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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The origin of illness and pathology in malaria is now largely attributed to high levels of circulating tumour necrosis factor (TNF), released from cells of macrophage lineage after triggering by the products of malarial schizogony. The role of lymphocytes and their products in malarial pathology is not yet known. This paper reports the presence of a related cytokine, lymphotoxin, which is produced only by lymphocytes, in the serum of malarial patients. This is the first report of raised serum levels of lymphotoxin in a systemic disease state. When injected into mice, recombinant human lymphotoxin induced hypoglycaemia and increased serum levels of interleukin-6. These changes, which are seen in severe experimental and human malaria, were also provoked by TNF. Both of these cytokines acted synergistically with interleukin-1, which has also been reported to be raised in malaria, to produce these alterations. These observations imply that lymphotoxin, as well as TNF, may contribute to the hypoglycaemia and raised serum interleukin-6 observed in malaria. This reduces the likelihood of effectively blocking the pathology of this disease by the use of neutralizing antibody directed against just one member of this family of functionally overlapping mediators.
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PMID:Increased lymphotoxin in human malarial serum, and the ability of this cytokine to increase plasma interleukin-6 and cause hypoglycaemia in mice: implications for malarial pathology. 128 10

Tumor necrosis factor and related cytokines are thought to be implicated in cell-mediated immunity and pathophysiology in malaria, but their mechanism of action has not been ascertained. Tumor necrosis factor has been reported to generate nitric oxide in vitro, so we have measured levels of this molecule and its products in the plasma of mice after they have received an injection of tumor necrosis factor, lymphotoxin, interleukin-1, gamma interferon, or interleukin-6, all of which have been reported to be increased in malaria. Total reactive nitrogen intermediate levels in plasma were assayed spectrophotometrically after exposing plasma to a copper-cadmium-zinc catalyst to convert nitrate to nitrite and then to Griess reagent. Tumor necrosis factor, lymphotoxin, and interleukin-1 all induced reactive nitrogen intermediates in vivo, with interleukin-1 showing the most activity. Tumor necrosis factor was then examined more closely. It induced more reactive nitrogen intermediates in malaria-infected mice than in normal mice, and appreciably more was in the form of nitrate than was in the form of nitrite. NG-methyl-L-arginine inhibited the in vivo generation of reactive nitrogen intermediates by tumor necrosis factor in a dose-dependent manner, implying that these molecules were arginine derived. These results are consistent with the possibility that tumor necrosis factor, lymphotoxin, and interleukin-1 may contribute to host pathology and parasite suppression through generation of nitric oxide.
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PMID:In vivo induction of nitrite and nitrate by tumor necrosis factor, lymphotoxin, and interleukin-1: possible roles in malaria. 150 Jan 82

The effect of induction of an acute-phase response and its mediators on the development of liver schizonts of the rodent malaria parasite Plasmodium berghei was investigated in Brown Norway rats. Subcutaneous injection of turpentine oil 24 h or 5 min before inoculation of sporozoites resulted in 80% and 35% reduction of schizont development, respectively. Turpentine oil induced high plasma levels of interleukin-6 (IL-6). Intraperitoneal administration of IL-1, IL-6 or both, significantly reduced liver schizont development. This reduction was also present if IL-6 had been administered 24 h after sporozoite inoculation. Inhibition induced by IL-1 could be prevented by simultaneous administration of polyclonal anti-IL-6. Administration of polyclonal anti-IL-6 without IL-1 resulted in a 40% increase of liver schizonts compared to control animals. We conclude that induction of an acute-phase response during experimental Plasmodium berghei infections in Brown Norway rats, strongly inhibits liver schizont development and that IL-6 is a key mediator in this process.
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PMID:Cytokines inhibit the development of liver schizonts of the malaria parasite Plasmodium berghei in vivo. 151 19

Kinetics of serum levels of interleukin-6 (IL-6) were studied in patients with acute Plasmodium falciparum malaria in relation to vitamin A and its binding proteins, retinol binding protein (RBP) and pre-albumin. It was found that IL-6 levels followed the rise and decrease of parasitaemia by 12 hr and correlated inversely with levels of vitamin A and its binding proteins. These data suggest that vitamin A supplementation alone might still be insufficient to restore a malaria-induced vitamin A deficiency.
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PMID:The role of interleukin-6 in vitamin A deficiency during Plasmodium falciparum malaria and possible consequences for vitamin A supplementation. 157 2

Because Plasmodium berghei ANKA induces cerebral malaria and P. vinckei does not, the former has often been studied as a model for human falciparum malaria. It lacks, however, many of the systemic changes seen in the human disease. Because both of these murine models and the human disease have now been defined in terms of excess tumor necrosis factor (TNF) production, the authors have more closely examined the two murine models in this light to see which provides the better overall model for falciparum malaria. Administering TNF to malaria-infected mice did not cause cerebral symptoms nor breakdown of the blood-brain barrier, which is the hallmark of P. berghei ANKA cerebral malaria and is generally absent in human cerebral malaria. Tumor necrosis factor did, however, induce hypoglycemia and liver injury, pathology that is seen in terminal P. vinckei and falciparum malaria, but is absent in terminal P. berghei ANKA malaria. Plasma TNF and interleukin-6 (IL-6) also were found to be consistently higher in infections caused by P. vinckei than in those caused by P. berghei ANKA. The pathology of P. vinckei malaria is thus consistent with raised systemic levels of TNF and other cytokines, as is falciparum malaria. The authors therefore conclude that P. vinckei malaria, although lacking a cerebral component, is the better model for the human disease.
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PMID:Malaria mimicry with tumor necrosis factor. Contrasts between species of murine malaria and Plasmodium falciparum. 173 26

In this paper, the effects of recombinant human interleukin-1 (IL-1) on non-specific resistance to infection are reviewed. In experiments in neutropenic mice, a single injection of a low dose of IL-1 (8-800 ng) appears to protect against death from lethal Pseudomonas aeruginosa and Candida albicans infections. In non-neutropenic mice protection can also be obtained with such dosages of IL-1 in infection caused by Klebsiella pneumoniae or Listeria monocytogenes. Low dosages of IL-1 are also able to prevent lethal cerebral malaria in mice. No effect has been found in murine cytomegalovirus infection. With the exception of C. albicans infection and malaria, protection is only obtained if IL-1 is given before the infection. The mechanism of protection has not been elucidated; in the Pseudomonas and Klebsiella infection, it could be demonstrated that survival was not due to a direct antibacterial effect of IL-1, not due to the action of granulocytes or increased hematopoietic recovery and not due to activation of macrophages and increased bactericidal mechanisms. In the experimental Listeria infection however, animals treated with IL-1 had lower bacterial counts in their organs. Since the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) are much less potent than IL-1 in these protection experiments, it is very unlikely that they are endogenous mediators of the protection induced by IL-1. The effect is not mediated via the cyclooxygenase pathway, since premedication with ibuprofen does not influence the protective effect of IL-1. Taking these data together, it is felt that IL-1 holds promise as a therapeutic agent in humans.
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PMID:Options for the treatment of serious infections with interleukin-1. 270 46

Cytokine regulation was compared in three groups of Gabonese patients with Plasmodium falciparum malaria before and after therapy; adults with uncomplicated malaria, children with uncomplicated malaria, and children with severe malaria. Plasma levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-8, TNF receptors (TNF R), and the TNF/TNF R ratios were significantly higher in severe malaria compared with uncomplicated malaria. High plasma levels of all immunoregulatory molecules were associated with slow cure after therapy. In all patients, phytohemagglutinin-induced cytokine production was depressed on admission compared with convalescence. A significant difference was the higher TNF production capacity in patients with severe malaria on day 2 and day 5 compared with that in patients with uncomplicated malaria. In contrast to IL-6 and IL-8, a high TNF production capacity during the acute phase of malaria predicted a rapid clinical and parasitologic cure in the patients. These findings illustrate the dual role of TNF in the protection and pathology of malaria.
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PMID:Prediction of accelerated cure in Plasmodium falciparum malaria by the elevated capacity of tumor necrosis factor production. 748 13

The development of antidisease immunity in children infected with Plasmodium falciparum is thought to be related to their immunologic responses to certain soluble parasite-derived exoantigens. We have assessed both cellular and humoral responses to these antigens in a cross-sectional study of a cohort of Gabonese schoolchildren who live in an area where malaria is holoendemic and perenially transmitted, in an attempt to identify immunologic markers of this early developing protective immunity. Concurrent parasitemia was found to have a significant influence on lymphoproliferative and antibody responses to the exoantigens. Individuals with higher levels of parasitemia had significantly lower proliferative and IgG isotype responses. Higher concentrations of specific IgG1 and IgG3, in particular, were associated with lower or no parasitemia, suggesting a possible protective role for these isotypes, whereas the level of IgM antibodies showed a trend towards higher concentrations in those with parasitemia, perhaps indicative of an exoantigen-induced T cell-independent response. Cytokine responses were unaffected by either the presence or the intensity of parasitemia and were dissociated from both proliferative and antibody response to the exoantigens. However, the mitogen-stimulated production of tumor-necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL)-6 was positively correlated with the corresponding lymphoproliferative responses. At the individual level, mitogen-stimulated TNF-alpha, interferon-gamma, IL-2, and IL-6 responses were positively correlated, as were mitogen- and exoantigen-induced TNF-alpha. The results are discussed in the light of current knowledge of immune responses to the exoantigens and the development of protective immunity to P. falciparum.
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PMID:Immunologic responses to soluble exoantigens of Plasmodium falciparum in Gabonese children exposed to continuous intense infection. 781 Aug 4

Both CD4+ and CD8+ T cells, as well as antibody, are known to be important in sporozoite immunity. Data from animal studies suggest that cytokines, in particular gamma-interferon and interleukin-6, are involved. The interplay of these various factors and their importance in vaccine development has, however, not yet been elucidated. In this study, we have studied cellular and humoral responses of individuals naturally exposed to malaria in a highly endemic region of Papua New Guinea to the circumsporozoite protein of Plasmodium falciparum, a prime vaccine candidate antigen. A paucity of any CD4+ lymphoproliferative response to this protein by Papua New Guineans was notable which parallels our recent observation of a paucity of CD8+ T cell response and contrasts markedly with the responses of other endemic populations. There was nevertheless a significant antibody response to the central conserved B cell epitope, (NANP)n, as well as to other critical epitopes. An inverse relationship between gamma-interferon production and interleukin-6 production and a positive correlation between gamma-interferon production and CS peptide-specific lymphoproliferation was observed. High levels of peptide-specific IL-6 production were associated with high levels of peptide-specific serum antibodies. Our data provide evidence for the limited activation of distinct CD4+ T cell subsets and for the existence of functionally distinct subpopulations of human CD4+ T cells with respect to cytokines known to be important in sporozoite immunity.
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PMID:Evidence for limited activation of distinct CD4+ T cell subsets in response to the Plasmodium falciparum circumsporozoite protein in Papua New Guinea. 791 66

Cell surface components of viridans streptococci and enterococci have been shown to stimulate the release of tumor necrosis factor alpha (TNF) and interleukin-6 from monocytes/macrophages. In the sera from 10 patients with subacute enterococcal or streptococcal endocarditis, however, the levels of both cytokines were low or undetectable, with elevated TNF levels on admission in 3 patients with complicated disease. Soluble TNF receptor levels were significantly elevated compared with those of healthy controls. When patients with malaria were used as a control group of acute intravascular infection with high circulating TNF values, the ratio between soluble TNF receptors and TNF on admission was significantly greater in the patients with subacute bacterial endocarditis. Besides different amounts of circulating TNF, enhanced TNF receptor shedding may have an important role in the pathogenesis of subacute versus acute clinical disease following human intravascular infection.
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PMID:Circulating tumor necrosis factor alpha (TNF), soluble TNF receptors, and interleukin-6 in human subacute bacterial endocarditis. 822 16


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