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)

In this report we report that recombinant human monocyte-macrophage colony-stimulating factor-1 (CSF-1) induces resident murine peritoneal cells (PCs) to transcribe several inflammatory cytokine genes, including interleukin (IL)-1 alpha, IL-1 beta, IL-6, and granulocyte-macrophage CSF in a dose-dependent and time-related manner. Peak mRNA levels were seen between 4 and 6 h. CSF-1 did not modulate the expression of tumor necrosis factor-alpha mRNA. The serum content of the culture medium appeared to regulate both the extent of CSF-1-induced gene transcription and the adherence properties of the cells. Decreasing the serum concentration significantly reduced CSF-1-induced transcription and was associated with the rapid spreading of the majority of the adherent cells. This reduced sensitivity to CSF-1 was paralleled by a markedly lower levels of c-fms mRNA encoding the CSF-1 receptor. Induced gene transcription was followed by the release of large quantities of IL-6 only. IL-1 activity remained associated with the cells. Neither supernatant nor cell lysate granulocyte-macrophage CSF activity was inducible above the low levels associated with control cultures. Evidence that the mononuclear phagocytes, as opposed to B or T cells, were the targets of CSF-1 was obtained in two ways: (1) PCs from B6 scid/scid and NOD scid/scid mice consisting of 78-86% MAC-1+, F4/80+ cells and few B or T cells, as shown by flow cytometry analysis, released 5- to 10-fold more IL-6 in response to CSF-1 stimulation than B6 PCs, which contained approximately 30% double-positive cells, and (2) pretreatment of B6 PCs with antibodies to the CSF-1 receptor blocked the CSF-1-induced secretion of IL-6. These data suggest that CSF-1 primes noninflammatory mononuclear phagocytes for a role in inflammatory responses but does not provide the necessary signals for either secretion or translation of all cytokines equally.
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PMID:The potential role of the macrophage colony-stimulating factor, CSF-1, in inflammatory responses: characterization of macrophage cytokine gene expression. 761 11

There is now increasing evidence that the hormonal form of vitamin D, 1,25(OH)2D3, is involved in the regulation of the immune system. Local production of the hormone in various infectious diseases can benefit the immune environment. 1,25(OH)2D3 exerts most of its actions only after it has bound to its specific nuclear receptor. These receptors are present in monocytes and activated lymphocytes. The hormone inhibits lymphocyte proliferation and immunoglobulin production in a dose-dependent fashion. It also blocks the accumulation of the mRNAs for IL-2, IFN-gamma and GM-CSF. It interferes with T helper cell (Th) function, reducing Th-induction of immunoglobulin production by B-cells and inhibits the passive transfer of cellular immunity by Th in vivo. The steroid hormone promotes suppressor cell activity and inhibits the generation of cytotoxic and NK cells. The expression of Class II antigen by lymphocytes and monocytes is also affected. In vivo, 1,25(OH)2D3 is particularly effective in preventing auto-immune diseases such as experimental auto-immune encephalomyelitis, murine lupus, and diabetes in NOD mice. Synthetic analogues of vitamin D3 that bind to receptors but have no hypercalcemic effect in vivo have recently been developed for therapeutic use.
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PMID:[Vitamin D and the immune system]. 809 May 62

Cells infiltrating the Langerhans' islets of prediabetic NOD females were isolated from 6 weeks to 6 months of age. These cells were assayed at a single-cell level for production of eight different cytokines by intracellular immunofluorescent staining. By in vitro stimulation with PMA and ionomycin for 4 hours the method is enhanced also to detect in vivo preactivated cells. During the early phase of insulitis from 6 to 12 weeks of age, mainly the monokines IL-1 alpha, IL-6, and TNF were detected. After stimulation, also IFN-gamma and low numbers of IL-10 and GM-CSF producing cells could be observed, but no IL-2 or IL-4 was seen. This cytokine pattern correlates with an increasing insulitis, and we suggest that these cytokines are important in attracting inflammatory cells to the islets, and may cause initial beta-cell destruction. During a later phase, between 4 and 6 months, there is a characteristic TH1 cytokine profile with production of IL-2 and IFN-gamma occurring after stimulation, as well as lymphocytes producing TNF, supposedly TNF-beta. During this period IL-10 was very rarely observed, and no IL-4 production could be found throughout the study. This indicates the absence of a TH2 cytokine profile in this lesion. In addition IL-6 production occurs in high frequencies at all ages, also in endocrine islet cells. We interpret this as a stress response caused by the inflammatory lesion. Our findings show that the effector phase in NOD insulitis is TH1 rather than TH2 mediated. We also demonstrate that cytokines, that may cause initial tissue destruction, are produced during the recruitment of inflammatory cells.
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PMID:Demonstration of a TH1 cytokine profile in the late phase of NOD insulitis. 866 48

Cells infiltrating the Langerhans' islets of prediabetic NOD females were isolated from 6 weeks to 6 months of age. These cells were assayed at a single-cell level for production of eight different cytokines by intracellular immunofluorescent staining. Quiescent in vivo preactivated cells were detected by in vitro stimulation with PMA and ionomycin for 4 h. The cell recruitment phase, between 6 and 12 weeks of age, is predominated by production of the monokines IL-1alpha, IL-6, and TNF After stimulation IFN-gamma and occasional IL-10 and GM-CSF producing cells could also be observed. This cytokine pattern occurs simultaneously with increasing insulitis, and we suggest that these cytokines are important in attracting inflammatory cells to the islets and maintaining the inflammatory state. A high frequency of endocrine cells producing IL-6 during this period may denote a stress response caused by initial beta-cell destruction due to cytokines released by the inflammatory cells. During the effector phase, between 4 and 6 months, there is a characteristic Th1 cytokine profile with lymphocytes producing IL-2, IFN-gamma and TNF, supposedly TNF-beta. No IL-4 production could be detected and IL-10 was very rarely found, indicating the absence of a Th2 response. Our findings show that the effector phase in NOD insulitis is a Th1 rather than a Th2-mediated event. We also demonstrate that cytokines that may cause initial tissue destruction are produced during the recruitment of inflammatory cells.
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PMID:Monokine-producing cells predominate in the recruitment phase of NOD insulitis while cells producing Th1-type cytokines characterize the effector phase. 918 76

Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor alpha (TNFalpha) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFalpha monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.
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PMID:Inhibition of granulocyte-macrophage colony-stimulating factor prevents dissemination and induces remission of juvenile myelomonocytic leukemia in engrafted immunodeficient mice. 938 8

We report a patient with familial myoclonus showing an extremely benign clinical course. The patient was a 70-year-old woman, who first noticed shaking of hands at age of 25. The symptom did not worsen for more than 40 years. She visited our hospital at the age of 70 because of disturbance in chores because of worsening of her hand shaking in the past one year. A family history showed that 4 members had similar symptoms and that the two were afflicted with fits of loss of consciousness. On neurologic examination, rhythmic myoclonic jerks were noted in all the extremities, more in the upper limbs, both at rest and during action. Tandem gait was mildly disturbed. The remainings of neurologic examination were normal. SEP and jerk-locked back averaging provided evidence of cortical myoclonus. EEG showed multifocal polyspike discharges. Gene analysis for DRPLA, pyruvate and lactate levels in serum and the cerebrospinal fluid, serum amino acid levels, and CSF HVA and 5-HIAA levels were all normal. No brain atrophy was noted in cranial MRI. Myoclonus was markedly reduced after administration of clonazepam. The clinical features and electrophysiological data of our patient are consistent with the clinical diagnosis of familial essential myoclonus and epilepsy/benign adult familial myoclonic epilepsy.
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PMID:[A case of familial myoclonus showing extremely benign clinical course]. 980 89

Retroviral transduction of human hematopoietic stem cells is still limited by lack of information about conditions that will maximize stem cell self-renewal divisions in vitro. To address this, we first compared the kinetics of entry into division of single human CD34+CD38- cord blood (CB) cells exposed in vitro to three different flt3-ligand (FL)-containing cytokine combinations. Of the three combinations tested, FL + hyperinterleukin 6 (HIL-6) yielded the least clones and these developed at a slow rate. With either FL + Steel factor (SF) + HIL-6 + thrombopoietin (TPO) or FL + SF + interleukin 3 (IL-3) + IL-6 + granulocyte-colony-stimulating factor (G-CSF), >90% of the cells that formed clones within 6 days undertook their first division within 4 days, although not until after 24 hours. These latter two, more stimulatory, cytokine combinations then were used to assess the effect of duration of cytokine exposure on the efficiency of transducing primitive CB cells with a gibbon ape leukemia virus-pseudotyped murine retroviral vector containing the enhanced green fluorescent protein (GFP) cDNA and the neomycin resistance gene. Fresh lin- CB cells exposed once to medium containing this virus plus cytokines on fibronectin-coated dishes yielded 23% GFP+ CD34+ cells and 52-57% G418-resistant CFC when assessed after 2 days. Prestimulation of the target cells (before exposing them to virus) with either the four or five cytokine combination increased their susceptibility. In both cases, the effect of prestimulation assessed using the same infection protocol was maximal with 2 days of prestimulation and resulted in 47-54% GFP+ CD34+ cells and 67-69% G418-resistant CFC. Repeated daily addition of new virus (up to three times), with assessment of the cells 2 days after the last addition of fresh virus, gave only a marginal improvement in the proportion of transduced CD34+ cells and CFC, but greatly increased the proportion of transduced LTC-IC (from 40% to >99%). Transplantation of lin- CB cells transduced using this latter 6-day protocol into NOD/SCID mice yielded readily detectable GFP+ cells in 10 of 11 mice that were engrafted with human cells. The proportion of the regenerated human cells that were GFP+ ranged from 0.2-72% in individual mice and included both human lymphoid and myeloid cells in all cases. High-level reconstitution with transduced human cells was confirmed by Southern blot analysis. These findings demonstrate that transplantable hematopoietic stem cells in human CB can be reproducibly transduced at high efficiency using a 6-day period of culture in a retrovirus-containing medium with either FL + SF + HIL-6 + TPO or FL + SF + IL-3 + IL-6 + G-CSF in which virus is added on the third, fourth, and fifth day.
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PMID:Optimization of retroviral-mediated gene transfer to human NOD/SCID mouse repopulating cord blood cells through a systematic analysis of protocol variables. 1034 Mar 97

We evaluated two bone marrow-derived dendritic cell (DC) populations from NOD mice, the murine model for type 1 human diabetes. DCs derived from GM-CSF [granulocyte/macrophage colony-stimulating factor] + interleukin (IL)-4 cultures expressed high levels of major histocompatibility complex (MHC) class II, CD40, CD80, and CD86 molecules and were efficient stimulators of naive allogeneic T-cells. In contrast, DCs derived from GM-CSF cultures had low levels of MHC class II costimulation/activation molecules, were able to take up mannosylated bovine serum albumin more efficiently than GM + IL-4 DCs, and were poor T-cell stimulators. The two DC populations migrated to the spleen and pancreas after intravenous injection. To determine the ability of the two DC populations to modulate diabetes development, DCs were pulsed with a mixture of three islet antigen-derived peptides or with medium before injection into prediabetic NOD mice. Despite phenotypic and functional differences in vitro, both populations prevented in vivo diabetes development. Pulsing of the DCs with peptide in vitro did not significantly improve the ability of DCs to prevent disease, which suggests that DCs may process and present antigen to T-cells in vivo. In addition, we detected GAD65 peptide-specific IgG1 antibody responses in DC-treated mice. Overall, these results suggest that a Th2 response was generated in DC-treated mice. This response was optimal when using GM + IL-4 DCs, which suggests that the balance between regulatory Th2 and effector Th1 cells may have been altered in these mice.
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PMID:Immunotherapy of NOD mice with bone marrow-derived dendritic cells. 1058 Apr 17

The patient was a 72-year-old man who had a history of subtotal gastrectomy for gastric ulcer at age of 37 years. He had no familial history of hereditary disorders. In 1980 he noticed mild ataxic gait which exaggerated while he closed eyes. The symptoms increased gradually, and four years later he noticed hypoesthesia of his soles. In 1983 he was admitted to the National Center Hospital for Mental, Nervous and Muscular Disorders for the first time. Neurological examination revealed dysarthria, ataxic gait, disturbance of coordination to a slight degree, and muscle strength of the upper and lower limbs were in normal range. Mild hypoesthesia of pain and temperature sensation, and marked decrease of deep sensation and vibration of the lower extremities were demonstrated. Romberg sign was positive. EMG studies revealed low amplitude of action potential and normal motor nerve conduction velocity. Biopsy of the sural nerve showed marked decrease of both large and small myelinated fibers. In 1998 he was admitted second time for the further examination. Laboratory examination including routine blood examination, blood chemistry including CRP, TPHA, vitamin B1, B2, B12, A, E, K, hexosaminidase A in leucocyte were in normal range. CSF was normal. Genetic studies including SCA 1, 2, 3, 6, DRPLA, CMT1A, CMTX 1 were all negative. MCV of lower limbs was in normal range, though SCV was not evoked in the upper and lower limbs. MRI studies showed mild atrophy of the bilateral lobulus of the cerebellum which was not so much changed in the last 5 years. The clinical symptoms revealed dominant posterior column disturbance, ataxia and sensory neuropathy. These combination was not described in the previous literature, and this case may be a new variant of the spinocerebellar degeneration.
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PMID:[A case with posterior column ataxia associated with cerebellar ataxia and sensory neuropathy]. 1061 59

IL-18 is a cytokine with potent IFN-gamma inducing activities as well as an important mediator of Th1 polarized immune responses. In this study we demonstrated that IL-18 induces the concentration-dependent production of the proinflammatory mediators IFN-gamma, IL-6, and GM-CSF, but not the anti-inflammatory cytokine, IL-10 from peripheral blood lymphocytes in the presence of mitogen. Three neutralizing IL-18 monoclonal antibodies (MAbs) were investigated, one of which (2C10) inhibited IL-18 bioactivity with an IC50 of 0.1 nM and had a K(D) of 3.9 x 10(-11) M. A NOD/SCID mouse model engrafted with human peripheral blood lymphocytes was developed to test the in vivo efficacy of this MAb. The IFN-gamma production induced by LPS administration was inhibited approximately 90% by prior dosing of MAb 2C10. The therapeutic utility of a high-affinity IL-18 MAb may be of benefit in Th1-driven autoimmune diseases such as rheumatoid arthritis and Crohn's Disease, where elevated levels of IL-18 have been observed.
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PMID:Characterization of the in vitro and in vivo activity of monoclonal antibodies to human IL-18. 1112 25


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