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

Protection against virulent challenge with murine Plasmodium yoelii malaria was induced by immunization with whole killed blood-stage parasites in copolymer P1004 and detoxified lipopolysaccharide as adjuvant. Similar immunization with Freund's complete adjuvant and other water-in-oil emulsions failed to protect. Protection was associated with the production of antibody of the IgG2a isotype against epitopes measured by immunofluorescence. Several formulations that did not protect elicited high antibody titers measured by enzyme-linked immunosorbent assays or titers of other isotypes measured by indirect immunofluorescent assay. The results provide additional evidence that the adjuvants influenced both the isotype and specificity of antibody. The implications of these findings for vaccine development are discussed.
 ...
PMID:Copolymer adjuvants in malaria vaccine development. 817 32

Numerous studies have demonstrated that most or all of the potent adjuvant activity of Gram-negative bacterial endotoxin resides in the lipid A moiety of lipopolysaccharide (LPS). Synthetic analogues of lipid A have provided insights into structure-activity relationships. Several cellular mechanisms of LPS and lipid A adjuvant activities have been identified. Activation of macrophages by LPS or lipid A results in cytokine secretions that enhance the immune response. LPS and lipid A cause recruitment of antigen-presenting cells, particularly macrophages. Liposomes containing lipid A serve as an in vivo adjuvant to recruit increased numbers of macrophages. Liposomal lipid A that has been phagocytized by cultured macrophages also serves as an "intracellular adjuvant" to cause increased immunologic presentation of liposomal antigen by the macrophages to specific T lymphocytes. Lipid A can abolish suppressor T cell activity, resulting in increased immune responses to polysaccharide antigens. Upon combination of lipid A or lipid A analogues with nonionic block polymers, modulation of murine antibody isotypes can be achieved with antibodies against a variety of antigens in vivo. Liposomes containing monophosphoryl lipid A (MPL) have been utilized in a phase I clinical trial of a proposed malaria vaccine in humans. The liposomal malaria vaccine resulted in very high levels of antibodies against the malarial antigen, and despite the presence of huge amounts of MPL (up to 2.2 mg), the liposomal lipid A was nonpyrogenic and safe for use in humans. Lipid A and lipid A analogues, and liposomes or other carriers containing lipid A, have shown considerable promise both as adjuvants for immunization of animals and for human vaccines.
 ...
PMID:Lipopolysaccharide, lipid A, and liposomes containing lipid A as immunologic adjuvants. 833 Sep 7

The effect of tumour necrosis factor-alpha on malaria-infected mice was studied. C57Bl/6J mice infected with Plasmodium berghei K173 exhibited an increased sensitivity to exogenous TNF. Injection of 15 micrograms TNF was lethal to some of the animals when given 5-7 days after infection, while when given later on in the infection (i.e. days 8-10) amounts as low as 2.5 micrograms TNF appeared to be lethal in all mice. The pathology in infected mice treated with TNF resembled that found in the brains of infected mice dying with cerebral malaria. Infected mice treated with TNF, however, also developed severe pathological changes in other organs. On the contrary, treatment with sublethal amounts of TNF (1.0 micrograms or less) given on days 8 and 9 after infection, protected mice against the development of cerebral malaria. In addition, infected mice exhibited and enhanced sensitivity for treatment with lipopolysaccharide (LPS). Sublethal amounts of LPS, however, did not prevent mortality as in TNF-treated mice (LPS-treated mice died at about the same time as infected mice that developed cerebral malaria), but no cerebral haemorrhages were found in the majority of LPS treated, infected animals. Treatment with dexamethasone during infection protected mice against the development of cerebral malaria, but did not suppress their increased sensitivity to exogenous TNF. Treatment of mice with liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP), used to eliminate macrophages (an important source of TNF), prevented the development of cerebral malaria, but only when given before day 5 of infection. Mice protected by treatment with lip-Cl2MDP, however, remained sensitive for LPS on the eighth day of infection.
 ...
PMID:Tumour necrosis factor-alpha and macrophages in Plasmodium berghei-induced cerebral malaria. 841 66

Phospholipid-containing antigens of malaria parasites stimulate macrophages to secrete tumour necrosis factor (TNF), induce hypoglycaemia and are toxic to mice. This TNF induction is inhibited by antisera made against the antigens, the inhibitory activity of which can be removed specifically by adsorption to phosphatidylinositol (PI) liposomes. Although the same was true of antisera made against PI, the inhibitory activity of antisera made against some other phospholipids appeared to be directed against a common determinant, probably the phosphate ester head group. We have shown previously that the activity of all the antisera was associated mainly with IgM and was not boosted by repeated injections of the antigens. To try and induce a secondary response against the parasite antigens using non-toxic molecules, mice were immunized with various phosphorylated compounds coupled to keyhole limpet haemocyanin (KLH). Three injections of PI-KLH or of phosphatidylserine (PS) coupled to KLH induced significantly higher titres of inhibitory antibody than one; furthermore, the inhibitory activity was mainly in the IgG fraction. The antisera did not inhibit TNF induction by lipopolysaccharide (LPS) or lipoteichoic acid. However, antisera against PS-KLH, though not PI-KLH, inhibited the induction of TNF by the phospholipid, platelet-activating factor (PAF). These antisera, and antisera from mice immunized with phospho-threonine or galactosamine-1-phosphate conjugated to KLH, contained inhibitory antibodies of differing specificities. Mice immunized with PI-KLH, PS-KLH or phospho-threonine-KLH did not develop hypoglycaemia when challenged with the parasite toxic antigens. These results indicate that the antigenicity of non-toxic analogues can be dramatically enhanced by coupling to a protein carrier.
 ...
PMID:Phospholipids coupled to a carrier induce IgG antibody that blocks tumour necrosis factor induction by toxic malaria antigens. 850 34

The purpose of this study was to investigate the ability of the antimalarial drug, Ro 42-1611 to block parasite mediated cytokine induction in vitro as well as cytoadherence of infected erythrocytes to melanoma cells in vitro. The biological activity of Ro 42-1611 was confirmed as it blocked Plasmodium falciparum growth in cultures. Ro 42-1611, had no major effect on TNF, IL-alpha or IL-6 cytokine release from mononuclear cells stimulated with malaria antigens or lipopolysaccharide and it did not affect cell viability. Ro 42-1611 only slightly suppressed cytoadherence of infected erythrocytes to melanoma cells. The therapeutic effect of To 42-1611 appears to be confined to its parasite killing activity.
 ...
PMID:The antimalarial drug, Ro 42-1611 (arteflene), does not affect cytoadherence and cytokine-inducing properties of Plasmodium falciparum malaria parasites. 852 91

To investigate the effect of the heme moiety of malaria pigment, hemozoin, on phagocyte functions, mouse macrophages were fed with insoluble beta-hematin, the synthetic heme-polymer chemically identical to the native pigment, or the soluble monomer, hematin. Production of inflammatory cytokines, interleukin 1 (IL1), tumor necrosis factor alpha (TNF alpha), and nitric oxide (NO) was assayed in the supernatants after stimulation with lipopolysaccharide. The results indicate that both beta-hematin and hematin induce a dose-dependent inhibition of macrophage production of TNF alpha and NO, but not of IL1. One-hour pretreatment with soluble hematin inhibited production of cytotoxic mediators by more than 50% compared to controls, while 6-hr exposure was necessary for insoluble beta-hematin to induce the same level of inhibition. However, the same treatment did not modify the production of TNF alpha and NO by mouse microglia cell lines. The inhibition was partially counterbalanced by adding sulphydryl group donors such as 2-mercaptoethanol, glutathione, or N-acetyl-cysteine during the preincubation time. The results of the present study confirm the inhibitory role of malaria pigment and show that such effect is due to the heme moiety and may be selective for the production of cytotoxic mediators by specific phagocytes. The implications of these findings in the control of malaria infection and disease and in the pathogenesis of severe malaria are discussed.
 ...
PMID:The heme moiety of malaria pigment (beta-hematin) mediates the inhibition of nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide-stimulated macrophages. 854 91

When murine peritoneal macrophages were loaded in vitro with Plasmodium vinckei hemozoin and stimulated with opsonized zymosan for 90 min or with lipopolysaccharide and/or murine interferon-gamma for 24 hr, significant decreases in the production of oxygen radicals and nitrogen oxides, respectively, could be detected by comparison with macrophages without hemozoin. Moreover, nonradioactive in situ hybridization and immunohistologic analysis in liver sections of P. vinckei-infected mice with more than 60% parasitemia showed that liver cells were still expressing considerable levels of inducible nitric oxide synthase in the late phase of murine malaria, but most of the liver macrophages presenting accumulation of malaria pigment were negative in this analysis. These results further indicate that malaria pigment accumulation may be responsible for toxicity and impairment of macrophage functions during murine malaria.
 ...
PMID:Effects of Plasmodium vinckei hemozoin on the production of oxygen radicals and nitrogen oxides in murine macrophages. 868 81

CD36 is an 88-kD integral membrane protein expressed on platelets, monocytes, macrophages, certain microvascular endothelia, and retinal pigment epithelium. It functions as an adhesive receptor for thrombospondin-1 (TSP-1), collagen, and malaria-infected erythrocytes and as a scavenger receptor for oxidized LDL and photoreceptor outer segments. The CD36-TSP-1 interaction plays a role in cell adhesion and the phagocytosis of apoptotic cells by macrophages. Because of the potential importance of the CD36-TSP-1 interaction in mediating atherogenic and inflammatory processes, we studied their expression in human peripheral blood monocytes exposed to soluble mediators known to regulate inflammation and atherogenesis. RNase protection assays showed 6- to 12-fold increases in CD36 mRNA in response to interleukin-4, monocyte colony-stimulating factor, and phorbol myristate acetate, while lipopolysaccharide and dexamethasone strongly downregulated CD36 mRNA. The downregulation of CD36 mRNA was associated with the disappearance of surface expression of CD36 antigen and loss of TSP-1 surface-binding capacity. Upregulation of CD36 mRNA was associated with a modest increase in surface antigen expression and a larger expansion of an intracellular pool of CD36. As with CD36, monocytes treated with monocyte colony-stimulating factor showed a rapid increase in TSP-1 mRNA expression. Moreover, while dexamethasone treatment decreased CD36 expression, it resulted in a rapid increase in TSP-1 mRNA, and while PMA increased CD36 mRNA, it rapidly decreased TSP-1 expression. Interferon gamma, which had no effect on CD36 mRNA, rapidly increased steady-state TSP-1 mRNA. Thus, expression of both CD36 and its ligand TSP-1 is regulated by soluble mediators, although certain mediators induce concordant changes and others discordant changes.
 ...
PMID:Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. 869 41

Malaria toxin causes hypoglycemia and induction of tumor necrosis factor. Extracts of parasitized erythrocytes which were coeluted and copurified with one of the two subtypes of mammalian insulin-mimetic inositolphosphoglycans similarly induced fibroblast proliferation in the absence of serum. In addition, induction of tumor necrosis factor in macrophages by malaria toxin and by lipopolysaccharide from Escherichia coli was enhanced by pretreatment of these toxins with alpha-galactosidase. Thus, parasitized erythrocytes contain both soluble inositolphosphoglycan-like insulin second messengers and endotoxin-like lipidic molecules.
 ...
PMID:Structural similarities among malaria toxins insulin second messengers, and bacterial endotoxin. 875 90

The excessive production of tumour necrosis factor (TNF) is associated with the pathology of blood-stage malaria and phosphatidylinositol-containing phospholipid antigens from parasitized erythrocytes stimulate its secretion by macrophages, thus acting as toxins. This brief report describes some properties of an inhibitor present in lysates from erythrocytes infected with malarial parasites that blocked the detection of recombinant TNF in an enzyme-linked immunosorbent assay and diminished or abolished the cytotoxicity of TNF. It was not found in control lysates of normal erythrocytes. Its addition to macrophage cultures stimulated by toxic malarial preparations or by bacterial lipopolysaccharide also blocked the detection of TNF. These findings may explain the contradictory results obtained from different assays for TNF, and emphasize the need for caution when interpreting the results of a single assay system. If released when parasitized erythrocytes rupture in vivo, the inhibitor could help protect both parasite and host from the damaging effects of TNF.
 ...
PMID:Malaria: a tumour necrosis factor inhibitor from parasitized erythrocytes. 877 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>