Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-2 (IL-2) is an important cytokine in the autoimmune process proceeding Type 1 diabetes. Our aim was to investigate, in two previously used animal models, the NOD mouse and the BB/W rat, the in vivo tissue distribution of radio-labeled IL-2. If the radio-labeled IL-2 accumulated significantly in the pancreas compared to surrounding organs it could allow imaging of lymphocyte infiltration of the islets of Langerhans by scintigraphic methods. IL-2 was labeled enzymatically with(125)Iodine. Radio-labeled IL-2 was injected iv in prediabetic NOD mice, diabetic NOD mice and Balb/c mice in the first animal model and in BB rats in the second model. Animals were sacrificed at different time points and the activity in different organs was measured. It was found that the mean activity in the pancreas in both diabetic and prediabetic NOD mice was significantly higher compared to pancreas from Balb/c mice (P< 0.001 and P=0.005, respectively). However, the mean activity in the pancreas was at the lower range of the surrounding organs in both animal models, thereby excluding the possibility of imaging the autoimmune process by scintigraphic methods. It is concluded that radio-labeled IL-2 did accumulate significantly in the pancreas of NOD mice compared to control mice but there is a need to develop new techniques in order to visualize the localized activity.
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PMID:Accumulation of(125)iodine labeled interleukin-2 in the pancreas of NOD mice. 1177 52

Previously we suggested that reovirus type 2 (Reo-2) infection induced autoimmune insulitis, resulting in mild diabetes in suckling mice. The effect of histamine (a lymphocyte function suppressor) on Reo-2-induced insulitis was examined. Systemic histamine administration reduced the development of insulitis and blood glucose elevation. Endogenous interleukin-2 (IL-2) activity by splenic cells and the production of antibodies to pancreatic islet cells were reduced by histamine treatment. In addition, histamine treatment increased cyclic adenosine monophosphate (cAMP) concentrations in the plasma. These results further suggest that the insulitis seen in Reo-2 infection in suckling mice is induced by an immune reaction.
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PMID:Systemic administration of histamine reduces reovirus type 2-induced insulitis in suckling DBA/1 mice. 1194 4

The pentameric B-subunit of cholera toxin (CTB) can be used as an efficient mucosal carrier of either immunogenic or tolerogenic T-cell epitopes. In this study a series of fusions was constructed between the genes encoding CTB and the B-chain of human insulin (InsB). The resulting fusion proteins were expressed in Escherichia coli and isolated as cytoplasmic inclusion bodies that were then dissolved and assembled in vitro. GM1 enzyme-linked immunosorbent assay (ELISA), sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analyses showed that the protein construct in which InsB was fused to the C-terminus of a CTB monomer (CI) assembled into structures that both bound to the receptor GM1 ganglioside and reacted with monoclonal antibodies to CTB and insulin. Fusion of InsB to the N-terminus of CTB resulted in protein that could not assemble into pentameric CTB. In vitro assays showed that the CI fusion protein was 300-fold more potent than native insulin at inducing interleukin-2 (IL-2) production by an insulin-specific T-cell hybridoma. When administered orally, the CI fusion protein induced efficient immunological suppression of ovalbumin-specific T-cell responses in mice co-immunized parenterally with insulin and ovalbumin. These results demonstrate the stability, GM1 receptor-binding activity and antigenic authenticity of the CI fusion protein as well as its ability to elicit insulin-specific T-cell responses in vitro. In addition, we demonstrate that the CI fusion protein induces efficient immunosuppression after oral administration, raising the possibility of using such constructs in the treatment of type-1 diabetes.
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PMID:Genetic fusion of human insulin B-chain to the B-subunit of cholera toxin enhances in vitro antigen presentation and induction of bystander suppression in vivo. 1204 53

Interleukin-2 is an effective agent against renal cell carcinoma and melanoma, but it has been associated with autoimmune sequelae such as hypothyroidism and vitiligo. A 64-year-old man with non-insulin-dependent diabetes and metastatic renal cell carcinoma developed insulin-dependent diabetes after his first cycle of therapy with high-dose (HD) interleukin-2. After additional therapy with interleukin-2, the patient developed generalized myasthenia gravis (MG) and polymyositis, both of which responded to treatment with corticosteroids and plasmapheresis. To investigate the role of IL-2 in the development of these autoimmune complications, autoantibody titers were assayed from serum obtained before and after IL-2 treatment and after treatment with corticosteroids plus plasmapheresis. Before IL-2 treatment, the patient had antibodies directed against insulin, islet cell antigens, and striated muscle. Acetylcholine receptor antibody levels were normal before starting IL-2. After treatment with IL-2, the patient developed acetylcholine receptor binding antibodies and exhibited an increase in the striated muscle antibody titer from 1:40 to 1:160. Recovery from the MG and polymyositis was associated with substantial decreases in the acetylcholine receptor and striated muscle antibody titers. These findings suggest that HD IL-2 accelerated the progression of latent autoimmune diabetes and myositis in this patient whose tolerance to islet cell antigens and striated muscle had already been broken and precipitated a break in tolerance to the acetylcholine receptor resulting in the development of MG. This case demonstrates the importance of prompt recognition of IL-2-induced MG and shows how this complication can be successfully managed with aggressive therapy.
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PMID:Induction of myasthenia gravis, myositis, and insulin-dependent diabetes mellitus by high-dose interleukin-2 in a patient with renal cell cancer. 1214 60

Type 1 diabetes has been associated with an increased frequency of activated T cells and T-cell hyperactivity to non-specific and disease-specific stimuli including the islet autoantigen glutamic acid decarboxylase 65 (GAD). To address whether T-cell hyperactivity is genetic or acquired we measured whole blood cytokines in vitro in response to GAD or tetanus in 18 identical twin pairs, nine discordant for type 1 diabetes. In addition, the activity of 2', 5' oligoadenylate synthetase (OAS) in blood mononuclear cells was measured as a marker of viral infection. Interleukin-2 (IL-2) basally and IL-2 and interferon-gamma (IFN-gamma) in response to GAD, were detected more frequently and at higher levels in diabetic compared to non-diabetic twins. IL-10 was not different between groups. OAS activity was increased in diabetic compared to non-diabetic twins and showed a correlation with basal IL-2 and GAD-stimulated IFN-gamma and IL-10. These findings suggest that T-cell hyperactivity in type 1 diabetes is an acquired trait and could reflect persisting virus expression.
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PMID:Evidence from twins for acquired cellular immune hyperactivity in type 1 diabetes. 1215 22

Among other functions, melatonin exerts both antioxidative and immunoregulatory roles. The indoleamine is secreted in the saliva, although its role into the mouth is not known. Diabetic patients frequently display oral cavity pathologies such as periodontal disease (PD), an inflammatory disease coursing with an increase in free radical production. Thus, we compared the degree of PD and interleukin-2 (IL-2) levels with melatonin concentrations in plasma and saliva of diabetic patients. A total of 43 diabetic patients (20 with type I and 23 with type II diabetes) and 20 age- and sex-matched controls were studied. Dental and medical history of all patients was in accordance with the criteria of the WHO. The periodontal status was evaluated by the Community Periodontal Index (CPI). Plasma and salivary melatonin levels were determined by specific commercial radioimmunoassays, and plasma IL-2 was measured using a commercial enzyme-linked immunosorbent assay kit. Diabetic patients had plasma and saliva melatonin levels of 8.98 +/- 7.14 and 2.70 +/- 2.04 pg/mL, respectively. These values were significantly lower (P < 0.001) than those obtained in plasma and saliva of controls (14.91 +/- 4.75 and 4.35 +/- 0.98 pg/mL, respectively). Plasma and salivary melatonin concentrations show a biphasic response in diabetic patients. Melatonin decreased in patients with a CPI index of 2, and then increased reaching highest levels in patients with a CPI index of 4. By contrast, IL-2 levels decreased from CPI index 1 to 4. The results indicate that, in diabetic patients, the presence of a marked impairment of the oral status, as assessed by the CPI index, is accompanied by an increase in plasma and salivary melatonin. The increase in salivary melatonin excretion may have a periodontal protective role.
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PMID:Relationship between salivary melatonin levels and periodontal status in diabetic patients. 1452 28

Th1 cytokines, such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), and Th1-inducing cytokines, such as IL-12, are involved in the pathogenesis of various organ-specific autoimmune diseases, including autoimmune diabetes. In this study, we investigated intracellular IFN-gamma release by T lymphocytes and IL-12 serum levels in 48 type 2 and 36 latent autoimmune diabetes of adults (LADA) diabetics and 25 control subjects in an attempt to evaluate their role in the pathogenesis of these clinical entities. Ionomycin (ION) and phorbol-12-myristate-13-acetate (PMA)-activated peripheral blood mononuclear cells (PBMCs) were stained with anti-CD4-FITC or anti-CD8-FITC and anti-IFN-gamma phycoerythrin (PE) monoclonal antibodies (mAbs) and analyzed by flow cytometry. IL-12 serum levels were determined by enzyme-linked immunosorbent assay (ELISA). In all study groups, IFN-gamma content of CD4(+) and CD8(+) lymphocytes was significantly upregulated by stimulation. Furthermore, it was observed that CD4(+) and CD8(+) lymphocytes from type 2 diabetics produced significantly lower levels of IFN-gamma compared with LADA patients and controls. However, the percentages of CD4(+)/IFN-gamma(+) and CD8(+)/IFN-gamma(+) cells from type 2 diabetics were significantly higher compared with controls. The flow cytometric picture of intracellular IFN-gamma release in LADA patients did not differ from that observed in controls. However, IL-12 serum levels in type 2 and LADA diabetics were lower than in controls. Because Th1 cytokines have been associated with the pathogenesis of autoimmune diabetes, these results preclude Th1 involvement in the autoimmune phenomena observed in LADA patients. In contrast, the low IFN-gamma levels observed in type 2 diabetics in combination with the low IL-12 serum levels might be a contributing factor in the frequently observed chronic complications in these patients.
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PMID:Intracellular IFN-gamma production and IL-12 serum levels in latent autoimmune diabetes of adults (LADA) and in type 2 diabetes. 1529 48

Type 1 diabetes is an autoimmune disease wherein autoreactive T-cells promote the specific destruction of pancreatic islet beta-cells. Evidence for a crucial role for Fas/FasL interactions in this destruction has been highly controversial because of the pleiotropic effects of Fas deficiency on the lymphoid and other systems. Fas-deficient mice are protected from spontaneous development of diabetes not because Fas has a role in the destruction of beta-cells, but rather because insulitis is abrogated. Fas may somehow be involved in the series of events provoking insulitis; for example, it may play a role in the physiological wave of beta-cell death believed to result in the export of pancreatic antigens to the pancreatic lymph nodes and, thereby, to circulating, naive, diabetogenic T-cells for the first time. To explore the implication of Fas in these events, we crossed the lpr mutation into the BDC2.5 model of type 1 diabetes to make it easier to monitor direct effects on the pathogenic specificity. We demonstrated that BDC2.5/NOD(lpr/lpr) mice have qualitatively and quantitatively less aggressive insulitis than do BDC2.5/NOD mice. In vitro proliferation assays showed that BDC2.5/NOD(lpr/lpr) splenocytes proliferated less vigorously than those from control mice in the presence of islet extracts, which reflects their inability to produce interleukin-2, resulting in weaker pathogenicity.
Diabetes 2004 Nov
PMID:Fas deficiency prevents type 1 diabetes by inducing hyporesponsiveness in islet beta-cell-reactive T-cells. 1550 59

GnRH-I and its receptor (GnRHR-I) have previously been demonstrated and shown to be biologically active in the immune system, notably within T cells. Recently however a second form of GnRH (GnRH-II) has been described in the human. The function of both these neuropeptides in B lymphocytes has not previously been explored. The present study investigates GnRH-I and GnRH-II expression in human peripheral mononuclear blood cells (PMBCs) and B lymphoblastoid cells (B-LCLs), as well as their action in regulating B-LCL proliferation in the presence and absence of interleukin-2 (IL-2), both in GnRHR-I mutated lymphocytes and in a normal control. RT-PCR and immunocytochemistry identified locally produced GnRH-I and GnRH-II in all cell groups. Treatment of normal B-LCLs with GnRH-I (10 (-9) M and 10 (-5) M) or with interleukin-2 (IL-2) (50 IU/ml) resulted in a significant increase in cell proliferation compared with the untreated control. IL-2 and GnRH-I (10 (-7) M, 10 (-6) M, 10 (-5) M) induced greater proliferation in normal B-LCLs than IL-2 treatment alone. No significant proliferation occurred in GnRHR-I defective B-LCLs, in response to either GnRH-I (10 (-9) and 10 (-5) M) or IL-2 treatment, nor to IL-2 and GnRH-I (10 (-10) to 10 (-5) M) co-treatment when compared to controls. Co-incubation of IL-2 and IL-2 + GnRH 10 (-5) M with a GnRH antagonist (Cetrorelix; 10 (-6) M) significantly attenuated the proliferation in normal B-LCLs. GnRH-II did not affect proliferation of normal B-LCLs alone, and did not alter the proliferative response to IL-2. Further investigation is required to clarify the physiological relevance of local GnRH-I/GnRH-II in immune system responsiveness.
Exp Clin Endocrinol Diabetes 2004 Nov
PMID:Expression of gonadotropin-releasing hormone type-I (GnRH-I) and type-II (GnRH-II) in human peripheral blood mononuclear cells (PMBCs) and regulation of B-lymphoblastoid cell proliferation by GnRH-I and GnRH-II. 1557 34

Due to their immunosuppressive effects, glucocorticoids (GC) are widely used in the treatment of inflammatory and autoimmune states. However, long-term GC treatment is associated with severe side effects. To increase the ratio of wanted and unwanted GC effects, is, therefore, a desirable goal, which could be achieved by either developing new "dissociating" GC or by combining conventional GC therapy with substances that selectively interfere with glucocorticoid receptor (GR) function. Vitamin B6 was previously shown to inhibit GR transactivation in non-immune cells. In the present study, we tested whether vitamin B6 would also interfere with GR function in immune cells and/or with transrepression in non-immune cells. Normal human lymphocytes and Jurkat T lymphoma cells were transfected with luciferase reporter constructs under the control of the interleukin-2 (IL-2) and the leukemia inhibitory factor (LIF) promoter, respectively. Cells were stimulated with phorbol ester, ionomycin, and different concentrations of dexamethasone, either in the absence (a vitamin B6-free medium was especially prepared for this study) or presence of vitamin B6. Both promoters were strongly induced in response to phorbol ester and ionomycin. Dexamethasone inhibited this effect in a dose-dependent manner both in the presence and absence of vitamin B6. Similar results were obtained at the protein level (IL-2- and LIF-specific ELISAs). Induction of a glucocorticoid response element (GRE)-driven promoter construct by dexamethasone in lymphoid cells was only marginally reduced by vitamin B6. In contrast, GR-mediated transactivation was strongly inhibited by vitamin B6 in HeLa cells, while GR-mediated transrepression of a matrix metalloproteinase 9 (MMP9) promoter construct was not affected. Our data indicate that vitamin B6 does not interfere with GC action in immune cells (wanted GC effects) while selectively inhibiting GR-dependent transactivation in non-immune cells (unwanted GC effects). Combination of GC treatment with supraphysiological doses of vitamin B6 may, thus, reduce the side effects of this type of immunosuppressive therapy, provided that the observed effects can be reproduced at subtoxic vitamin B6 concentrations in vivo.
Exp Clin Endocrinol Diabetes 2004 Nov
PMID:Vitamin B6 modulates glucocorticoid-dependent gene transcription in a promoter- and cell type-specific manner. 1557 35


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