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:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV-induced neurological disease is postulated to be caused by indirect mechanisms. Tumor necrosis factor (TNF)alpha is increased in the brains in human immunodeficiency virus (HIV)-associated dementia and in the spinal cord in vacuolar myelopathy and may play a pathogenetic role in these diseases. Microglia, astrocytes and infiltrating macrophages can be induced to produce TNF alpha and each has been identified as a source of TNF alpha in neurological disease. Reverse transcriptase synthesis of cDNA and polymerase chain reaction amplification of the cDNA was combined with immunocytochemistry to identify the cellular source of TNF alpha in HIV-induced neurological disease. Cells positive for TNF alpha mRNA were more abundant in white matter than gray matter of the brain from demented individuals. TNF alpha mRNA-positive cells in brains and spinal cords were almost exclusively macrophage-lineage cells. Only rare TNF alpha mRNA-positive cells were astrocytes. We conclude that macrophage-lineage cells are the primary source of elevated central nervous system TNF alpha mRNA in providing further evidence that macrophage activation is an important element in the pathogenesis of HIV-associated neurological disease.
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PMID:Cellular localization of tumor necrosis factor mRNA in neurological tissue from HIV-infected patients by combined reverse transcriptase/polymerase chain reaction in situ hybridization and immunohistochemistry. 911 60

Tumor necrosis factor-alpha (TNF-alpha) and platelet-activating factor (PAF) have been implicated in the pathogenesis of human immunodeficiency virus (HIV)-associated encephalopathy. The effects of pentoxifylline on brain PAF levels were examined in mice infected with the LP-BM5 murine leukemia virus (MuLV). Seven weeks after viral inoculation, significant increases in serum TNF-alpha and brain PAF levels were observed. One week of treatment with pentoxifylline initiated 6 weeks postinfection significantly reduced both serum TNF-alpha and brain PAF levels. A significant positive correlation was observed between the levels of these substances (r = 0.62; P < 0.01). This study demonstrates that pentoxifylline treatment was effective in decreasing the levels of TNF-alpha in the serum and PAF levels in the brain of mice infected with the LP-BM5 MuLV.
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PMID:Pentoxifylline decreases brain levels of platelet activating factor in murine AIDS. 915 42

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were measured by ELISA in 4.5-h, lipopolysaccharide-stimulated whole blood cultures of 347 human immunodeficiency virus type 1-infected patients and 107 healthy seronegative controls. The production of TNF-alpha was decreased in both AIDS and non-AIDS patients, whereas the production of IL-1beta was decreased in AIDS patients only. The production of TNF-alpha and IL-1beta was positively affected by the concentrations of CD14+ monocytes and CD8+ lymphocytes; however, in patients, the concentration of CD4+ lymphocytes and the presence of AIDS had a negative effect on cytokine production as determined by multiple linear regression analysis. It is concluded that low whole blood cytokine production is mainly caused by low numbers of cells, but a functional defect may also exist.
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PMID:Decreased short-term production of tumor necrosis factor-alpha and interleukin-1beta in human immunodeficiency virus-seropositive subjects. 918 Jan 95

Tumor necrosis factor (TNF)-alpha controls T-cell activation and is a major inducer of human immunodeficiency virus (HIV)-1 replication in chronically infected cells. Therefore, we have investigated its role in primary cultures of HIV-infected human T lymphocytes by using neutralizing anti-TNF-alpha antibodies or TNF-alpha. Primary resting T lymphocytes produced TNF-alpha and supported HIV replication after T-cell receptor activation. Addition of neutralizing anti-TNF-alpha antibodies drastically reduced p24 antigen release and prevented CD4+ cell depletion associated with infection. Anti-TNF-alpha also prevented nuclear factor-kappa B (NF-kappa B) activation, and a good correlation between this inhibition and inhibition of HIV replication was observed. Moreover, supplementing the cultures with high doses of IL-2 reverted anti-TNF-alpha inhibition of cell proliferation but did not affect the inhibition of HIV p24 antigen release or NF-kappa B activation in the same cultures. Moreover, anti-TNF-alpha inhibited HIV-1 long terminal repeat (LTR)-driven transcription of a reporter gene in primary T cells in response to activation, either in the presence or the absence of HIV-1 Tat. Our results support an important role for autocrine TNF-alpha secretion in controlling HIV replication in primary T cells because of its ability to maintain NF-kappa B elevated in the nucleus of T cells.
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PMID:Replication of human immunodeficiency virus-1 in primary human T cells is dependent on the autocrine secretion of tumor necrosis factor through the control of nuclear factor-kappa B activation. 943 95

In the human lymphoblastoid T cell line JJhan-5.1, stably transfected with a human immunodeficiency virus-1 long terminal repeat luciferase vector, the level of luciferase activity is dependent on activation of the nuclear factor kappaB (NF-kappaB) transcription factor. Tumor necrosis factor-induced luciferase activity was not modified in JJhan-5.1 cells co-cultivated with murine adenocarcinoma EMT-6 cells but was strongly decreased when nitric oxide (NO) synthase 2 expression was induced in these cells. Two NO synthase inhibitors counteracted this inhibitory effect. Tumor necrosis factor-alpha binding to JJhan-5.1 cells was not modified after incubation with EMT-6 cells. Viability and protein synthesis in JJhan-5.1 cells were also unchanged. Induction of NF-kappaB DNA binding activity was inhibited when EMT-6 cells expressed NO synthase 2 activity. Aminoguanidine, which completely abolished nitrite production, prevented this inhibition. NF-kappaB activation was also strongly inhibited by S-nitrosoglutathione but was marginally affected by N-(2-aminoethyl)-N-(2-hydroxy-2-nitrosohydrazino)-1, 2-ethylenediamine. Taken together, these results indicated that NO-related species, released by EMT-6 effector cells and probably different from NO itself, inhibited NF-kappaB activation in human lymphoblastoid target cells. Consequently, transcriptional activity of a long terminal repeat-driven luciferase gene construct was markedly diminished.
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PMID:Inhibition of NF-kappaB and HIV-1 long terminal repeat transcriptional activation by inducible nitric oxide synthase 2 activity. 946 73

This work aims at identifying the thymocyte subpopulation able to support human immunodeficiency virus (HIV) replication under the biological stimuli of the thymic microenvironment. In this report we demonstrate that interaction with thymic epithelial cells (TEC) induces a high-level replication of the T-tropic primary isolate HIV-1(B-LAIp) exclusively in the mature CD4(+) CD8(-) CD3(+) thymocytes. Tumor necrosis factor (TNF) and interleukin-7 (IL-7), secreted during this interaction, are critical cytokines for HIV long terminal repeat transactivation through NF-kappaB-dependent activation. TNF is the major inducer of NF-kappaB and particularly of the p50-p65 complex, whereas IL-7 acts as a cofactor by sustaining the expression of the p75 TNF receptor. The requirement for TNF is further confirmed by the observation that the inability of the intermediate CD4(+) CD8(-) CD3(-) thymocytes to replicate the virus is associated with a defect in TNF production during their interaction with TEC and correlates with the absence of nuclear NF-kappaB activity in these freshly isolated thymocytes. Addition of exogenous TNF to the intermediate thymocyte cultures induces NF-kappaB activity and is sufficient to promote HIV replication in the cocultures with TEC. The other major subpopulation expressing the CD4 receptor, namely, the double-positive (DP) CD4(+) CD8(+) CD3(+/-) thymocytes, despite the entry of the virus, do not produce a significant level of virus, presumably because they are unresponsive to TNF and IL-7. Together, these data suggest that in vivo, despite an efficient entry of the virus in all the CD4(+) subpopulations, a high viral load may be generated exclusively within the mature CD4(+) CD8(-) CD3(+) subset of thymocytes. However, under conditions of inflammatory response after infection, TNF might also be present in the intermediate thymocyte compartment, leading to efficient HIV replication in these cells.
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PMID:Thymocyte-thymic epithelial cell interaction leads to high-level replication of human immunodeficiency virus exclusively in mature CD4(+) CD8(-) CD3(+) thymocytes: a critical role for tumor necrosis factor and interleukin-7. 1043 43

The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key regulatory protein in the HIV-1 replication cycle. Tat interacts with cellular transcriptional factors and cytokines, such as tumor necrosis factor (TNF-alpha), and alters the expression of a variety of genes in HIV-1-infected and noninfected cells. To further elucidate the mechanisms by which HIV-1 Tat amplifies the activity of TNF-alpha, we transfected the HIV-1 tat gene into an epithelial (HeLa) cell line. We observed that Tat-expressing cells had increased NF-kappa B-dependent trans-activational activity due to enhanced NF-kappa B--DNA binding in response to TNF-alpha treatment. Tumor necrosis factor receptor (TNFR) p55 was the prominent receptor, as neutralizing antibodies to TNFR p55, but not to TNFR p75, blocked TNF-alpha-mediated NF-kappa B activation. Furthermore, tat-transfected cells were more sensitive to TNF-alpha-induced cytotoxicity and only the neutralizing antibodies to TNFR p55 completely protected the cells. To determine whether TNFR p55 was involved in amplification of cellular response to TNF-alpha by HIV-1 Tat, we investigated the effect of TNF-alpha on TNFR p55 expression in the tat-transfected cells. TNF-alpha treatment resulted in a reduction in both TNFR p55 mRNA and protein levels in the control cells but not in the tat-transfected cells as determined with Northern blot and Western blot analyses, respectively. Our results indicate that HIV-1 Tat may inhibit TNF-alpha-induced repression of TNFR p55 and thereby amplify TNF-alpha activity in these stably transfected cells.
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PMID:HIV type 1 Tat inhibits tumor necrosis factor alpha-induced repression of tumor necrosis factor receptor p55 and amplifies tumor necrosis factor alpha activity in stably tat-transfected HeLa Cells. 1152 82

Gram-positive organisms causing sepsis have gained more significance in the past years. Especially patients with acquired immunodeficiency have been shown to be at risk for gram-positive infections. The mortality in Streptococcus pneumoniae bacteremia has been shown to be as high as 20%. Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the "sepsis cascade." The previously described positive effect of monoclonal TNF antibody (anti-TNF-mAb) in gram-negative sepsis should be controlled in gram-positive pneumococcal sepsis. In a porcine model, pneumococcal sepsis was induced, and the course and outcome of a group treated with anti-TNF-mAb were compared to those of an untreated control. Streptococcus pneumoniae serotype 6 B was isolated from patients with systemic infection. The isolates were prepared, cryopreserved at -80 degrees C, and recultivated in a standardized fashion as needed. Then 10(9) bacteria were injected intravenously. Pigs of the German Landrace type with a weight of 20-30 kg were anesthetized using standardized midazolam and ketamine intravenous anesthesia. After introduction of central venous, arterial, and urinary catheters, bacteria were injected intravenously via the ear vein. In the therapy group, animals were treated with anti-TNF-mAb (5 mg/kg body weight) intravenously immediately prior to pneumococci injection. Survival and survival times were primary endpoints. Biochemical and vital parameters were also compared. In the anti-TNF-mAb group, 4/11 animals died (35%), compared to 6/11 (55%) in the control group. The mean survival times were 11 and 10 h, respectively (n.s.). TNF levels were significantly different. The TNF peak at 90-240 min was not present in the anti-TNF group (340 pg/ml vs. 19 pg/ml, p = .034). Leukocyte counts differed also significantly. After an initial drop in both groups, we observed a leukocytosis of up to 32.8 +/- 5.0 g/L in the anti-TNF-group, while in the control group leukocyte counts remained below 15.0 g/L (13.3 +/- 3.0 g/L, p = .007). All other parameters did not differ significantly. Thus, anti-TNF-mAb effectively suppresses the TNF peak following gram-positive septicemia. In the presented setting, these effects did not influence overall survival or survival times.
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PMID:Anti-TNF antibody treatment has no positive effect on survival in a model of pneumococcal sepsis in pigs. 1170 Sep 23

Tumor necrosis factor a (TNF-alpha) is a pleiotropic cytokine involved in several diseases. Various effects of TNF-alpha are mediated by the induction of a cellular state consistent with oxidative stress. Glutathione (GSH) is a major redox-buffer of eukaryotic cells and is important in the defense against oxidative stress. We hypothesized that persistent TNF-alpha secretion could induce oxidative stress through modulation of GSH metabolism. This hypothesis was examined in a transgenic mouse model with low, persistent expression of human TNF-alpha in the T cell compartment. Major findings were i) marked tissue-specific changes in GSH redox status and GSH regulating enzymes, with the most pronounced changes in liver; ii) moderate changes in GSH metabolism and up-regulation of GSH-regulating enzymes were observed in lung and kidney from transgenic mice; and iii) liver, lung and kidney from transgenic mice had decreased levels of total glutathione, whereas splenic CD4+ and CD8+ T cells had a marked increase in oxidized glutathione as the major change. Oxidative stress induced by persistent low-grade exposure to TNF-alpha in transgenic mice appears to involve marked organ-specific alterations in glutathione redox status and glutathione-regulating enzymes with the most pronounced changes in the liver. These mice constitute a useful model for immunodeficiency syndromes and chronic inflammatory diseases involving pathogenic interaction between TNF-alpha and oxidative stress.
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PMID:Human TNF-alpha in transgenic mice induces differential changes in redox status and glutathione-regulating enzymes. 1220 44

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


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