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)

The induction of T helper cell subsets during the course of non-lethal or lethal blood-stage Plasmodium chabaudi AS infection was investigated using inbred strains of mice which differ in the level of resistance to this intraerythrocytic parasite. Resistant C57Bl/6 mice experience a non-lethal course of infection characterized by moderate levels of both parasitaemia and anaemia and resolution of primary acute infection by 4 weeks, while susceptible A/J mice experience lethal infection with fulminant parasitaemia and severe anaemia. T helper subset function was assessed during infection by determining the kinetics of spleen cell production in vitro of the Th1-derived cytokine, interferon-gamma (IFN-gamma), and of the Th2-derived cytokine, IL-5, using sandwich ELISAs. Spleen cells from resistant C57Bl/6 mice were found to produce high levels of IFN-gamma within 1 week of infection in response to both the mitogen concanavalin A (Con A) and malaria antigen. Furthermore, CD4+ T cells were found to be the source of IFN-gamma while both CD4+ and CD8+ T cells were found to produce IL-5. Decreased IFN-gamma production after day 10 was concomitant with significant production of IL-5 between 2 and 3 weeks post infection. In contrast, spleen cells from susceptible A/J mice produced high levels of IL-5 within the first week of infection. In addition, these animals were found to have high serum levels of IL-5. These results, thus, confirm previous observations that resolution of primary blood-stage P. chabaudi infection occurs by sequential activation of Th1 CD4+ T cells followed by activation of the Th2 subset, and in addition, suggest that induction of a strong Th2 response early in infection may lead to a severe and lethal course of malaria.
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PMID:Differential induction of helper T cell subsets during blood-stage Plasmodium chabaudi AS infection in resistant and susceptible mice. 809 4

Monoclonal antibodies (mAb) have revolutionised many areas of medicine, particularly research and diagnostics. Murine, human and humanized mAb have all been developed. The most important clinical applications to date have been in the fields of transplantation and oncology. Experimental and limited clinical trials suggest mAb are emerging as a new therapeutic strategy in the critically ill. Antibodies against a variety of bacteria or their products are potentially useful in gram-positive and gram-negative shock. Anti-cytokine and anti-neutrophil adhesion molecule mAb may be effective not only in septic shock but also in other conditions associated with acute inflammation and cytokine release, e.g., acid aspiration, ischaemia/reperfusion injury (myocardial infarction, haemorrhagic shock, aortic aneurysm repair). Antibodies inhibiting neutrophil adhesion may also be efficacious in asthma, pulmonary fibrosis, meningitis and cerebral malaria. The use of these and other mAb in intensive care is an exciting prospect and future clinical studies will determine the extent of their role in the management of the critically ill.
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PMID:Monoclonal antibodies--immunotherapy for the critically ill. 812 30

Tumour necrosis factor-alpha (TNF-alpha) is an endogenous mediator of shock and inflammation. Many of the life-threatening and severe pathologies associated with complicated and cerebral malaria are thought to result from the overproduction of this cytokine in response to agents of parasite origin. The identification and characterization of these agents may therefore provide the molecular basis for a detailed understanding of the disease process. Recently it has been shown that glycosylphosphatidylinositols are a novel class of glycolipid toxin produced by the parasite, which substitute for the endogenous inositolglycan-based signal transduction pathways of the host. Glycosylphosphatidylinositol stimulates high levels of TNF-alpha and interleukin-1 production by macrophages and induces hypoglycaemia through an insulin-mimetic activity, and may therefore contribute to the cerebral syndrome and other malarial pathophysiology. That monoclonal antibodies to parasite-derived glycosylphosphatidylinositol can neutralize the toxic activities of whole parasite extracts is also demonstrated here. These findings suggest a central role for glycosylphosphatidylinositol of parasite origin in the aetiology of severe malaria and suggest novel approaches for the immunotherapy or immunoprophylaxis of disease.
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PMID:Neutralizing monoclonal antibodies to glycosylphosphatidylinositol, the dominant TNF-alpha-inducing toxin of Plasmodium falciparum: prospects for the immunotherapy of severe malaria. 812 25

This review describes the role of cytokines produced by CD4+ T cells and macrophages in response to the erythrocytic stages of P. chabaudi chabaudi and other malaria infections in mice. Since virtually all compartments of the immune system are activated during the response against malaria, the variety of cytokines produced during infection is considerable. There is, however, a clear differential expression of different cytokines during primary infection. Th1-related cytokines are predominantly produced during the acute phase of infection, and lead mainly to the induction of macrophage-derived cytokines. This antibody-independent pathway is probably on the one hand, sufficient for parasite control early in infection via macrophage-associated inflammatory responses, but can, on the other hand, also lead to the pathological consequences of infection. As the infection progresses, the pattern of cytokine production shifts towards a Th2-like response. B cells play a crucial role in this process. A major consequence of this switch to a production of Th2-related cytokines later in infection would be the down-regulation of IFN-gamma-induced macrophage activation and the promotion of antibody production by mature B cells. This suggest that the mechanism of parasite control in the later stages of infection is predominantly antibody-dependent.
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PMID:The roles of cytokines produced in the immune response to the erythrocytic stages of mouse malarias. 812 18

Serial clinical and metabolic changes were monitored in 115 Gambian children (1.5-12 years old) with severe malaria. Fifty-three children (46%) had cerebral malaria (coma score < or = 2) and 21 (18%) died. Admission geometric mean venous blood lactate concentrations were almost twice as high in fatal cases as in survivors (7.1 mmol/L vs. 3.6 mmol/L; P < 0.001) and were correlated with levels of tumour necrosis factor (r = 0.42, n = 79; P < 0.0001) and interleukin 1-alpha (r = 0.6, n = 34; P < 0.0001). Admission blood venous glucose concentrations were lower in fatal cases than survivors (3.2 mmol/L, vs. 5.8 mmol/L; P < 0.0001). Treatment with quinine was associated with significantly more episodes of post-admission hypoglycaemia when compared with artemether or chloroquine. After treatment, lactate concentrations fell rapidly in survivors but fell only slightly, or rose, in fatal cases. Plasma cytokine levels fluctuated widely after admission. Sustained hyperlactataemia (raised lactate concentrations, 4 h after admission) proved to be the best overall prognostic indicator of outcome in this series. Lactic acidosis is an important cause of death in severe malaria.
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PMID:Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance. 815 8

A mixture of Plasmodium falciparum exoantigens inducing lymphocyte activation and cytokine production was shown to contain the malaria vaccine candidate, the serine-stretch protein. This protein was shown serologically to correspond to Ag2, an exoantigen recognized by antibodies linked with protection against malaria. The glycophorin-binding protein, the histidine-rich protein II, the S-antigen, the heat shock protein 70, the ring-infected erythrocyte surface antigen, and the apical membrane antigen-1 were also shown serologically to be present in the mixture of exoantigens.
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PMID:Serine-stretch protein (SERP) of Plasmodium falciparum corresponds to the exoantigen Ag2, a target of antibodies associated with protection against malaria. 816 1

Tumour necrosis factor (TNF) concentrations are increased in the plasma during a malarial illness, and are highest in patients with severe or fatal disease. We have studied the plasma concentrations of two soluble receptors (sTNF-R1 and sTNF-R2), which act as binding proteins for TNF, in children with falciparum malaria. In 52 Malawian children with malaria, plasma concentrations of both sTNF-R1 (mean (S.D.) 4759(2552) pg/ml) and sTNF-R2 (59077(37102) pg/ml) were greatly increased when compared with levels of convalescence (sTNF-R1 718(68), and sTNF-R2 8015(7021) pg/ml), and in controls without malaria (486(1353) and 4380(2168)). Concentrations of both receptors correlated with plasma levels of TNF measured by immunoradiometric assay, but not with those of another cytokine, IL-6. The mean plasma concentrations of both immunoreactive TNF and soluble TNF receptors were greater in patients with cerebral malaria than those with uncomplicated malaria. Despite high levels of immunoreactive TNF in the plasma of patients acutely ill with malaria, no bioactive TNF could be detected in these patients by the WEHI cell bioassay. Soluble TNF receptors are present in greatly increased concentrations in the plasma of patients with malaria and may play a role in mediating or modulating the pathogenetic effects of the cytokine.
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PMID:Circulating plasma receptors for tumour necrosis factor in Malawian children with severe falciparum malaria. 818 73

There is now considerable evidence that cerebral malaria may be related to the over-production of tumour necrosis factor (TNF). Nevertheless, our knowledge is very poor concerning the biological events which lead up to this TNF over-production. Furthermore, interleukin-6 (IL-6) is produced in large amounts during malaria infection and seems to have inhibitory action on TNF production. Anti-malarial drugs were investigated for their ability to interfere with TNF and IL-6 secretion by human non-immune macrophages stimulated by lipopolysaccharides (LPS) or Plasmodium falciparum culture supernatant. Macrophages were pretreated with chloroquine, quinine, proguanil, mefloquine or halofantrine before stimulation. TNF and IL-6 production were suppressed in a dose-dependent manner when macrophages were treated with chloroquine, but not with other anti-malarial drugs. Considering that chloroquine probably acts via lysosomotropic mechanisms, and that iron metabolism may interfere with the non-specific immune response, we focused our attention on these biochemical events in order to investigate the mechanisms by which chloroquine inhibits cytokine production. Our results demonstrated that chloroquine-induced inhibition of TNF and IL-6 production is not mediated through a lysosomotropic mechanism, and that chloroquine probably acts on TNF secretion by disrupting iron homeostasis. Inhibition of IL-6 production seems not to be mediated through these pathways. These observations suggest that chloroquine may help to prevent cerebral malaria whatever the drug sensitivity of the parasite strain, and may provide new tools for an anti-disease therapy regardless of the emergence of parasite multi-drug resistance.
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PMID:Chloroquine-induced inhibition of the production of TNF, but not of IL-6, is affected by disruption of iron metabolism. 824 53

IL-10 is a monocyte/lymphocyte derived cytokine which has been shown to inhibit certain cellular immune responses such as delayed hypersensitivity. In particular, the production of tumour necrosis factor (TNF), IL-1 and IL-6, which are involved in malaria pathology, are strongly inhibited by IL-10. Accordingly, we examined whether IL-10 could be involved in a human acute parasitic infection such as Plasmodium falciparum malaria. Human IL-10 levels in plasma were determined by two-site ELISA method, taking care to avoid non-specific reactions due to autoantibodies. Fourteen cerebral, 11 severe, and 20 mild malaria cases had mean IL-10 levels of 2812, 2882 and 913 pg/ml, respectively, while 98% of healthy individuals had undetectable (less than 100 pg/ml) circulating IL-10. Thirteen of the 25 cerebral/severe cases had > 2000 pg/ml. In 11 hospitalized patients, circulating IL-10 levels were found to return to virtually normal levels 7 days after antimalarial chemotherapy when biological and clinical malaria features had disappeared (mean levels fell from 3880 to 333 pg/ml). Further studies are required to determine whether these elevated levels of IL-10 play a beneficial role by reducing the parasite-induced inflammatory response, or a detrimental one by decreasing the cellular immune responses.
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PMID:High levels of circulating IL-10 in human malaria. 830 5

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.
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PMID:Lipopolysaccharide, lipid A, and liposomes containing lipid A as immunologic adjuvants. 833 Sep 7


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