Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the circumsporozoite protein (CSP) of the malaria parasite is the most immunologically characterized protein, the goal of using this protein in an effective vaccine has not yet been realized. Monoclonal antibody against the repetitive immunodominant B-epitope of the CSP can protect mice from malaria, but vaccines that induce antibody against this epitope do not consistently induce protection. Toward developing a rationale for a CSP-based effective vaccine, we have re-investigated the ability of anti-CSP repeat antibodies, as induced by different CSP vaccine formulations with several adjuvants, to confer sterile immunity against sporozoite challenge. Using Plasmodium berghei rodent malaria model and several CSP subunit vaccine constructs, we found that a formulation consisting of the P. berghei CSP repetitive epitope, (DPPPPNPN)2 (CS), conjugated to BSA by carbodiimide, formulated in a block copolymer and detoxified lipopolysaccharide (RaLPS) adjuvant, was particularly promising. Mice were immunized and boosted with vaccines that contain varying malarial peptide-carrier ratios of 6:1 (CS6-BSA), 55:1 (CS55-BSA) and 170:1 (CS170-BSA). Following immunization, the animals were challenged with live sporozoites. Two types of effects were observed in vaccinated mice. First, sterile immunity was induced in 100%, 50% and 29% of mice that were immunized with the CS170-BSA, CS55-BSA, and CS6-BSA vaccine conjugates, respectively. The second effect of immunization was observed with the CS170-BSA conjugate vaccine primed mice; a boost in IFA titers followed sporozoite challenge. In addition, we observed that IgG1 isotype titer against the surface of the sporozoite, as measured by IFA, and antibody avidity parallel sterile immunity. These findings reiterate the potential of the CSP as a malaria vaccine candidate antigen, and suggest that the induction of sterile immune responses depends on inducing antibody of the appropriate isotype, avidity and specificity.
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PMID:Re-investigation of the circumsporozoite protein-based induction of sterile immunity against Plasmodium berghei infection. 881 31

Tumor necrosis factor alpha (TNF alpha) is a central mediator of the immunological response and the location of the gene within the major histocompatibility complex (MHC) has prompted much speculation about the role of TNF alpha alleles in inflammatory and MHC-associated autoimmune diseases. A G to A transition polymorphism at position -308 of the TNF alpha promoter/enhancer region has been described. The uncommon -308A allele was shown to be strongly associated with human leukocyte antigen (HLA)-DR3, known to be related to a TNF alpha "high producer" phenotype. In support for a clinical relevance, the -308A allele is implicated in susceptibility for cerebral malaria. In this study, we determined the junctional consequences of the TNF -308 polymorphism. Therefore, we analyzed both allelic forms (TNF alpha(-308G) and TNF alpha(-3O8A)) of the TNF alpha enhancer/promoter region (-598/+108) in a transient transfection system, using chloramphenicol acetyltransferase (CAT) as reporter gene. The T cell line Jurkat and the B cell line Raji served as hosts in these experiments. The results showed no differences in the level of inducible reporter gene expression between the TNF(-3O8G)/CAT and the TNF(-308A)/CAT constructs. These data were confirmed by allele specific TNF alpha transcript quantification (ASTQ) analysis, which demonstrated that both TNF alleles contribute equally to the total amount of mRNA in peripheral blood mononuclear cells (PBMCs) stimulated with phorbol 12-myristate 13-acetate (PMA)/anti-CD3. In analogy, no difference between the level of transcription of the -308A and -308G alleles was observed in lipopolysaccharide (LPS)-stimulated peripheral blood monocytes. This study indicates that the TNF alpha -308 G to A transition is not responsible for differential TNF alpha production induced by standard in vitro stimuli.
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PMID:Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation. 883 66

Tumor necrosis factor (TNF) is recognized as a central mediator of sepsis, septic shock, and multiple organ failure. These host reactions are associated with increased TNF levels in circulation, presumably due to increased TNF production. A previously described nucleotide variation at position -308 in the promoter region of the human TNF gene was shown to be associated with the clinical outcome of malaria. In this study we addressed the relevance of the -308 polymorphism for expression of the human TNF gene in response to bacterial endo- toxin in vivo and in vitro. First, we typed 80 patients suffering from severe sepsis and 153 healthy individuals and found no association of the -308 variation with incidence of the disease. In contrast, the NcoI marker in the closely linked lymphotoxin-alpha (LT-alpha) gene showed association with survivaL This discrepancy can be explained by the linkage of the TNFB2(NcoI) allele to the common TNF1 (-308) allele. Second, we generated reporter gene constructs with the promoter deletions and with both -308 variation in the context of the extended human TNF promoter region. Although such constructs were highly inducible by lipopolysaccharide (LPS) in transient transfections into a macrophage cell line, the -308 variation had no significant effect on transcription, consistent with the promoter deletion study. We conclude that the functional consequence of the -308 polymorphism may be unrelated to transcriptional response of the TNF gene to bacterial endotoxin.
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PMID:-308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. 883 66

The immunological specificites of two human rheumatoid factor-reactive IgG monoclonal antibodies derived from unstimulated rheumatoid synovial lymphocytes have been analysed. A malaria antigen-reactive IgG monoclonal antibody from an immune donor served as a control. Purified IgG monoclonal antibody from one IgG-RF hybridoma (L1), but not from the other IgG-RF hybridoma (D1) or the anti-malaria monoclonal antibody, exhibited dose-dependent binding to multiple self and non-self antigens such as ds-DNA, cytochrome-c, bovine thyroglobulin, transferrin, cellulose and lipopolysaccharide and therefore was considered polyreactive. The immunological specificity was confirmed by inhibition experiments using the same soluble antigens as inhibitors. The polyreactivity of the IgG-RF MoAb was markedly inhibited by absorption with glycoproteins such as thyroglobulin, a commonly used target for xenoreactive natural antibodies, and cytochrome-c, indicating that the monoclonal antibody is reactive with epitopes expressed on these ligands. Since some naturally occurring antibodies are carbohydrate specific, the authors tested the IgG-RF MoAb for possible carbohydrate specificity. Absorption with certain polysaccharides containing only one or two different sugar moieties did not inhibit the binding reactivities to any of the tested antigens. Polyreactivity of the monoclonal antibody, unlike most xenoreactive natural antibodies, was not caused by reactivity with (gal alpha 1-3gal) as indicated by the remaining binding reactivity after alpha-galactosidase treatment of the antigen. Removal of the N-linked glycosylation sites within the Fc portion of target IgG markedly reduced the antibody binding. The findings suggest that the carbohydrate content of the antigen is necessary for binding of the polyreactive IgG-RF MoAb. Reactivity to carbohydrate antigens may readily explain the so-called multispecificity of certain antibodies.
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PMID:Binding specificities of a polyreactive and a monoreactive human monoclonal IgG rheumatoid factor: role of oligosaccharides. 894 98

Pentoxifylline and the two analogues HWA138 and HWA448, at concentrations exceeding 60 micrograms/ml, inhibited malaria antigen or lipopolysaccharide (LPS) induced TNF-alpha and IL-1 alpha secretion, but not IL-6 secretion, from human peripheral blood mononuclear cells in vitro. HWA448 had lower inhibitory activity in vitro than pentoxifylline and HWA138. A small enhancement of cytokine secretion was induced by pentoxifylline and the two analogues at low concentrations. The drugs did not affect cell viability. Pentoxifylline, HWA138 and HWA448 also inhibited LPS induced TNF production in vivo in female CF1xBalb/c mice. The drugs were inhibitory at 0.5-1 mg per mouse when mixed with LPS, and 1 mg per mouse of the drugs was inhibitory when injected 1 h before LPS challenge. HWA448 had similar inhibitory activities in vivo compared to pentoxifylline and HWA138, possibly because of the longer serum half-life of HWA448. The pentoxifylline analogues may have lower toxicity than pentoxifylline itself and may therefore be useful in future treatment of diseases induced by endotoxic substances.
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PMID:Inhibition of LPS and Plasmodium falciparum induced cytokine secretion by pentoxifylline and two analogues. 916 Jan 1

Various molecules expressed on the surface of platelets have been shown to mediate the protective or deleterious role of these cells in immuno-inflammatory mechanisms. Increasing evidence points to the involvement of the cell adhesion molecules, gpIIb-IIIa, P-selectin, CD31, LFA-1, and CD36 in the interaction between platelets and endothelial cells as well as other cell types. The possible role of these molecules in the ability of platelets to support endothelium and to protect against tumour necrosis factor mediated cytolysis or parasitic invasion are reviewed. The involvement of platelets as effectors of tissue damage in cerebral malaria, lipopolysaccharide induced pathology, and pulmonary fibrosis is also discussed. This has then been extended to include the intercellular mechanisms underpinning their pathogenic role in metastasis, transplant rejection, stroke, brain hypoxia, and related conditions. A better understanding of the complex regulation and hierarchical organisation of these various platelet adhesion molecules may prove useful in the development of new approaches to the treatment of such diseases.
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PMID:Role of platelet adhesion in homeostasis and immunopathology. 935 Mar

When mice previously cured of a Plasmodium vinckei infection were subsequently infected with Salmonella enteritidis the course of bacterial infection was significantly retarded, showing increased survival duration as compared with control infections in naive mice. Moreover, on stimulation with lipopolysaccharide and/or interferon-gamma, spleen cells from malaria-cured mice showed an increased capacity to produce tumor necrosis factor, interleukin 6, and reactive nitrogen intermediates as compared with spleen cells from naive mice. However, no significant variation in the capacity of spleen cells to release reactive oxygen intermediates was observed between previously malarious and naive mice. The most significant increases were observed in the capacity for reactive nitrogen intermediate production after P. vinckei malaria. These results suggest that the observed protection of mice against salmonellosis in the convalescent phase after malaria may be mediated by nitric oxides.
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PMID:Protection of mice previously infected with Plasmodium vinckei against subsequent Salmonella enteritidis infection is associated with nitric oxide production capacity. 949 29

The effect of quinine on fever induced by lipopolysaccharide and brewer's yeast has been investigated in rats. Oral administration of 50 or 100 mg kg(-1) quinine, doses which had no effect on normothermic rats, significantly reduced lipopolysaccharide- (50 microg kg(-1), i.m.) and yeast- (2 g kg(-1)) induced fever in rats. Pentoxifylline (100 mg kg(-1)), a tumour necrosis factor antagonist also attenuated the febrile response induced by lipopolysaccharide, but not that by yeast, in a manner similar to quinine. Piroxicam (5 mg kg(-1)), a cyclooxygenase inhibitor suppressed both types of fever with a longer duration of action. In addition to its anti-pyretic effect, quinine had a significant anti-inflammatory effect in the carrageenan model of acute inflammation in the hind-paw of rats. The results indicate the anti-inflammatory and anti-pyretic potential of quinine which might be important in addition to its anti-plasmodial action in the therapy of cerebral malaria.
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PMID:A study of the anti-pyretic effect of quinine, an alkaloid effective against cerebral malaria, on fever induced by bacterial endotoxin and yeast in rats. 953 Sep 92

Tumour necrosis factor (TNF) is known to have procoagulant activity, and platelet depletion is a feature of TNF-mediated systemic inflammatory responses. The aim of this study was to investigate the role of fibrinogen consumption in the development of TNF-mediated systemic inflammatory responses and in the associated depletion of platelets. Three murine models of TNF-mediated systemic inflammatory responses were examined: the systemic toxicity reactions (STR) induced by TNF or lipopolysaccharide (LPS) and severe malaria (SM), a prominently neurological complication of Plasmodium berghei ANKA infection in susceptible mice. There was an acceleration in the consumption of fibrinogen during TNF-STR but not during LPS-STR or SM. However, a concomitant reduction in platelet count was found in all conditions. Mice preliminarily depleted in fibrinogen by treatment with ancrod, an enzyme that specifically degrades fibrinogen, showed no protection against mortality during TNF- or LPS-STR or SM, although they were protected against tissue damage during a modification of the classical local Shwartzman reaction. During TNF- and LPS-STR platelets were even lower in ancrod-treated than control mice and during SM they were not significantly different. This study shows that fibrinogen consumption, although accelerated by the direct injection of TNF, is not necessary for the development of TNF-mediated systemic inflammatory responses in mice, at variance with local pathology, and does not contribute to the associated depletion of platelets.
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PMID:Mortality and platelet depletion occur independently of fibrinogen consumption in murine models of tumour necrosis factor-mediated systemic inflammatory responses. 961 77

The effects of synthetic malaria pigment (beta-haematin, BH) on the expression of the intercellular adhesion molecule 1 (ICAM-1) and platelet endothelial cell adhesion molecule 1 (PECAM-1) and the production of interleukin-6 (IL-6) by human microvascular endothelial cells were measured using flow cytometry analysis and immunoenzymatic assay. BH alone did not affect basal levels of ICAM-1, PECAM-1 or IL-6. When added to cell cultures before or with, but not after, lipopolysaccharide or tumour necrosis factor alpha, BH at 1-100 micrograms/mL induced a dose-dependent inhibition of ICAM-1 and PECAM-1 expression and IL-6 production. Cell viability and human leucocyte antigen A,B,C expression remained unaffected. Similar, though more variable, results were obtained using human umbilical vein endothelial cells. These results suggested that accumulation of pigment within endothelial cells following repeated malaria infection reduces local inflammation and parasite sequestration through inhibition of either cytokine production or parasitized erythrocyte receptors on endothelial cells.
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PMID:The effect of synthetic malaria pigment (beta-haematin) on adhesion molecule expression and interleukin-6 production by human endothelial cells. 969 53


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