Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0751781 (NOD)
6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A macroscopic low-voltage-activated (LVA) inward current was found in pancreatic beta-cells isolated from NOD mice. However, this current was not present in nondiabetic prone mouse (e.g., Swiss-Webster) pancreatic beta-cells. We performed pharmacological analyses on this current in NOD insulinoma tumor cells (NIT-1). This cell line was developed from pancreatic beta-cells of a transgenic NOD mouse. The sodium-channel blocker, tetrodotoxin (TTX; 2 micromol/l) had no effect on this LVA current. The amplitudes of currents elicited by a -20 mV test pulse retained similarity when the extracellular sodium concentration was increased from 0 to 115 mmol/l; when the extracellular calcium concentration was decreased from 10 to 2 mmol/l, there was an approximate 50% reduction of this current elicited by a -30 mV test pulse. Neither the L-type calcium-channel blocker, nifedipine (3 micromol/l), nor the N-type calcium-channel blocker, omega-CgTx-GVIA (1 micromol/l), at -30 mV produced an appreciable effect. The T-type calcium-channel blockers, nickel (3 micromol/l) and amiloride (250 micromol/l), effectively reduced the peak of this current. In 2 mmol/l calcium external solution, the threshold of voltage-dependent activation of this calcium current was approximately -65 mV, and the peak current occurred at -20 mV. Half-maximum steady-state inactivation was around -43 mV. The mean time constant of slow deactivating tail currents generated by a preceding 20 mV pulse was 2.53 ms. The intracellular free calcium concentration was two- to threefold higher in NOD mouse pancreatic beta-cells compared with Swiss-Webster pancreatic beta-cells. We concluded that there are LVA calcium channels abnormally expressed in NOD mouse beta-cells. This LVA calcium channel may be factorial to the high cytosolic free calcium concentration observed in these cells, and thereby may contribute to the pathogenesis of NOD mouse beta-cells.
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PMID:Abnormally expressed low-voltage-activated calcium channels in beta-cells from NOD mice and a related clonal cell line. 892 51

Our group previously reported an assay for the study of lymphocyte adhesion to insulin-producing cells in which xenogeneic rat insulinoma (RIN) cells were used as targets. The present study found an increased number of RIN-cytoadherent lymphocytes in 63 patients with Type 1 diabetes compared with 150 control subjects and in 211 NOD mice compared with 104 BALB/c mice (p < 0.001). Proteins concentrated from spontaneous RIN cell culture supernatants inhibited increased RIN-adhesion of NOD splenocytes or lymphocytes from diabetic patients (p < 0.001). In addition, increased RIN binding was dose-dependently abolished by RIN membrane extracts. The fact that RIN binding was inhibited by proteins from both membrane and the culture supernatant from RIN cells suggests that soluble inhibitory proteins were spontaneously released into the supernatant from a hydrophobic membrane-bound form. This tended to be confirmed since inhibition obtained with both preparations involved a 55-75 kDa HPLC protein fraction. The possibility that the membrane form of the inhibitory protein was anchored by a glycosylphosphatidylinositol (GPI) tail was evaluated. When RIN cells were treated with PI-PLC, their ability to bind lymphocytes from diabetic patients or NOD splenocytes decreased (p < 0.001) to control levels. Co-incubation with the 55-75 kDa fraction of proteins cleaved from RIN cells by PI-PLC also lowered the number of RIN-adherent NOD splenocytes to control levels. SDS-PAGE and IEF analyses of the 55-75 kDa inhibitory fraction from RIN cell supernatant revealed a major band with Mr 66 kDa and PI5.4, which may correspond to a protein with similar characteristics noted on 2-D electrophoresis of proteins cleaved from RIN cells by PI-PLC. Specific labelling of GPI moieties with 3H-ethanolamine, 3H-glucosamine, or 14C-glucosamine, as well as conversion of the hydrophobic Triton-X114 solubilised form into a hydrophilic form after PI-PLC treatment, confirmed the presence of a GPI anchor in this approximately 66 kDa RIN protein, which could thus be the molecule inhibiting adhesion in the system. Our data suggest that GPI-proteins from insulin-producing cells may influence the immune system both in their membrane-anchored and soluble forms. When considering the binding model, in which beta cells were tumoral and xenogeneic to diabetic lymphocytes, this potential influence of GPI-proteins suggests possible implications in situations of lymphocyte-beta cell interaction, i.e. anti-beta cell autoimmunity, immune reaction against insulinomas, and reaction against islet xenografts.
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PMID:Proteins spontaneously released by rat insulinoma (RIN) cells are anchored on cell membrane by a glycosyl-phosphatidyl-inositol link and inhibit increased RIN cell adhesion of lymphocytes from type 1 diabetic patients and non-obese diabetic mice in vitro. 898 53

We have recently observed that inhibition of NF-kappaB in NIT-1 insulinoma cells protects them from tumour necrosis factor (TNF)-induced cell death in vitro, possibly because expression of interleukin-1 (IL-1)beta-converting enzyme (ICE), a member of the cysteine protease pathway of cell death, is decreased. In the current study we have examined the effect of the same inhibitor of NF-kappaB on class I major histocompatibility complex (MHC) protein expression in NIT-1 cells and shown that inhibition of NF-kappaB activation decreased basal and TNF-induced class I MHC levels. Although inducible nitric oxide synthase (iNOS) may also be inhibited by inhibition of NF-kappaB, this could not be demonstrated in NIT-1/delta sp cells because wild-type NIT-1 cells express very little iNOS. When NIT-1/delta sp12 cells, expressing high levels of the NF-kappaB inhibitor, are transplanted into immunodeficient NOD/scid mice, tumorigenesis and death by hypoglycemia proceed similarly to untransfected NIT-1 cells. Untransfected NIT-1 cells were killed by co-transfer of splenic T cells from diabetic but not non-diabetic NOD mice. NIT-1/delta sp12 cells were protected from killing in vivo by T cells from diabetic mice, in that tumours developed in four out of five mice and the kinetics of tumour development were not significantly delayed. NIT-1/delta sp12 cells were not protected from killing by T cells from mice previously primed with NIT-1 cells. In conclusion, inhibition of NF-kappaB is likely to suppress several different pathways of immune-mediated cell death in beta-cells and protects NIT-1 cells from immune attack by diabetogenic T cells in vivo. Inhibition of NF-kappaB is a potentially effective strategy for protection of pancreatic beta-cells in autoimmune diabetes.
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PMID:Protection of NIT-1 pancreatic beta-cells from immune attack by inhibition of NF-kappaB. 921 57

A CD8 T-cell clone (YNK1.3) generated from acutely diabetic NOD mouse islets, showed proliferation and cytotoxicity when challenged with NOD and BALB/c islet cells and NOD-derived insulinoma cells. When 1-2 x 10(7) YNK1.3 cells were administered to 7-10-day-old NOD mice, the cells transferred overt diabetes very rapidly in each of the 16 recipients within 4 days of cell transfer. However, of 14 recipients receiving YNK 1.3 cells above 14 days of age none became diabetic. Fluorescent dye-labelled YNK1.3 cells extensively accumulated in the islets by 36 h after transfer in 7-day-old NOD recipients, while no significant insulitis was seen in 21-day-old recipients. Over half of NOD-scid recipients (5/9) rapidly became diabetic within 5 days after transfer of 1-2 x 10(7) YNK1.3 cells at 7 days of age, whereas only one of 12 recipients over 14 days of age became diabetic. Furthermore, YNK1.3 cells also transferred diabetes to H-2Kd-matched very young BALB/c-scid and CB17-scid mice, but not to C57BL/6-scid mice. Thus, optimally activated islet-specific CD8 T-cell clones are able to rapidly transfer diabetes to NOD and MHC class I compatible scid mice when a large enough number is administered at 7 days of age. Administration of monoclonal antibodies against adhesion molecules involved in the trafficking of lymphocytes from the circulation into the inflammatory tissues, could not prevent the cellular infiltration of YNK1.3 cells into the islets in 7-day-old NOD recipients. The results indicate that islet cells in the mouse around 7 days of age are generally susceptible to cytotoxic CD8 T cells, suggesting, therefore, that CD8 T cells may play an important role in the initiation of autoimmune diabetes in NOD mice.
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PMID:CD8 cytotoxic T-cell clone rapidly transfers autoimmune diabetes in very young NOD and MHC class I-compatible scid mice. 930 Feb 41

Exogenous insulin may prevent the auto-immunity of diabetes in rodents. We studied the preventive effect of a safe endogenous insulin delivery in the diabetes-prone NOD mouse by immuno-protected human insulinoma grafts. Perm-selective macrocapsules seeded with human insulinoma were implanted in 34 young NOD mice, 4 and 8 weeks old. The animals were observed 18 months and compared to 34 NOD mice grafted with empty fibers and 25 simply observed. Before grafting, the capacity of the macrocapsules to release insulin was assessed in vitro by perifusion studies and by implantation to 12 diabetic NOD mice. At perifusion, the insulin release of the macrocapsules responded to step changes in glucose. During the in vivo study, the capsules reduced the glycemia of diabetic mice from 18+/-3.5 to 7.3+/-2.1 mmol/L. In the study groups, the survival rate without diabetes (50-70%) was statistically different from controls (10-20%). Recipient's splenocytes transplanted to irradiated male NOD mice transferred the autoimmunity in 75-83% of grafted mice and 86-100% of controls. Insulitis was persistent in all, although milder in the grafted mice. Encapsulated insulinoma prevents diabetes in the NOD mouse without abolishing the auto-immunity. The quantity and quality of the tissues needed and the best moment to graft them have to be determined. The prevention of diabetes by encapsulated pancreatic tissue is appealing because of its simplicity and safety.
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PMID:Grafted immunoisolated human benign insulinoma reduces the incidence of diabetes in young NOD mice without abolishing the auto-immunity. 946 74

Insulin replacement by injection is clearly not a cure for Insulin Dependent Diabetes Mellitus (IDDM). Replacement of the destroyed islets by pancreas or islet allograft transplantation can achieve the good metabolic control required to prevent diabetic complications, but tissue supply is limited. The problem of islet supply to treat the 1 million IDDM patients in the USA could be overcome by using immortalized islet beta-cells as a donor source. However, before either allogeneic or xenogeneic immortalized beta-cells are used, some major problems have to be overcome: control of immortalized cell growth, allograft or xenograft rejection and recurrence of autoimmunity. To tackle these problems we have used a cell impermeable immunoisolation device containing mouse insulinoma cells. Transplantation of devices with insulinomas from NOD mice carrying the Rat-insulin promoter regulated SV40 T-Antigen transgene (RIP-TAg), normalized the blood glucose levels of diabetic NOD mice. Insulinomas from allogeneic CBA/NOD-RIP-TAg mice were also capable of normalizing diabetic NOD mice. Not only were non-fasting blood glucoses normalized but when given an intraperitoneal injection of glucose, the corrected mice had a near normal clearance of glucose from the blood. When the devices were removed from normalized mice they became diabetic again, demonstrating that the immunoisolation device was capable of protecting against both alloimmune and autoimmune destruction. The results with allogeneic mouse beta-cells suggest the possibility that immortalized human beta-cells could be an effective source of tissue to correct diabetes in IDDM patients without the use of immunosuppression.
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PMID:Correction of diabetic nod mice with insulinomas implanted within Baxter immunoisolation devices. 993 Sep 67

CD4+ lymphocytes are the most important effector cells in autoimmune diabetes of NOD mice, although some role of CD8+ T cells has been demonstrated. However, it is unknown how CD4+ lymphocytes are able to destroy pancreatic beta-cells that do not express MHC (major histocompatibility complex) class II molecules. Apoptotic cell death mediated by an interaction of Fas with Fas ligand (FasL) could be a mechanism by which MHC class II-negative pancreatic beta-cells are destroyed by CD4+ T lymphocytes. We have examined the expression of Fas molecules in pancreatic islet cells, as well as in a NOD-derived mouse insulinoma cell line (MIN6N8). In addition, the role of Fas-mediated apoptosis in pancreatic islet cell death was explored in vitro. Although Fas expression was not detected by flow cytometric analysis, Fas transcripts were demonstrated in MIN6N8 cells and pancreatic islet cells by the sequencing analysis of the cloned reverse transcription polymerase chain reaction products using Fas-specific primers. IFN (interferon)-gamma, tumor necrosis factor-alpha, interleukin-1 and their combinations failed to enhance Fas expression. Unsorted activated splenocytes from diabetic NOD mice had cytotoxic T lymphocyte activity of a small degree against IFN-gamma-treated MIN6N8 cells with FasL upregulation. However, agonistic anti-Fas antibody with or without cycloheximide did not exert cytotoxicity against MIN6N8 cells or pancreatic islets. FasL transfectant cells also did not kill MIN6N8 cells. Our data indicate that pancreatic beta-islet cells express a small amount of Fas molecules but Fas molecules do not mediate apoptosis of islet cells at least in vitro.
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PMID:Fas is expressed in murine pancreatic islet cells and an insulinoma cell line but does not mediate their apoptosis in vitro. 1043 99

Interleukin-18 (IL-18) mRNA is expressed in islets of NOD mice during the early stages of insulitis and IL-18 has therefore been implicated as a contributing factor in immune-mediated beta-cell destruction. However, a recent study failed to show any effect of human IL-18 on the function of isolated rat islets. Since species differences have been shown between human and murine IL-18, the aims of this study were to investigate 1) if species homologous IL-18 alone or following IL-12 pre-exposure affected rat islet function, 2) if IL-18 dose-dependently modulated IL-1 beta or interferon-gamma (IFN-gamma) + tumor necrosis factor-alpha (TNF-alpha) actions on islet function, and 3) if IL-18 and IL-18 receptor (IL-18R) were expressed in rat islet beta-cells. Insulin release and nitric oxide (NO) production from isolated rat islets were measured after incubation with or without cytokines. RT-PCR was used to quantitate mRNA expression of IL-18 and the IL-18R signaling chain (IL-18R beta). There were no significant effects of 0.625-10 nM recombinant murine (rm) IL-18 alone on accumulated or glucose-challenged insulin release or NO production after 24 hours. Fifteen pg/ml of recombinant human (rh) IL-1 beta as well as 200 U/ml recombinant rat (rr) IFN-gamma + 250 U/ml rhTNF-alpha significantly increased islet NO production and inhibited both accumulated and glucose-challenged islet insulin release. However, rmIL-18 failed to modulate these effects of IL-1 beta or IFN-gamma + TNF-alpha. Although IL-12 induces IL-18R expression in Th1 and B lymphocytes, 24-hours rmIL-12 preincubation neither sensitized islets to effects of 10 nM of rm or rrIL-18 alone nor primed the islets to IL-1 beta actions on insulin release and NO production. IL-18R beta mRNA, which was expressed in human peripheral blood mononuclear cells (PBMC), was not expressed in rat insulinoma (RIN) cells or in isolated rat islets, even after exposure to IL-1 beta and/or IFN-gamma + TNF-alpha or IL-12. IL-18 mRNA was constitutively expressed in RIN cells, in FACS-purified rat beta-cells and in intact rat and mouse islets, and was up-regulated by IFN-gamma in an interferon regulatory factor-1- IRF-1) and NO - independent manner. However, IL-18 protein was undetectable in lysates and supernates of RIN cells by ECL, Western blotting and immunoprecipitation. In conclusion, we show for the first time that IL-18 but not IL-18R is expressed in rodent islet beta-cells. The physiological importance and pathological role of IL-18 originating from islet beta-cells deserve further investigation.
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PMID:Interleukin-18 mRNA, but not interleukin-18 receptor mRNA, is constitutively expressed in islet beta-cells and up-regulated by interferon-gamma. 1090 98

In a model of transplantation rejection, we have tested whether a graft manipulated to secrete immunomodulators could protect itself from immune destruction. An insulinoma cell line having the NOD genotype but also expressing the neoantigen, SV40 T antigen, was transfected with CTLA4Ig or LFA3Ig to block signals in the co-stimulatory/adhesion pathways. This neoantigen is potent at inducing graft rejection. Secretion of CTLA4Ig and LFA3Ig by transfectants promoted survival of the insulinoma graft in young NOD mice. In immunodeficient mice, cell growth was similar for all transfectants. However, in immunocompetent NOD mice the survival/growth of test grafts was significantly better than that of the controls. Graft survival was enhanced additively, when the two test transfectants were cotransplanted. Endowing the graft the ability to secrete immunomodulators that block individual co-stimulatory/adhesion signals can contribute to transplantation success. Blockade of two signals (CD2 and CD28) in these pathways enhances this success.
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PMID:Enhanced survival of grafts genetically endowed with the ability to block CD2 and B7. 1133 32

We present here the first report of a metalloporphyrin-based antioxidant that can prevent or delay the onset of autoimmune diabetes. Type 1 diabetes is an autoimmune process whereby T-cells recognize pancreatic beta-cell antigens and initiate a leukocyte infiltrate that produces proinflammatory cytokines and reactive oxygen species (ROS), ultimately leading to beta-cell destruction. Because islet beta-cells have a reduced capacity to scavenge free radicals, they are very sensitive to ROS action. Metalloporphyrin-based superoxide dismutase (SOD) mimics scavenge ROS and protect cells from oxidative stress and apoptosis. To investigate the effect of SOD mimics and the role of oxidative stress in the development of autoimmune diabetes in vivo, we used a diabetogenic T-cell clone, BDC-2.5, to induce rapid onset of diabetes in young nonobese diabetic-severe combined immunodeficient mice (NOD.scid). Disease was significantly delayed or prevented altogether by treatment of recipient mice with an SOD mimic, AEOL-10113, before transfer of the BDC-2.5 clone. To investigate the mechanisms of protection, in vitro assays for T-cell proliferation and gamma-interferon (IFN-gamma) production were carried out using the T-cell clone BDC-2.5. We found that the SOD mimic significantly inhibited antigen-presenting cell-dependent T-cell proliferation and IFN-gamma production in vitro. In addition, pretreatment of lipopolysaccharide (LPS)-stimulated peritoneal macrophages with SOD mimic inhibited the LPS-dependent increase in TNF-alpha as well as the NADPH oxidase-dependent release of superoxide. Finally, this compound protected NIT-1 insulinoma cells from interleukin-1beta and alloxan cytotoxicity in vitro.
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PMID:A metalloporphyrin-based superoxide dismutase mimic inhibits adoptive transfer of autoimmune diabetes by a diabetogenic T-cell clone. 1181 41


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