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

A natural body protein is probably a major cause of the deadliest complication of malaria, a finding that could point toward new methods of treatment. Studies in an experimental model indicate that tumor necrosis factor (TNF), a protein also known as cachectin, is an essential element in highly fatal cerebral malaria. This contention is supported by the following observations. First, during the course of an infection by P. berghei ANKA strain, mice of a CM-susceptible strain express markedly elevated levels of TNF in their serum at the time that neurological signs are evident. Second, in contrast, either mice from nonsusceptible strains, susceptible strains depleted of CD4+ T lymphocytes, or susceptible mice inoculated with malaria organisms incapable of producing CM all fail to express high serum TNF activity. Third, passive immunization against mouse TNF significantly prolong the survival of P. berghei-infected CBA/Ca mice, and prevented the development of neurologic signs to an extent that was highly significant. Treatment with the anti-TNF antibody also prevents the histopathological lesions that are characteristic of CM, i.e. plugging of cerebral vessels by macrophages, lymphoid and parasitized erythrocytes. We have recently shown that this increased TNF release and macrophage accumulation are schematically made of two components, each mediated by different cytokines presumably released by stimulated CD4+ T lymphocytes: (a) a quantitative component: increased accumulation of macrophages results from the concomitant release of IL-3 and GM-CSF, and (b) a qualitative component: macrophage number has not only to be raised, but macrophages need to be activated by IFN-gamma. Thus, CM appears to be the result of a cytokine cascade mediated by the immune response. TNF might also be involved in the pathogenesis of human cerebral malaria. Indeed, we have recently shown that in african children with falciparum malaria, elevated serum concentrations of this molecule are associated with severe neurological involvement and fatal outcome. Clinical trials of treatment with monoclonal anti-TNF antibodies are presently underway in an attempt to reduce mortality and morbidity in african children with cerebral malaria.
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PMID:Essential role of tumor necrosis factor and other cytokines in the pathogenesis of cerebral malaria: experimental and clinical studies. 135 36

Evidence is presented here that tumor necrosis factor/cachectin (TNF), is of crucial importance in the pathogenesis of cerebral malaria. First, the central lesion of CM, hemorrhagic necrosis of cerebral vessels, corresponds to lesions observed during other pathological conditions associated with high serum TNF levels, such as endotoxemic shock or administration of TNF. Second, in both mouse and human, there is a close correlation between high serum TNF levels and CM. At least in mouse, high TNF levels and CM depend upon T lymphocytes of the CD4+ phenotype. Third, passive immunization against mouse TNF significantly prolongs the survival of P. berghei-infected CBA/Ca mice, and prevents the development of neurologic signs. Treatment with the anti-TNF antibody also prevents hemorrhagic necrosis of brain vessels. Fourth, in the mouse model, a cytokine cascade including at least GM-CSF, IL-3 and IFN-gamma is required for the elevation of TNF level. This cascade appears to involve two components: (a) a quantitative component: increased accumulation of macrophages results from the concomitant release of IL-3 and GM-CSF, and (b) a qualitative component: macrophage number has not only to be raised, but macrophages need to be activated by IFN-gamma. Fifth, metabolic parameters of CM and its main lesion in both mouse and human, i.e. the hemorrhagic necrosis of small brain vessels, correspond to the known properties of TNF.
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PMID:Tumor-necrosis factor and other cytokines in cerebral malaria: experimental and clinical data. 257 74

Acute Plasmodium yoelii murine malaria is associated with a marked depression of splenic T cell responses. The present study was undertaken to address the question if a defect in T cell proliferation results from a relative increase of a non-T cell population in the spleen or real biological changes occurring in T cells of the spleen after infection. When animals were acutely infected, the splenic cells responded poorly to cross-linked anti-CD3 mAb, Con A, and PWM stimulation. At this stage, a very limited array of cytokine was expressed. We failed to detect the transcripts for IL-2R p55, IL-2, IL-6, IL-10, and IFN-gamma in mice with acute P. yoelii malaria irrespective of the number of splenocytes subjected to RT-PCR. In contrast, late in the infection when mice cleared the parasites and became resistant to reinfection, mRNAs for the above cytokines as well as for IL-4, IL-5, GM-CSF, and TNF-alpha were detectable. During this late phase of infection, lymphocytes proliferated vigorously in response to TCR- and T cell mitogen-mediated stimulation. Surprisingly, during an early phase (as early as 3 days postinfection) with low parasitemia, before the establishment of T cell unresponsiveness, a broad array of cytokine expression including IL-2 and IFN-gamma expression as well as marked lymphoproliferative response upon T cell mitogen- and TCR-mediated stimulation was observed. When the expression of cytokine gene in freshly isolated (ex vivo) splenocytes from P. yoelii-infected animals was investigated, a similar pattern of cytokine profile was detected. We devised a methodology in which RNA from an increasing number of splenocytes (ranging from 1 to 16 million) was used to compensate for any difference in the frequency of splenic T cells between immune and acutely infected mice and to augment target molecules which could be measured simultaneously by PCR. The data presented in this study led us to speculate that "anergy" or relative increase of a non-T cell population cannot account solely for the T cell unresponsiveness in the acute phase of infection. We suggest that inactivation or/and ablation of reactive T cells may explain T cell hyporesponsiveness during acute malaria.
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PMID:Plasmodium yoelii in mice: differential induction of cytokine gene expression during hyporesponsiveness induction and restimulation. 784 88

The scientific interest in the physical interaction of Plasmodium falciparum-infected erythrocytes with host cells stems from the suggestion that excessive binding in the microvasculature leads to severe malaria. The authors studied, therefore, two parasites for their ability to adhere to normal human cells and to induce cytokine production, one parasite lacking a binding capacity (DD2) and one which adhered to CD36+ transfected CHO cells (MCAMP). The MCAMP parasites readily bound to platelets and erythrocytes and to monocytes, polymorphonuclear granulocytes and EBV-transformed B cells as seen by light and electron microscopy. Platelets were frequently attached in large numbers to the infected erythrocyte surface and groups of infected erythrocytes were sometimes held together by several platelets. Nine out of 17 cytokines tested were found to be secreted into the culture supernatants after 35 h of co-cultures containing monocytes or unfractionated peripheral blood mononuclear cells (PBMC) and parasites (IL-1RA, IL-6, IL-8, IL-10, TGF beta, TNF alpha, G-CSF, IL-1-beta, and GM-CSF). Three additional cytokines were also present in low levels (< 200 pg/ml, IL-2, IL-4, IFN gamma) in the culture supernatants after incubation of the cells for 4 days. TNF alpha, IL-RA, and IL-8 were secreted from polymorphonuclear granulocytes, LGLs and T cells. Platelets and, to a lesser degree, monocytes and T cells secreted large amounts of TGF beta (10-30 ng/ml). Cytokines may participate in the pathogenesis but also the suppression of immune responses seen during acute malarial infections.
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PMID:Adhesion of Plasmodium falciparum-infected erythrocytes to human cells and secretion of cytokines (IL-1-beta, IL-1RA, IL-6, IL-8, IL-10, TGF beta, TNF alpha, G-CSF, GM-CSF. 855 86

We compared the tumor necrosis factor (TNF-alpha), interferon gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF) serum levels in 87 patients with malaria from the Brazilian Amazon. They included asymptomatic infected individuals and symptomatic patients with mild disease or severe malaria with or without cerebral involvement. As controls we examined individuals living in endemic areas without past history of malaria. The TNF-alpha serum levels were increased in patients with malaria and progressively decreased in those with severe disease 7 days after specific treatment. We found correlation between parasitaemia, TNF-alpha levels and severity of the disease. The correlation between high TNF-alpha levels and severe malaria was independent of cerebral involvement. The increase in both IFN-gamma and GM-CSF levels among malarious patients was not related to the degree of severity or mortality. IFN-gamma concentration, however, was associated with high parasitaemia at admission.
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PMID:Tumor necrosis factor alpha interferon gamma and macrophage stimulating factor in relation to the Severity of Plasmodium falciparum malaria in the Brazilian Amazon. 865 Jul 40

A plasmid DNA vaccine encoding the circumsporozoite protein of malaria (pCSP) induces protective immunity in adult mice but persistent tolerance when administered to neonates. In an effort to improve antigen presenting cell (APC) function in newborns, we co-administered pCSP with a plasmid encoding granulocyte-macrophage colony stimulating factor (pGMCSF). This combination of plasmids prevented the development of neonatal tolerance, instead eliciting a primary IgG anti-CSP immune response. Mice primed as neonates and boosted as adults mounted anamnestic responses characterized by high serum antibody titers, cytotoxic T-cell activity and antigen-specific interferon gamma (IFNgamma) production. Neonatal administration of pGMCSF accelerated the maturation of local dendritic cells, suggesting that APC function plays a key role in determining whether tolerance or immunity results from neonatal exposure to antigen.
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PMID:Prevention of neonatal tolerance by a plasmid encoding granulocyte-macrophage colony stimulating factor. 1054 30

The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human gammadelta+ and alphabeta+ T cells, T-cell lines and clones stimulated with Plasmodium falciparum-antigen-or T-cell mitogen in vitro were investigated. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the gammadelta- and the alphabetaT cells. Despite this fact, only gammadeltaT cells inhibited, both Vdelta1+ and Vdelta2+, the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell-to-cell contact and was not observed until the second parasite replication implied that the likely gammadeltaT-cell target was the extracellular merozoite or schizont. The failure of alphabetaT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the gammadeltaT cells. Both the gammadelta- and alphabetaT cells expressed mRNA for a large number of cytokines. Interferon (IFN)-gamma, interleukin (IL) IL-5, IL-6, IL-8, tumour necrosis factor alpha (TNFalpha), tumour necrosis factor beta (TNF-beta)/lymphotoxin (LT) and T-cell growth factor beta-1 (TGF-beta1) were observed in all activated clones tested. No IL-3 was detected, while IL-1beta, IL-2, IL-4, IL-10 and GM-CSF were variably expressed. In conclusion, our data show that gammadeltaT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated alphabetaT cells do not. Thus, it is likely that the gammadeltaT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.
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PMID:Human gamma delta T cells that inhibit the in vitro growth of the asexual blood stages of the Plasmodium falciparum parasite express cytolytic and proinflammatory molecules. 1060 13

MuStDO 5 is a multivalent plasmid DNA vaccine for malaria comprised of five plasmid DNAs encoding five proteins from Plasmodium falciparum and one plasmid DNA encoding human GM-CSF. To evaluate the safety of MuStDO 5, a series of pre-clinical studies were conducted in mice and rabbits. In pharmacology studies in mice, GM-CSF could not be detected in the serum following either intramuscular or a combined intramuscular/intradermal administration of the vaccine, but was readily detected in the muscle following intramuscular administration. In a tissue distribution study in mice, MuStDO 5 plasmid DNA was detected by PCR initially in highly vascularized tissues, while at later time-points the plasmid DNA was detected primarily at the site(s) of injection. In GLP safety studies in mice and rabbits, repeated intramuscular/intradermal administration of the MuStDO 5 vaccine was found to be safe and well tolerated without any evidence of autoimmune pathology.
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PMID:Safety of a GM-CSF adjuvant-plasmid DNA malaria vaccine. 1143 36

Two chimpanzees were vaccinated intramuscularly against malaria using plasmid DNA expressing the pre-erythrocytic antigens thrombospondin related adhesion protein (PfTRAP) and liver stage specific antigen-1 (PfLSA-1) of Plasmodium falciparum together with GM-CSF protein. A recombinant modified vaccinia virus Ankara (MVA) expressing PfTRAP was injected intramuscularly 6 weeks later to boost the immune response. This sequence of antigen delivery induced a specific and long-lasting T cell and antibody response to PfTRAP as detected by ELISPOT assay and ELISA. Antibody responses were detected after four DNA injections, and were boosted by injection of recombinant MVA expressing PfTRAP. Interferon-gamma secreting antigen-specific T cells were detected in both animals, but only after boosting with recombinant MVA. By screening a panel of PfTRAP-derived peptides, an epitope was identified that was recognized by cytotoxic T lymphocytes in one of the chimpanzees studied. T cells specific for this epitope were present in PBMCs and liver-infiltrating lymphocytes at a frequency of between 1 in 200 and 1 in 500. The high immunogenicity of this prime-boost regimen in chimpanzees supports further assessment of this delivery strategy for the induction of protection against P. falciparum malaria in humans.
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PMID:A prime-boost immunisation regimen using DNA followed by recombinant modified vaccinia virus Ankara induces strong cellular immune responses against the Plasmodium falciparum TRAP antigen in chimpanzees. 1153 6

To develop a multi-stage, multi-antigen, multi-immune response-inducing vaccine against malaria we have focused on DNA vaccines because of their simplicity of construction and modification, ease of mixing, and effectiveness in inducing CD8+ T cell responses. DNA malaria vaccines induce CD8+ T cell dependent protection in mice and CD8+ CTL in rhesus monkeys and humans after intramuscular needle administration. Clinical trials in normal, healthy humans are in progress or planned, assessing alternative methods and routes of administration, and the capacity of a plasmid expressing human GM-CSF to enhance the protective efficacy of a five-gene liver-stage malaria vaccine. In mice, we have demonstrated that priming with the combination of DNA plasmids encoding a Plasmodium yoelii protein and murine GM-CSF and boosting with recombinant poxvirus expressing the same P. yoelii protein induces a 30-fold increase in antigen-specific antibodies, a 10-fold increase in antigen-specific IFN-gamma spot forming cells, a significant (p<0.05) increase in protection, and the capacity to reduce the dosage of DNA by 10-100 fold, compared to immunizing with DNA alone. In Aotus monkeys priming with DNA and boosting with recombinant protein in adjuvant is more protective than homologous priming and boosting with either DNA or recombinant protein in adjuvant. Clinical trials are now planned using these immunization strategies. Because of the complexity and cost of the heterologous regimens, we are working to make DNA vaccination alone as immunogenic and protective as the prime-boost approach. Our most encouraging findings have resulted from altering codon usage from the highly A+T rich P. falciparum native sequence to that more closely resembling mammalian sequences. Although much progress is required for the development of a vaccine that provides sustainable protective immunity against malaria, a strategy using DNA vaccine technology as a core component of such a vaccine is promising.
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PMID:Can malaria DNA vaccines on their own be as immunogenic and protective as prime-boost approaches to immunization? 1171 10


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