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 in nonobese diabetic (NOD) mice results from selective destruction of pancreatic islet beta-cells following islet infiltration by mononuclear leukocytes. Cytokines produced by islet-infiltrating mononuclear cells may be involved in beta-cell destruction. Therefore, we analyzed cytokine mRNA expression, by reverse-transcriptase PCR (RT-PCR) assay, in mononuclear leukocytes isolated from pancreatic islets of four groups of mice: diabetes-prone female NOD mice; female NOD mice protected from diabetes by injection of CFA at an early age; male NOD mice with a low diabetes incidence; and female BALB/c mice that do not develop diabetes. We found that mRNA levels of IL-1 beta, IL-2, IL-4, IL-10, and IFN-gamma in mononuclear cells from islets of diabetes-prone female NOD mice increased progressively as these cells infiltrated the islets from age 5 wk to diabetes onset (> 13 wk). However, only IFN-gamma mRNA levels were significantly higher in islet mononuclear cells from 12-wk-old diabetes-prone female NOD mice than from less diabetes-prone NOD mice (CFA-treated females, and males) and normal mice (BALB/c). In contrast, IL-4 mRNA levels were lower in islet mononuclear cells from diabetes-prone female NOD mice than from NOD mice with low diabetes incidence (CFA-treated females and males). Splenic cell mRNA levels of IFN-gamma and IL-4 were not different in the four groups of mice. These results suggest that islet beta-cell destruction and diabetes in female NOD mice are dependent upon intra-islet IFN-gamma production by mononuclear cells, and that CFA-treated female NOD mice and male NOD mice may be protected from diabetes development by down-regulation of IFN-gamma production in the islets.
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PMID:IFN-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice. 772 37

The 12th International Immunology of Diabetes Workshop was held during April 1993 in Orlando, Florida, to review research progress since the 11th Immunology of Diabetes Workshop meeting in Nagasaki, Japan, one and a half years before. The NOD mouse may have as many as 10 susceptibility genes, including its novel IA major histocompatibility complex antigen and a defective interferon-gamma receptor, whereas human IDDM is so far known to be encoded by cis and trans complementation products of certain DQ genes on chromosome 6q, and a gene in the insulin-like growth factor II region on chromosome 11p. A unique protein regulator of the X box promotor of the highly susceptible DQB1*0302 allele has also been found. Islet cell antibody negative siblings of IDDM patients appear to have lower than expected abilities to secrete insulin in response to intravenous glucose. Sera from patients before and/or after developing IDDM immunoprecipitate two native proteins of 64,000- and 38,000-M(r) glutamic acid decarboxylase (GAD65) reacting to conformational epitopes. However, a multitude of other autoantibodies often reacting to denatured proteins through linear epitopes have also been identified. The first workshop for GAD antibody assays was successfully completed; however, the 38,000-M(r) antigen has not yet been identified. Other autoantibodies reactive to gangliosides and to sulfatides continue to be reported. Insulitis has come to be recognized as a sometimes protective event. Protective insulitis predominates in older lesions. It can be induced by as disparate means as tuberculin antigen administration, by interleukin-4 treatments, by transfer of T-cell lines generated in autologous mixed lymphocyte responses, and by immunization to insulin B-chain, whereas oral islet cell antigens, such as insulin, can delay diabetes onset in the NOD mouse.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The 12th International Immunology and Diabetes Workshop. Orlando, Florida. 810 Jul 86

The NOD mouse is an animal model of IDDM that shows many of the characteristics of human IDDM. It has been proposed that beta-cell destruction in IDDM progresses over time in a linear manner. Recently, we and others have demonstrated that T helper type 1 (Th1) cells have pathogenic roles in the NOD model and proposed that cytokine balances change as the disease progresses. However, it has not been demonstrated how or when the cytokine balances change or how the beta-cell destruction progresses. We have recently demonstrated that the cytokine profiles of CD45RB(low) CD4+ cells correlate either with their pathogenic or with their protective roles in the NOD mouse. To further analyze this apparent correlation between the shift in cytokine level and IDDM, we examined the anti-CD3-induced cytokine profiles of this subset from NOD mice of various ages compared with that from age-matched I-Ak transgenic NOD and BALB/c mice as controls. A significantly higher ratio of anti-CD3-induced interferon-gamma/interleukin-4 was found in diabetic NOD mice (P < 0.0001) but not in age-matched nondiabetic NOD mice. This cytokine ratio did not change significantly until the onset of diabetes in NOD mice. Based upon these results, we propose that IDDM in the NOD mouse progresses as a predominant inflammatory beta-cell dysfunction without actual beta-cell destruction until late in the disease process. This supports the possibility that late-stage immunotherapy may preserve islet beta-cell mass.
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PMID:Beta-cell destruction may be a late consequence of the autoimmune process in nonobese diabetic mice. 869 Jan 53

IL-4 has been shown to protect against diabetes development in rodent models of insulin-dependent (type I) diabetes mellitus (IDDM). To study IL-4 production in human IDDM, PBMC from IDDM patients and controls were stimulated in vitro with PHA, anti-CD3 mAb, or PMA and ionophore. IL-4 production by PBMC or T cells was strongly impaired in IDDM patients at diabetes onset (p < 0.0001). The mean IL-4 response of patients in the honeymoon stage was higher than the mean of the new onset patients, but significantly lower than the control group (p = 0.01). Patients with IDDM of longer duration (>2 yr) showed a wide range of IL-4 responses and their mean IL-4 response was lower than the controls; however, the difference was not statistically significant. IL-4 mRNA levels were measured using competitive reverse transcription PCR. The results showed greatly reduced mRNA levels in new onset IDDM. In contrast, IL-1 production (measured by ELISA) and IFN-gamma mRNA (measured by reverse transcription PCR) were not significantly different in IDDM. The results suggest an imbalance of inflammatory vs anti-inflammatory cytokine production at the onset of IDDM. Deficient IL-4 production as seen at the onset of IDDM may play a role in the development of diabetes by allowing the inflammatory/autoimmune process in pancreatic islets to progress.
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PMID:Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus. 890 50

Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent (type 1) diabetes mellitus (IDDM) caused by T cells which destroy the insulin-producing islet beta-cells. Since cytokines are involved in this auto-immune beta-cell damage, we used an ELISPOT assay to enumerate the islet-associated T cells that secreted interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) or interleukin-4 (IL-4). We used mitogenic anti-CD3 antibody to activate all the T cells capable of responding, irrespective of their antigen specificity. We found that NOD females, more susceptible than males to IDDM, accumulated islet IFN-gamma producers more rapidly with age than did the males. Acceleration of male IDDM by cyclophosphamide led to a marked increase in IFN-gamma secreting islet T cells. In contrast, a decrease in IFN-gamma-producing islet T cells was associated with arrest of IDDM by administration of peptide p277 of the 60 kDa heat-shock protein (hsp60) to 12-week-old female NOD mice. The p277-treated mice later manifested a greater number of islets and fewer leukocytes per islet than did the mice treated with a bacterial hsp60 peptide. Thus, the development of diabetes could be correlated with the accumulation in the islets of T cells producing IFN-gamma, and destructive insulitis could be downregulated by the administration of a single peptide.
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PMID:Islet T cells secreting IFN-gamma in NOD mouse diabetes: arrest by p277 peptide treatment. 948 Jul 25

The cytokine interleukin-1beta (IL-1beta) has been postulated to be involved in beta-cell destruction in IDDM. It has also been suggested that this action by IL-1beta is mediated by nitric oxide (NO) generation. Recently it has been reported that Th2-cell promoting cytokines e.g. interleukin-4 (IL-4) and interleukin-13 (IL-13) can reduce NO formation from activated macrophaghes after cytokine activation. In the present study we examined the effect of IL-13 on IL-1beta suppression of islet function. For this purpose rat pancreatic islets were cultured in medium RPMI 1640 + 10% fetal calf serum and exposed for 42 h to human IL-13 (0. 0.1, 1 and 10 ng/ml) in the presence or absence of human IL-1beta (25 U/ml) during the last 24 h of culture. IL-13 alone did not affect any islet functions during prolonged exposure. The highest concentration of IL-13 counteracted IL-1beta suppression of islet glucose oxidation, but not insulin release. Moreover, IL-13 failed to reduce IL-1beta stimulated NO production, as measured by medium nitrite levels. Acute exposure to IL-13 caused a slight stimulation of islet insulin secretion. When IL-4 (10 ng/ml) was combined with IL-13 no synergistic action of the two cytokines was observed in the counteraction of IL-1beta mediated changes. In conclusion, the present study showed that IL-13 could partially prevent IL-1beta induced inhibition of the glucose metabolism, and this effect appeared to be unrelated to NO levels. So far it has not been possible to demonstrate in vitro that Th2-cell promoting cytokines such as IL-4 and IL-13 can effectively reduce cytokine-induced NO from islet cells, as has been reported for macrophages. However, it cannot be excluded that Th2-cell promoting cytokines can be effective in reducing a Th1-cell mediated anti-beta-cell response in vivo.
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PMID:Interleukin-13 counteracts suppression induced by interleukin-1beta of glucose metabolism but not of insulin secretion in rat pancreatic islets. 955 Feb 83

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.
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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.
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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

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


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