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)

Tumor necrosis factor beta (TNF-beta) (lymphotoxin) may play an important role in the immune response and pathologic inflammatory diseases. Insulitis is an important early step in the development of insulin-dependent diabetes mellitus. To understand better the role of TNF-beta in the regulation of inflammation and type 1 diabetes, we produced transgenic mice in which the murine TNF-beta gene was regulated by the rat insulin II promoter. The transgene was expressed in the pancreas, kidney, and skin of transgenic mice. The expression of TNF-beta in the pancreas of transgenic mice resulted in a leukocytic inflammatory infiltrate consisting primarily of B220+ IgM+ B cells and CD4+ and CD8+ T cells. The insulitis is reminiscent of the early stages of diabetes, though the mice did not progress to diabetes.
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PMID:Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas. 127 67

Tumor necrosis factor-alpha (TNF) is a multifunctional protein hormone that contributes to host defense and perinatal immunologic development. Dysregulated TNF production, however, occurs during the pathogenesis of autoimmune diseases and may be inherent to their development. In animal models of autoimmunity, dysregulated TNF synthesis has resulted from mutations in TNF gene regulatory sequences, specifically those sequences involved in translational control of TNF gene expression. In this study, we have determined whether mutations in the TNF translational control sequences are present in pediatric patients with type I diabetes mellitus and connective tissue diseases. Blood samples were collected from 48 patients with connective tissue diseases, 32 patients with diabetes, and 29 controls. A 250-bp fragment of the translational control sequences present in the TNF 3'-untranslated region was amplified by the polymerase chain reaction, sequenced, and analyzed relative to the published TNF sequence. In this study, all patients and controls exhibited the normal sequence, with no insertions or deletions in the translational control motifs. We conclude that polymorphisms in the TNF 3'-untranslated region occur infrequently, if at all, in patients with diseases examined here.
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PMID:Sequence analysis of the tumor necrosis factor gene in pediatric patients with autoimmunity. 773 52

Interleukin-1 (IL-1) has been implicated as an effector in insulitis of Type 1 (insulin-dependent) diabetes. Exposure of a beta-cell line (beta TC1) to IL-1 beta resulted in an increase of preproinsulin mRNA at 0.5 h followed by a gradual decrease. Tumor necrosis factor-alpha (TNF-alpha) mRNA expression by beta TC1 cells was demonstrated 1-3 h after the addition of IL-1 beta. TNF bioactivity was detected in homogenates of beta TC1 cells exposed to IL-1. The supplementation of cycloheximide (CHX) together with IL-1 beta resulted in the superinduction of TNF-alpha mRNA, suggesting that de novo protein synthesis is not required in IL-1-induced TNF-alpha mRNA expression. Endogenous TNF-alpha of beta-cells may be involved in the islet lesion of type 1 diabetes.
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PMID:Interleukin-1 induction of tumor necrosis factor-alpha mRNA and bioactive tumor necrosis factor-alpha in a pancreatic beta-cell line by a mechanism requiring no de novo protein synthesis. 833 33

Cytokines produced by islet-infiltrating mononuclear leukocytes may be involved in islet beta-cell destruction and IDDM. To determine which cytokine(s) might be involved in islet beta-cell destruction, we used a reverse transcriptase-polymerase chain reaction assay to compare levels of cytokine mRNA expression in mononuclear leukocytes freshly isolated from islets of four groups of BB rats aged 60-75 days: diabetes-prone (DP) rats, DP rats protected from diabetes by injection of complete Freund's adjuvant (CFA) at age 25 days, acutely diabetic rats, and diabetes-resistant (DR) rats. We found that islet mononuclear leukocyte levels of gamma-interferon (IFN-gamma) mRNA were significantly higher in DP and diabetic rats than in DR rats, whereas CFA-treated DP rats had similar IFN-gamma mRNA levels to DR rats. Also, interleukin (IL)-2 mRNA levels tended to be higher in islet leukocytes from DP and diabetic rats than from DR rats. Tumor necrosis factor-alpha, IL-4, and IL-10 mRNA levels were not significantly different in islet leukocytes from the four groups of rats. These findings suggest that production of T-helper 1 (Th1)-type cytokines, IFN-gamma and IL-2, by islet-infiltrating cells in BB rats is associated with beta-cell destruction and IDDM development.
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PMID:Cytokine gene expression in pancreatic islet-infiltrating leukocytes of BB rats: expression of Th1 cytokines correlates with beta-cell destructive insulitis and IDDM. 863 48

Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. Various cytokines may play an important role in the pathogenesis of this disease. Tumor necrosis factor (TNF)-alpha contributes to the further development of perivascular cellular infiltration and demyelination in the central nervous system (CNS). Phosphatidylserine (PS), a major anionic phospholipid of mammalian cells, has been proposed to function as a regulator of immune and inflammatory responses, especially reducing TNF-alpha production and release in mice. We studied the effect of PS on TMEV-induced demyelinating disease (TMEV-IDD). We injected TMEV intracerebrally into susceptible SJL/J mice and induced TMEV-IDD. PS were injected intraperitonealy, and clinical course and various immunological indicators were closely studied. The results show that when PS were administered in the effector phase. TMEV-IDD was significantly (P < 0.01) suppressed both clinically and histologically. In an ELISPOT assay, the number of TNF-alpha producing spleen cells was low in PS treated mice compared with saline treated control mice. mRNA of TNF-alpha was not detected in spleen cells of mice PS treated in the effector phase. These data suggest that administration of PS suppresses TMEV-IDD by suppressing TNF-alpha production in the effector phase.
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PMID:Phosphatidylserine suppresses Theiler's murine encephalomyelitis virus-induced demyelinating disease. 914 44

Tumor necrosis factor (TNF)-alpha and lymphotoxin (LT) alpha/beta play multiple roles in the development and function of the immune system. This article focuses on three important aspects of the effects of these cytokines on the immune response and on autoimmunity. In several experimental systems (Jurkat T cells, murine T-cell hybridomas), TNF-alpha appears to cause a downregulation of signaling through the TCR, revealed by changes in calcium flux, activation of p21, p23 and ZAP70, and a decrease in nuclear activation of NF-kappaB. Previous and present results suggest that TNF-alpha interferes in some manner with signaling through the TCR, at a locus yet to be delineated. Transgenic expression of LTbetaR-Fc in nonobese diabetic (NOD) transgenic mice results in prevention of type 1 diabetes in NOD mice as long as the level of expression of the fusion protein (under the control of the cytomegalovirus promoter) remains above a level of 2-3 microg/ml. Once the expression levels of the fusion protein have dropped below this critical level, the diabetic process resumes and the animals become diabetic at 40-50 weeks of age, whereas nontransgenic littermates develop diabetes by 25-30 weeks of age. The paradoxical effects of neonatal TNF-alpha administration in NOD mice in increasing incidence of and hastening onset of type 1 diabetes, while neonatal anti-TNF administration completely prevents all signs of islet cell autoimmunity, are due partly to the low levels of CD4+CD25+ T cells in NOD mice. These low levels are reduced by a further 50% on neonatal administration of nontoxic levels of TNF-alpha. In contrast, neonatal administration of anti-TNF-alpha results in a dramatic increase in the levels of CD4+CD25+ regulatory T cells, to levels beyond those seen in wild-type untreated NOD mice. TNF-alpha and LTalpha/beta thus have pleomorphic regulatory effects on the development and expression of autoimmunity.
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PMID:Multiple roles for tumor necrosis factor-alpha and lymphotoxin alpha/beta in immunity and autoimmunity. 1211 Jan 33

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine, which also influences blood pressure (BP). The G-308A polymorphism of the TNF-alpha gene is associated with altered TNF-alpha production. The prevalence of the TNF-alpha-308A allele is reportedly higher among patients with type 1 diabetes mellitus (T1DM) than in the healthy population. In this study we investigated whether this genetic polymorphism might correlate with BP values in diabetic adolescents. Ambulatory BP monitoring (ABPM) was performed in 126 adolescents with T1DM (mean age: 14 +/- 2.4 years). The TNF-alpha G-308A genotype was determined by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methodologies. ABPM results were related to healthy reference values and are given as standard deviation score (SDS). The prevalence of the -308A allele was higher in diabetic adolescents than the Hungarian reference population (0.26 vs 0.14, p < 0.01). TNF-alpha genotype was associated both with systolic and diastolic BP values (p < 0.01 and p < 0.01, respectively). In patients with TNF-alpha-308GG and -308GA/AA genotypes, the 24-h systolic BP average values were 0.37 +/- 1.33 and -0.38 +/- 1.28 SDS, while 24-h diastolic BP average values were 0.09 +/- 1.30 and -0.67 +/- 1.31 SDS. Hence, the TNF-alpha-308A allele carrier state appears to be associated with lower systolic and diastolic BP values.
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PMID:Association between G-308A polymorphism of the tumor necrosis factor-alpha gene and 24-hour ambulatory blood pressure values in type 1 diabetic adolescents. 1248 96

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

Tumor necrosis factor (TNF) is important in the pathogenesis of autoimmune diabetes. It has an important role in immunological and inflammatory processes, and has also been shown to induce apoptotic cell death. We have shown that TNF + IFNgamma induce islet cell death in vitro. TNF exists as a biologically active transmembrane molecule (tmTNF), which is then cleaved to form soluble TNF (sTNF). We reasoned that sTNF, which has been used in previous studies, may not represent TNF in its physiological form. We compared the contributions of caspase activation and nitric oxide production to beta cell death induced by either tmTNF or sTNF together with IFNgamma. CHO cells transfected with a mutated TNF were used as a source of tmTNF. Either sTNF or tmTNF, together with IFNgamma, induced caspase-dependent cell death of the NIT-1 insulinoma cell line, as measured by DNA fragmentation and a fluorogenic caspase 3 activation assay. TNF + IFNgamma did not induce caspase 3 activation in primary mouse islets. Instead, iNOS gene expression was induced and cell death which was partly NO-dependent occurred. We conclude that the role of TNF in the development of type 1 diabetes is likely to be the activation of gene expression and not apoptosis. It appears that both tmTNF and sTNF act by a similar mechanism to induce beta cell death.
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PMID:Transmembrane TNF and IFNgamma induce caspase-independent death of primary mouse pancreatic beta cells. 1256 16

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


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