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)

Cytokine responses in human host-protective immunity to malaria have yet to be completely elucidated. No data appear to exist on the cytokine patterns in non-human primate models immunized with malarial antigens. Expression of mRNA transcripts of 10 cytokines, the adhesion molecule ICAM-1 and inducible nitric oxide synthase (iNOS) in peripheral-blood mononuclear cells (PBMC) from nine Aotus monkeys was analysed by reverse-transcriptase PCR. Five of the monkeys had been immunized with multiple-antigen peptides (MAP) of the Plasmodium vivax circumsporozoite protein and two with constructs of the P. falciparum merozoite surface protein-1 (MSP-1). The other two monkeys served as non-immunized controls. PBMC were cultured for 24 h after stimulation with phytohaemagglutinin mitogen, MAP and MSP-1 antigens. Elevated expression of interleukin-6 (IL-6), IL-10, IL-12, tumour necrosis factor-alpha (TNF-alpha), TNF-beta and iNOS was seen in response to the MAP. Monkeys immunized with either P. falciparum MSP r190L or synthetic 190L peptides expressed predominantly the type-1 cytokines (IL-1 beta, IL-12, interferon-gamma, TNF-alpha, TNF-beta) characteristic of splenic, cell-mediated activity with macrophage activation and nitric oxide production.
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PMID:Expression of cytokine genes in Aotus monkeys immunized with synthetic and recombinant Plasmodium vivax and P. falciparum antigens. 979 28

The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine. T cell proliferation and interferon-gamma production in vitro were observed in response to RTS,S or hepatitis B surface antigen. Seven previously protected volunteers received sporozoite challenge, and 2 remained protected (1/1 for vaccine 1, 0/1 for vaccine 2, and 1/5 for vaccine 3). The prepatent period was 10.8 days for the control group and 13.2 days for the vaccinees (P < .01). Immune responses did not correlate with protection. Further optimization in vaccine composition and/or immunization schedule will be required to induce longer-lasting protective immunity.
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PMID:Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine. 980 46

Plasmodium chabaudi infection of mice provides an excellent model for examining acquired immunity to the blood-borne stage of malaria infection. CD4+ T-cell receptor (TCR) alphabeta-bearing T lymphocytes play a critical role in mediating protection, ascribed to both T helper (Th) 1 and Th2 subsets. One factor that may influence the Th1/Th2 cell balance is infective dose. In this study, we found that the size of the infective dose of P. chabaudi, and thus the level of antigen presented to the immune system, correlated with the balance of responder CD4+ T-cell phenotypes. Increasing the infective dose in a resistant mouse strain enhanced the Th1 cytokine (interferon-gamma; IFN-gamma) response and reduced the Th2 cytokine (interleukin-4; IL-4) response. In contrast, increasing the infective dose in a susceptible mouse strain led to a prominent and accelerated up-regulation of IL-4 production. These data show that the dose of antigen can significantly affect the balance between Th1- and Th2-mediated immune functions during infection of the mammalian host with blood-stage malaria parasites. This demonstration that parasite numbers may modulate CD4+ T-cell regulation has novel implications for the successful implementation of antimalarial vaccination and chemotherapeutic strategies.
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PMID:Infective dose modulates the balance between Th1- and Th2-regulated immune responses during blood-stage malaria infection. 982 63

Upon infection with Plasmodium berghei ANKA (PbA), various inbred strains of mice exhibit different susceptibility to the development of cerebral malaria (CM). Tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-gamma) have been shown to be crucial mediators in the pathogenesis of this neurovascular complication. Brain microvascular endothelial cells (MVEC) represent an important target of both cytokines. In the present study, we show that brain MVEC purified from CM-susceptible (CM-S) CBA/J mice and CM-resistant (CM-R) BALB/c mice exhibit a different sensitivity to TNF. CBA/J brain MVEC displayed a higher capacity to produce IL-6 and to up-regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in response to TNF than BALB/c brain MVEC. In contrast, no difference was found in the induction of E-selectin after TNF challenge. CM-S brain MVEC were also significantly more sensitive to TNF-induced lysis. This differential reactivity to TNF was further substantiated by comparing TNF receptor expression on CM-S and CM-R brain MVEC. Although the constitutive expression of TNF receptors was comparable on cells from the two origins, TNF induced an up-regulation of both p55 and p75 TNF receptors in CM-S, but not in CM-R brain MVEC. A similar regulation was found at the level of TNF receptor mRNA, but not for receptor shedding. Although a protein kinase C inhibitor blocked the response to TNF in both the brain MVEC, an inhibitor of protein kinase A selectively abolished the response to TNF in CM-R, but not CM-S brain MVEC, suggesting a differential protein kinase involvement in TNF-induced activation of CM-S and CM-R brain MVEC. These results indicate that brain MVEC purified from CM-S and CM-R mice exhibit distinctive sensitivity to TNF This difference may be partly due to a differential regulation of TNF receptors and via distinct protein kinase pathways.
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PMID:Differential reactivity of brain microvascular endothelial cells to TNF reflects the genetic susceptibility to cerebral malaria. 986 35

It is now largely established that the immune and neuroendocrine systems cross-talk by using similar ligands and receptors. In this context, the thymus-hypothalamus/pituitary axis can be regarded as a paradigm of connectivity in both normal and pathological conditions. For example, cytokines and thymic hormones modulate hypothalamic-pituitary functions: (a) interleukin (IL)-1 seems to upregulate the production of corticotropin-releasing factor and by adrenocorticotropin by hypothalamic neurons and pituitary cells, respectively; (b) thymulin enhances LH secretion. Conversely, a great deal of data strongly indicate that the hypothalamic-pituitary axis plays a role in the control of thymus physiology. Growth hormone (GH) for example, enhances thymulin secretion by thymic epithelial cells (TEC), both in vivo and in vitro, also increasing extracellular matrix-mediated TEC/thymocyte interactions. Additionally, gap junction-mediated cell coupling among TEC is upregulated by ACTH. In a second vein, it was shown that GH injections in aging mice increased total thymocyte numbers and the percentage of CD3-bearing cells, as well concanavalin-A mitogenic response and IL-6 production. In addition to mutual effects, thymus-pituitary similarities for cytokine and hormone production have been demonstrated. Cytokines such as IL-1, IL-2, IL-6, interferon-gamma, transforming growth factor-beta and others can be produced by hypothalamic and/or pituitary cells. Conversely, hormones including GH, PRL, LH, oxytocin, vasopressin and somatostatin can be produced intrathymically. Moreover, receptors for various cytokines and hormones are expressed in both the thymus and the hypothalamus/pituitary axis. Lastly, it is noteworthy that a thymus-pituitary connectivity can also be seen under pathological situations. In this regard, an altered HPA axis has been reported in AIDS, human falciparum malaria and murine rabies, that also show a severe thymic atrophy.
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PMID:Immunoneuroendocrine connectivity: the paradigm of the thymus-hypothalamus/pituitary axis. 987 43

The contribution of T cell-mediated responses was studied with regard to resistance to reinfection in groups of Gabonese children participating in a prospective study of severe and mild malaria due to infection with Plasmodium falciparum. In those admitted with mild malaria, but not in those with severe malaria, production of IFN-gamma by peripheral blood mononuclear cells (PBMC) in response to either liver-stage or merozoite antigen peptides was associated with significantly delayed first reinfections and with significantly lower rates of reinfection. Proliferative or tumor necrosis factor responses to the same peptides showed no such associations. Production of interferon-gamma by PBMC in response to sporozoite and merozoite antigen peptides was observed in a higher proportion of those presenting with mild malaria. Differences in the Th1/Th2 cytokine balance may be linked to the ability to control parasite multiplication in these young children, helping to explain the marked differences observed in both susceptibility to infection as well as in clinical presentation.
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PMID:Interferon-gamma responses are associated with resistance to reinfection with Plasmodium falciparum in young African children. 1006 95

Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-alpha (TNF-alpha) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-alpha (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-gamma (IFN-gamma) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1beta levels. Antibody treatment reduced IFN-gamma concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-alpha was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination half-life of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.
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PMID:Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria. 1043 50

The B and T cell responses to EB200, a repetitive part of the Plasmodium falciparum antigen Pf332, were examined in malaria-exposed Senegalese adults. Most donors had high levels of antibodies to recombinant EB200 and 17 overlapping peptides spanning EB200. Taking proliferation and/or cytokine (interferon-gamma and interleukin-4) production as a measure of T cell activation, eight of the EB200-derived peptides induced responses in > 40% of the donors tested. There was no general association between the different types of T cell responses measured, emphasizing the importance of including multiple parameters when analyzing T cell responses and suggesting that EB200 induces functionally distinct T cell responses. The most efficient peptide for induction of proliferative responses was one previously shown to induce T cell responses in five different H-2 congenic mouse strains primed with EB200, suggesting that this is a universal T cell epitope. The presence of multiple B and T cell epitopes in EB200, widely recognized by humans, is important since EB200 has been shown to elicit protective antibody responses in monkeys and may be considered for inclusion in malaria subunit vaccines.
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PMID:Human immune responses to the highly repetitive Plasmodium falciparum antigen Pf332. 1043 71

A baculovirus recombinant antigen corresponding to the C-terminal 19 000 MW fragment of Plasmodium falciparum merozoite surface protein 1 (MSP119), has been used to prime T cells from individuals with no previous exposure to malaria, to provide help for the induction of a parasite specific antibody response in vitro. Although MSP119 alone could induce a small but detectable T-cell response, which included interleukin-4 (IL-4) secretion, this response was significantly increased by the presence of IL-2. In addition, IL-4 was shown to synergize with IL-2 for the induction of antigen-specific T-cell responses. If interferon-gamma (IFN-gamma), IL-12, or neutralizing anti-IL-4 antibody was present at the time of priming, the T-cell responses were abolished. Parasite-specific immunoglobulin G (IgG) could be detected after secondary restimulation with MSP119, IL-10 and anti-CD40 monoclonal antibody in cultures containing MSP119 primed T cells, autologous B cells, IL-2 and IL-4. No antibody was secreted in the absence of primed T cells in this B-cell culture assay. These data show that recombinant MSP119, a leading malaria vaccine candidate, can prime non-immune human lymphocytes under defined in vitro experimental conditions, which include regulatory cytokines and/or other costimulatory molecules. This is a complementary approach for exploring immunogenic mechanisms of potential vaccine candidates such as P. falciparum antigens in humans.
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PMID:Immune responses to Plasmodium falciparum-merozoite surface protein 1 (MSP1) antigen, II. Induction of parasite-specific immunoglobulin G in unsensitized human B cells after in vitro T-cell priming with MSP119. 1044 73

Antimalarial drugs are widely used in malaria endemic areas, both for chemoprophylaxis and also empirically to treat patients presenting with fever. Previously, we have reported that chloroquine enhances the severity of Semliki forest virus (SFV) and encephalomyocarditis virus infection. The studies presented herein show that a broad spectrum of antimalarial drugs augmented the replication of SFV in mice, concomitant with greater tissue damage and up-regulation of mRNA levels of various inflammatory cytokine genes, including interleukin-1 receptor antagonist (IL-1Ra), II-1alpha, IL-1beta, IL-6, IL-12p40, and interferon-gamma inducing factor. Furthermore, chloroquine enhances IL-1Ra production in RAW cells in vitro. Since IL-1Ra is known to be up-regulated in a number of viral infections, we propose that a further enhancement of its expression by antimalarials may be responsible for the increased severity of viral infection in our studies. Thus, the widespread use of antimalarials in malaria-endemic areas may predispose the population to viral infections. Further studies are in progress to delineate mechanism(s) involved in cytokine up-regulation and acceleration of viral replication.
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PMID:Acceleration of viral replication and up-regulation of cytokine levels by antimalarials: implications in malaria-endemic areas. 1076 17


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