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)

Dendritic cells (DC) are crucial for the induction of immune responses and thus an inviting target for modulation by pathogens. We have previously shown that Plasmodium falciparum-infected erythrocytes inhibit the maturation of DCs. Intact P. falciparum-infected erythrocytes can bind directly to CD36 and indirectly to CD51. It is striking that these receptors, at least in part, also mediate the phagocytosis of apoptotic cells. Here we show that antibodies against CD36 or CD51, as well as exposure to early apoptotic cells, profoundly modulate DC maturation and function in response to inflammatory signals. Although modulated DCs still secrete tumor necrosis factor-alpha, they fail to activate T cells and now secrete IL-10. We therefore propose that intact P. falciparum-infected erythrocytes and apoptotic cells engage similar pathways regulating DC function. These findings may have important consequences for the treatment of malaria and may suggest strategies for modulating pathological immune responses in autoimmune diseases.
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PMID:A role for CD36 in the regulation of dendritic cell function. 1144 63

The balance between pro- and antiinflammatory cytokines may be important in malaria presentation and outcome. Malaria tends to be more severe in children than in adults, presumably because partial immunity develops with age. However, the full nature of, and age-related differences in, anti-malarial immunity are unknown. We compared: (1) serum and cell-specific cytokines of patients with acute malaria to those of patients with other acute illnesses and to those of healthy adults and (2) the cytokine responses of parasitemic children and parasitemic adults. Flow cytometry was done on the peripheral blood mononuclear cells of 148 hospitalized children, 161 febrile hospitalized adults, and 20 healthy adults in Malawi, Africa, a malaria-endemic country. Serum cytokines were also assessed for 80 of these patients. Thirty-eight participants were parasitemic with Plasmodium falciparum. Serum interleukin (IL)-10 (an antiinflammatory, immunoregulatory, and type 2 cytokine) levels were higher in malaria patients than in other patients (medians 502 pg/mL vs 16 pg/mL, P = 0.002), and the percentages of various lymphocyte populations making IL-6 (a proinflammatory, type 2 cytokine regulating iron distribution) were lower in malaria patients than in other patients (e.g., for spontaneous production by children's CD8(+) T cells: medians 1.4% vs 33.1%, P = 0.004). For adult patients, the percentages of lymphocytes spontaneously making IL-4 (a type 2 cytokine) were significantly lower in those with malaria than in those without malaria (medians 0.9% vs 2.1%, P = 0.005). The percentages of monocytes spontaneously making IL-8 (a chemotactic, proinflammatory chemokine) were higher in parasitemic children than in parasitemic adults (medians 5.8% vs 1.7%, P = 0.003). A number of cellular proinflammatory, type 1 parameters were significantly higher in all children (with or without malaria) than in all adults; these included the percentages of various lymphocyte populations making IL-6, both IL-6 and interferon-gamma, or IL-8. These data support the importance of IL-10 in malaria parasitemia. Given the lack of an IL-4 (type 2) response, IL-10's primary role may be immunoregulatory rather than type 2 in nature. In this study, the immune response to malaria was more proinflammatory in children than in adults. This difference, if corroborated by other studies, could be related to malaria's greater severity in children.
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PMID:Cytokines and malaria parasitemia. 1146 50

Manzamine A, a sponge-derived alkaloid, was recently shown to possess in vivo antimalarial activity against the blood stages of the rodent malaria parasite Plasmodium berghei. A single intraperitoneal dose of 100 micromol/kg of manzamine A suppressed parasite growth but was followed by parasite recrudescence. Forty percent of mice with recrudescing parasites were able to recover and clear the fulminating parasitaemia. Examination of sera from these mice revealed that infected mice treated with manzamine A had a suppressed IFN-gamma production but an increase in their IL-10 and IgG production. The prolonged survival of infected mice treated with manzamine A and the eventual clearance of recrudescing parasites in some of these mice involve a down-regulation of Thl responses and a switch to antibody dependent-Th2 responses.
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PMID:Immune-mediated parasite clearance in mice infected with Plasmodium berghei following treatment with manzamine A. 1157 May 56

Cytokines function at the cellular, microenvironmental level, but human cytokine assessment is most commonly done at the macro level, by measuring serum cytokines. The relationships between serum and cellular cytokines, if there are any, are undefined. In a study of hospitalized patients in Malawi, we compared cytometrically assessed, cell-specific cytokine data to serum interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) levels in 16 children and 71 (IL-2, -4, -6, -10) or 159 (IL-8, IFN-gamma, and TNF-alpha) adults, using Wilcoxon rank sum tests and Pearson's (r(p)) and Spearman's (r(s)) rank correlations. For the entire study group, correlations between identical serum and cellular cytokines mainly involved IL-8 and IFN-gamma, were few, and were weakly positive (r < 0.40). Blood culture-positive persons had the most and strongest correlations, including those between serum IL-2 levels and the percentages of lymphocytes spontaneously making IL-2 (r(s) = +0.74), serum IL-8 levels and the percentages of lymphocytes spontaneously making IL-8 (r(p) = +0.66), and serum IL-10 levels and the percentages of CD8(+) T cells making TNF-alpha (r(p) = +0.89). Human immunodeficiency virus (HIV)-positive persons had the next largest number of correlations, including several serum IL-8 level correlations, correlation of serum IL-10 levels with the percentages of lymphocytes producing induced IL-10 (r(s) = +0.36), and correlation of serum IFN-gamma levels and the percentages of lymphocytes spontaneously making both IL-6 and IFN-gamma in the same cell (r(p) = +0.59). HIV-negative, malaria smear-positive, and pediatric patients had few significant correlations; for the second and third of these subgroups, serum IL-8 level was correlated with the percentage of CD8(-) T cells producing induced IL-8 (r(s) = +0.40 and r(s) = +0.56, respectively). Thus, the strength of associations between serum and cellular cytokines varied with the presence or absence of bloodstream infection, HIV status, and perhaps other factors we did not assess. These results strongly suggest that serum cytokines at best only weakly reflect peripheral blood cell cytokine production and balances.
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PMID:Comparison of serum and cell-specific cytokines in humans. 1168 46

Individuals living in malaria-endemic areas eventually develop clinical immunity to Plasmodium falciparum. That is, they are able to limit blood parasite densities to extremely low levels and fail to show symptoms of infection. As the clinical symptoms of malaria infection are mediated in part by pro-inflammatory cytokines it is not clear whether the acquisition of clinical immunity is due simply to the development of antiparasitic mechanisms or whether the ability to regulate inflammatory cytokine production is also involved. We hypothesize that there is a correlation between risk of developing clinical malaria and the tendency to produce high levels of proinflammatory cytokines in response to malaria infection. In order to test this hypothesis, we have compared the ability of peripheral blood mononuclear cells from malaria-naive and malaria-exposed adult donors to proliferate and to secrete IFN-gamma in response to P. falciparum schizont extract (PfSE). In order to determine how PfSE-induced IFN-gamma production is regulated, we have also measured production of IL-12p40 and IL-10 from PfSE-stimulated PBMC and investigated the role of neutralizing antibody to IL-12 in modulating IFN-gamma production. We find that cells from naive donors produce moderate amounts of IFN-gamma in response to PfSE and that IFN-gamma production is strongly IL-12 dependent. Cells from malaria-exposed donors living in an area of low malaria endemicity produce much higher levels of IFN-gamma and this response is also at least partially IL-12 dependent. In complete contrast, cells from donors living in an area of very high endemicity produce minimal amounts of IFN-gamma. No significant differences were detected between the groups in IL-10 production, suggesting that this cytokine does not play a major role in regulating malaria-induced IFN-gamma production. The data from this study thus strongly support the hypothesis that down-regulation of inflammatory cytokine production may be a component of acquired clinical immunity to malaria but the mechanism by which this is achieved remains to be elucidated.
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PMID:Changes in cytokine production associated with acquired immunity to Plasmodium falciparum malaria. 1173 69

Liver-stage antigen (LSA)-1 is a candidate vaccine molecule for Plasmodium falciparum malaria, but knowledge of the evolution of naturally acquired immune responses to LSA-1 in African children is lacking. We therefore assessed cellular immune responses to two defined T cell epitopes of LSA-1, during and after uncomplicated P. falciparum malaria in a group of Gabonese children. In terms of their prevalence, interferon (IFN)-gamma responses of peripheral blood mononuclear cells (PBMC) to an LSA-1 N-terminal peptide, T1, were significantly higher when measured during the acute phase compared with convalescence. IFN-gamma responses to the LSA-J (hinge region) peptide showed a similar profile, but at a lower prevalence. Depletion experiments confirmed that CD8+ T cells are a major source of peptide-driven IFN-gamma, but both lymphoproliferation and the production of IL-10 in response to either of the peptides was low in all children at all times. PBMC from 25% of the children failed to produce IFN-gamma in response to either peptide at any time-point. The results suggest that lymphocytes producing IFN-gamma in response to at least one T cell epitope of LSA-1 are most frequent in the peripheral circulation during the acute phase of P. falciparum malaria. Thus, in this case, the generalised suppression of cell-mediated responses which characterises acute malaria does not affect liver-stage antigen-specific IFN-gamma production. These findings imply that measurements of the frequency of parasite antigen-specific cellular immune responses in clinically healthy individuals may represent significant underestimations, which has important implications for the design of field-based vaccine antigen-related studies.
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PMID:Plasmodium falciparum liver-stage antigen-1 peptide-specific interferon-gamma responses are not suppressed during uncomplicated malaria in African children. 1178 Nov 92

Plasmodium falciparum malaria is a major cause of death in the tropics. The 19-kDa subunit of P. falciparum merozoite surface protein 1 (MSP-1(19)), a major blood stage vaccine candidate, is the target of cellular and humoral immune responses in animals and humans. In this phase I trial of MSP-1(19), immunization of nonexposed human volunteers with either of the two allelic forms of recombinant MSP-1(19) induced high levels of antigen-specific Th1 (gamma interferon) and Th2 (interleukin 4 [IL-4] and IL-10) type lymphokines. The adjustment of the antigen dose and number of immunizations regulated the level of specificity of immune responses and Th1/Th2 bias of responses induced by vaccination. Novel conserved and allelic T-cell epitopes which induced cross-strain immune responses were identified. Importantly, responses to many of these novel epitopes were also present in adults exposed to malaria, both in east (Kenya) and west Africa (The Gambia). These data suggest that epitope-specific naturally acquired MSP-1(19) immune responses in endemic populations can be boosted by vaccination.
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PMID:Induction of T helper type 1 and 2 responses to 19-kilodalton merozoite surface protein 1 in vaccinated healthy volunteers and adults naturally exposed to malaria. 1185 28

The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-gamma), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-gamma, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 +/- 2.8 pg/ml; controls, 3.2 +/- 0.7 pg/ml) and IFN-gamma (39.2 +/- 67.6 pg/ml; controls, 8.4 +/- 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 +/- 2.6 pg/ml), whereas IFN-gamma levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 +/- 200.4 pg/ml and 56.6 +/- 38.4 pg/ml, respectively; controls, 17.4 +/- 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 +/- 1.2 pg/ml; controls, 2.4 +/- 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 +/- 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-gamma levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-gamma may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.
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PMID:Role of Th1 and Th2 cytokines in immune response to uncomplicated Plasmodium falciparum malaria. 1187 76

Cytokines regulate cellular immune activity and are produced by a variety of cells, especially lymphocytes, monocytes, and macrophages. Multiparameter flow cytometry is often used to examine cell-specific cytokine production after in vitro phorbol 12-myristate 13-acetate and ionomycin induction, with brefeldin A or other agents added to inhibit protein secretion. Spontaneous ex vivo production reportedly rarely occurs. We examined the spontaneous production of interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) by peripheral-blood B lymphocytes, T cells, CD8(-) T cells, CD8(+) T cells, CD3(-) CD16/56(+) lymphocytes (natural killer [NK] cells), CD3(+) CD16/56(+) lymphocytes (natural T [NT] cells), and/or monocytes of 316 acutely ill hospitalized persons and 62 healthy adults in Malawi, Africa. We also evaluated the relationship between spontaneous and induced cytokine production. In patients, spontaneous TNF-alpha production occurred most frequently, followed in descending order by IFN-gamma, IL-8, IL-4, IL-10, IL-6, and IL-2. Various cells of 60 patients spontaneously produced TNF-alpha; for 12 of these patients, TNF-alpha was the only cytokine produced spontaneously. Spontaneous cytokine production was most frequent in the immunoregulatory cells, NK and NT. For IL-2, IL-4, IL-6, IL-8, and IL-10, spontaneous cytokine production was associated with greater induced production. For TNF-alpha and IFN-gamma, the relationships varied by cell type. For healthy adults, IL-6 was the cytokine most often produced spontaneously. Spontaneous cytokine production was not unusual in these acutely ill and healthy persons living in an area where human immunodeficiency virus, mycobacterial, malaria, and assorted parasitic infections are endemic. In such populations, spontaneous, as well as induced, cell-specific cytokine production should be measured and evaluated in relation to various disease states.
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PMID:Spontaneous cytokine production and its effect on induced production. 1220 58

Opsonin-independent macrophage phagocytosis was investigated as a possible mechanism of controlling early blood-stage Plasmodium chabaudi AS infection. Early during infection, peritoneal macrophages from resistant C57BL/6 (B6) mice exhibited increased phagocytosis of parasitized red blood cells (pRBCs) and free merozoites, which was absent in mice with deficient interferon (IFN)-gamma production during infection, including susceptible A/J, interleukin (IL)-12 p40, and IFN-gamma gene knockout mice. IFN-gamma treatment of macrophages collected from B6 and A/J mice early during infection enhanced phagocytosis of pRBCs, but IL-10 treatment inhibited this function. In vitro and in vivo studies in which type I and II class A scavenger receptor-deficient mice and inhibitors of scavenger and mannose receptors were used revealed that scavenger receptors other than class A type I and II and mannose receptors may play a role in malaria parasite uptake. These results indicate that opsonin-independent phagocytosis contributes to the IFN-gamma-dependent control of acute blood-stage malaria infection.
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PMID:Opsonin-independent phagocytosis: an effector mechanism against acute blood-stage Plasmodium chabaudi AS infection. 1240 2


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