expression of peripheral blood lymphocytes may be a useful surrogate marker for the immune activity of type 1 diabetes (e.g., in intervention trials).
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PMID:Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes. 1214 60

Cytokines released from activated antigen-presenting cells and T-lymphocytes are crucially involved in the pathogenesis of type 1 diabetes. Previous studies have shown that proinflammatory cytokines play an important role in the induction of autoimmunity and beta-cell damage. Inhibition of insulin expression has been described, but their effects on other major target autoantigens, such as the tyrosine phosphatase-like protein IA-2, is not known. In the present study, we established sensitive real-time RT-PCR to measure IA-2, insulin, and inducible nitric oxide (NO) synthase (iNOS) mRNA expression. Rat insulinoma INS-1 cells were stimulated with IL-1beta, TNF-alpha, interferon (IFN)-gamma, and IL-2 as well as with two combinations of these cytokines (C1: IL-1beta + TNF-alpha + IFN-gamma; C2: TNF-alpha + IFN-gamma). Treatment with IL-1beta, TNF-alpha, or IFN-gamma alone caused a significant down-regulation of IA-2 and insulin mRNA levels in a time and dose-dependent manner, whereas IL-2 had no effect. Exposure to cytokine combinations strongly potentiates the inhibitory effects. Incubation of cells with C1 and C2 for 24 h induces a significant inhibition of IA-2 mRNA levels by 78% and 58%, respectively. Under these conditions, an up to 5 x 10(4)-fold increase of iNOS gene expression was observed. The hypothesis that the formation of NO is involved in IA-2 regulation was confirmed by the finding that the coincubation of C1 with 4 mM L-N(G)-monomethyL-L-arginine, an inhibitor of the iNOS, partly reversed the down-regulation of IA-2. Further, incubation with the synthetic NO-donor S-nitroso-N-acetyl-D-L-penicillamine significantly decreased IA-2 mRNA level to 51% of basal levels. In conclusion, we have demonstrated for the first time that IL-1beta, TNF-alpha, and IFN-gamma exert a strong inhibitory effect on expression of the diabetes autoantigen IA-2. The action of IL-1beta may be partly mediated by the activation of the NO pathway.
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PMID:Effect of proinflammatory cytokines on gene expression of the diabetes-associated autoantigen IA-2 in INS-1 cells. 1223 95

Type 1 diabetes is believed to be a Th1 lymphocyte-mediated disease, and both environmental and genetic factors play a role in its pathogenesis. It was recently found that interleukin (IL)-18 acts as a proinflammatory cytokine and, in synergy with IL-12, promotes development of Th1 lymphocyte response by induction of gamma-interferon production. The aim of our study was to evaluate the frequency of known polymorphisms in the IL-18 promoter in patients with type 1 diabetes in comparison with healthy control subjects, since higher levels of IL-18 were recently reported in the subclinical stage of type 1 diabetes. We studied two recently described single-nucleotide polymorphisms of the promoter of IL-18 gene at the position -137 and -607, which have been suggested to cause differences in transcription factor binding and have an impact on IL-18 gene activity. The genotype distribution differed significantly between patients with type 1 diabetes and control subjects. The difference reflected an increase in the GC genotypes and a decrease in GG genotypes at position -137 in the promoter of IL-18 gene. AA genotype at position -607 was found only in the control group. The results also demonstrated that the contribution of -137GC genotypes to genetic susceptibility to type 1 diabetes differs depending on the combination of IL-18 promotor gene haplotypes. Our study suggests the first evidence of an association between type 1 diabetes and polymorphisms in the promoter of IL-18 gene.
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PMID:Interleukin-18 promoter polymorphisms in type 1 diabetes. 1240 30

We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in three phase I (type 1 diabetes, rheumatoid arthritis, multiple sclerosis) and one phase II clinical trials in multiple sclerosis. In a phase I open-label trial in type 1 diabetes, ingested IFN-alpha preserved residual beta-cell function in recent onset patients. In a second phase I trial, treatment of rheumatoid arthritis with ingested IFN-alpha reduced the secretion of interleukin (IL)-1, a pro-inflammatory cytokine. In a third phase I trial in multiple sclerosis, there was a significant decrease in peripheral blood mononuclear cell IL-2 and IFN-gamma production after ingesting IFN-alpha. In a phase II randomized, placebo-controlled, double-blind trial in multiple sclerosis, 10,000 IU ingested IFN-alpha significantly decreased gadolinium enhancements compared with the placebo group at month 5. Tumor necrosis factor-alpha and IFN-gamma cytokine secretion in the 10,000 IU group at month 5 showed a significant decrease that corresponded with the effect of ingested IFN-alpha on decreasing gadolinium enhancements. Ingested IFN-alpha was not toxic in any of these clinical trials. These studies suggest that ingested IFN-alpha may have a potential role in the treatment of autoimmunity.
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PMID:Ingested type I interferon: state of the art as treatment for autoimmunity. 1248 7

We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in three phase I (type 1 diabetes, rheumatoid arthritis, multiple sclerosis) and one phase II clinical trials in multiple sclerosis (MS). In a phase I open-label trial in type 1 diabetes, ingested IFN-alpha preserved residual beta cell function in recent onset patients. In a second phase I trial, treatment of rheumatoid arthritis (RA) with ingested IFN-alpha reduced the secretion of interleukin-1 (IL-1), a proinflammatory cytokine. In a third phase I trial in MS, there was a significant decrease in peripheral blood mononuclear cell (PBMC) IL-2 and IFN-gamma production after ingesting IFN-alpha. In a phase II randomized, placebo-controlled, double-blind trial in MS, 10,000 IU ingested IFN-alpha significantly decreased gadolinium enhancements compared with the placebo group at month 5. Tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma cytokine secretion in the 10,000 IU group at month 5 showed a significant decrease that corresponded with the effect of ingested IFN-alpha on decreasing gadolinium enhancements. Ingested IFN-alpha was not toxic in any of these clinical trials. These studies suggest that ingested IFN-alpha may have a potential role in the treatment of autoimmunity.
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PMID:Ingested type I interferon: a potential treatment for autoimmunity. 1258 87

At onset of type 1 diabetes, the islet autoantibody status of patients has been reported to predict progression of the disease. We therefore tested the hypothesis that the systemic immunoregulatory balance, as defined by levels of circulating cytokines and chemokines, is associated with islet autoantibody status. In 50 patients with recent-onset type 1 diabetes, antibodies to GAD and insulinoma-associated antigen 2 (IA-2) were analyzed by radioimmunoassay; cytoplasmic islet cell antibodies were determined by indirect immunofluorescence. Cytokine and chemokine concentrations were measured by rigidly evaluated double antibody enzyme-linked immunosorbent assay. Of four classically defined Th1/Th2 cytokines (gamma-interferon, interleukin [IL]-5, IL-10, IL-13), none showed an association with multiple autoantibody positivity. Of six mediators mainly produced by innate immunity cells, three were associated with multiple autoantibody status (IL-18 increased, MIF and MCP-1 decreased) and three were unaffected (IL-12, MIP-1beta, IP-10). GAD and/or IA-2 antibody titers negatively correlated with systemic concentrations of MIF, MIP-1beta, and IL-12. Combining the data of several cytokine and chemokine levels made it possible to predict islet antibody positivity in individual patients with 85% sensitivity and 94% specificity. These data suggest a close association of islet antibody status with systemic immunoregulation in type 1 diabetes.
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PMID:An association of autoantibody status and serum cytokine levels in type 1 diabetes. 1271 43

Recent studies incriminating tumor necrosis factor (TNF)-alpha as the final effector in pancreatic beta-cell death in type 1 diabetes underscore the potential role of TNF-alpha-dependent NF-kappaB activation as an important modulator of pancreatic beta-cell death in autoimmune diabetes. Although nuclear factor (NF)-kappaB activation has been implicated in the protection of target cells against apoptosis by a variety of death effectors, its role in pancreatic islet cell death is not clear. We studied the role of NF-kappaB activation in pancreatic islet cell death by using a gamma-interferon (IFN-gamma)/TNF-alpha synergism model we had previously reported. TNF-alpha induced inhibitor of kappaB (IkappaB) degradation and p65 translocation from cytoplasm to nuclei in MIN6N8 insulinoma cells. The NF-kappaB DNA-binding nuclear complex activated by TNF-alpha contained both the p65 and p50 subunit. IFN-gamma pretreatment did not affect TNF-alpha-induced NF-kappaB activation. Treatment with a proteasome inhibitor blocked p65 translocation and induced susceptibility to TNF-alpha in otherwise resistant insulinoma cells or primary pancreatic islet cells. Specific inhibition of NF-kappaB activation by adenoviral transduction of IkappaB "superrepressor" also sensitized insulinoma cells and primary islet beta-cells to TNF-alpha-induced apoptosis. These results suggest the protective role of NF-kappaB activation against cytokine-mediated pancreatic beta-cell death, contrary to previous reports implicating NF-kappaB as a mediator of pancreatic islet cell death.
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PMID:Nuclear factor kappaB protects pancreatic beta-cells from tumor necrosis factor-alpha-mediated apoptosis. 1271 48

We have been investigating the potential utility of engineered cell lines as surrogates for primary islet cells in treatment of type 1 diabetes. To this end, two strategies that have emerged for procuring cell lines with resistance to immune-mediated damage are 1) selection of cytokine-resistant cell lines by growth of INS-1 insulinoma cells in iteratively increasing concentrations of interleukin (IL)-1beta + gamma-interferon (IFN-gamma), and 2) stable overexpression of the anti-apoptotic gene bcl-2 in INS-1 cells. Herein, we show that bcl-2-overexpressing cells are resistant to the cytotoxic effects of reactive oxygen and nitrogen species (ROS/RNS), but are only modestly protected against high concentrations of IL-1beta + INF-gamma, whereas the converse is true in cytokine selected cells. We also found that the combination of bcl-2 expression and cytokine selection confers a broader spectrum of resistance than either procedure alone, such that the resultant cells are highly resistant to cytokines and ROS/RNS, with no impairment in glucose-stimulated insulin secretion. INS-1-derived cells with combined bcl-2 expression and cytokine selection are also more resistant to damage induced by coculture with mitogen-activated peripheral blood mononuclear cells. Surprisingly, application of the cytokine selection procedure to bcl-2-overexpressing cells does not result in impairment of nuclear factor-kappaB translocation, iNOS expression, and NO production, as clearly occurs upon application of the selection procedure to cells without bcl-2 overexpression. Further investigation of the diverse pathways involved in the development of cytokine and ROS/RNS resistance may define simplified and specific strategies for preservation of beta-cell mass.
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PMID:Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy. 1276 53


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