Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protective immunity to asexual malaria parasites appears to be mediated predominantly by the CD4+ subset of T lymphocytes. To examine the role of this T-cell population in the immune response to the murine malaria parasite Plasmodium chabaudi, CD4+ clones derived from infected mice were raised and propagated in vitro. Analysis of the reactivity of clones responsive to parasite antigen demonstrated that the CD4+ cell response is heterogeneous and is consistent with the idea of two functionally distinct CD4+ subsets. Those populations derived early during primary infection secreted interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) upon antigenic stimulation in vitro, i.e. they had a cytokine repertoire typical of the delayed-type inflammatory T-helper 1 (Th1) CD4+ subset. In contrast, cells taken after clearance of a secondary infection produced IL-4 and acted as effective helper cells for anti-malarial antibody (Ab) synthesis in vitro, and thereby had the characteristics of Th2 cells. The appearance in vivo of Th1 and then Th2 clones specific for P. chabaudi-parasitized erythrocytes (pRBC) supports the proposal from limiting culture analyses that for this malaria parasite resolution of primary parasitaemia is predominantly through the action of cytokines rather than Ab, and that final clearance requires helper cells and specific immunoglobulin.
 ...
PMID:Functional characterization of protective CD4+ T-cell clones reactive to the murine malaria parasite Plasmodium chabaudi. 135 18

Although a number of mechanisms have been put forward for immunity to malaria, their importance remains to be clarified. One of the important findings is that nonactivated monocytes and macrophages showed marked antiplasmodial activity in vitro. Recently we postulated that parasites may induce host factors that may depress the natural antiplasmodial activity of monocytes. In this investigation we identify IL-4 as a lymphokine that could function in this capacity. Human monocytes and macrophages in the absence of antiplasmodial antibody showed substantial killing of the asexual erythrocytic forms of Plasmodium falciparum as determined by a radiometric assay. Suppression of this killing was seen if the mononuclear phagocytes were pretreated with human rIL-4 at concentrations of 10 to 250 U with optimum activity between 100 and 250 U/2 x 10(5) cells. Cells from some individuals were rendered completely inactive by the IL-4 treatment. In contrast, IL-4 did not affect the neutrophil-mediated anti-P. falciparum activity. Our work identifies a potentially important parasite immune evasion mechanism involving IL-4 suppression of macrophage antiparasite activity.
 ...
PMID:IL-4 inhibits macrophage-mediated killing of Plasmodium falciparum in vitro. A possible parasite-immune evasion mechanism. 160 52

Serum cytokine profiles were evaluated in immunized and nonimmunized human volunteers after challenge with infectious Plasmodium falciparum sporozoites. Three volunteers had been immunized with x-irradiated sporozoites and were fully protected from infection. Four nonimmune volunteers all developed symptomatic infection at which time they were treated. Sera from all volunteers were collected at approximately 20 time points during the 28-d challenge period; levels of IL-1 alpha, IL-1 beta, IL-2, IFN-gamma, tumor necrosis factor-alpha, IL-4, IL-6, granulocyte macrophage-colony-stimulating factor, and soluble CD4, CD8, and IL-2 receptor (sCD4, sCD8, and sIL-2R, respectively) were determined by ELISA. C-reactive protein (CRP) was assayed by radial immunodiffusion. Parasitemic subjects developed increases in CRP and IFN-gamma, with less marked increases in sIL-2R and sCD8; the other cytokines tested did not change. CRP increases were abrupt and occurred at the onset of fever (day 14 after challenge). IFN-gamma increases were also abrupt, preceding those of fever and CRP by one day. Increases in sIL-2R and sCD8 were more gradual. Increases in fever, CRP, IFN-gamma, and sCD8 were concordant in each volunteer. Early IL-6 increases were noted in the protected vaccinees. Thus, after challenge with virulent P. falciparum, unique systemic cytokine profiles were detectable both in immunized, nonparasitemic volunteers and in unvaccinated, parasitemic subjects. The contrasting cytokine profiles in the two groups may relate to mechanisms of protection and immunopathology in experimental human malaria.
 ...
PMID:Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge. 164 22

A longitudinal study was conducted between October 1989 and February 1990 in a malaria holoendemic area of Gabon to determine the plasma concentration of various cytokines in individuals continuously exposed to infection with malaria parasites. No cases of severe malaria were seen and fever was the main presenting symptom of clinical malaria. Parasite rates were highest in children 6-9 years old but clinical malaria was seen essentially in children below 6 years of age. The incidence of clinical malaria was highest in November and February corresponding to the beginning and end of heavy rains respectively. Parasite rates did not show any seasonal variations. Overall, there was no seasonal variation in plasma cytokine levels but both IL-6 and IL-4 levels were highest in February. Plasma concentration of TNF-alpha and IFN-gamma were higher in parasitaemic than aparasitaemic individuals and donors who had clinical malaria had higher levels of TNF-alpha, IFN-gamma and IL-6 than asymptomatic parasitaemic donors. There was a negative correlation between age of the individual and the concentration of plasma TNF-alpha and IFN-gamma suggesting that the production of these cytokines could be modulated by repeated malarial infections. Asymptomatic parasitaemic children 5-7 years of age had higher levels of plasma TNF-alpha than clinically similar children below or above this age group suggesting that refractoriness to the clinical effects of TNF-alpha may be an important factor in the ability of these children to resist clinical malaria.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cytokines in the pathogenesis of malaria: levels of IL-I beta, IL-4, IL-6, TNF-alpha and IFN-gamma in plasma of healthy individuals and malaria patients in a holoendemic area. 166 45

Several immunodominant B and T cell epitopes of the P. falciparum blood stage antigen Pf155/RESA, a vaccine candidate, are located in the central (5') and C-terminal (3') invariant repeat regions of the molecule. Here we have attempted to functionally analyze human T cell responses to some of the T cell epitopes. For this purpose short synthetic peptides corresponding to these epitopes were used to study the induction of in vitro expression of IL-4 mRNA, IFN-gamma secretion, proliferation and B cell help for antibody production. In individual malaria immune donors these different T cell activities were not correlated. The findings emphasize the importance of examining multiple parameters of T cell activation when estimating the total proportion of individuals responding to a defined antigen. IL-4 mRNA was expressed in activated T cells of donors who had elevated serum concentrations of antibodies to the peptide used for T cell activation. These results suggest the involvement of IL-4 producing T helper cells in the induction of Pf155/RESA specific antibody production in individuals in which immunity has been induced by natural infection. Taken together, these findings also suggest that functionally distinct CD4+ T cells occur in humans similarly to what has been described in mice. In further experiments, we have also attempted to establish MHC class II restriction of the immune response to these epitopes at the level of the donor populations. When studying monozygotic twins, antibody responses to Pf155/RESA derived peptides and some of the T cell responses could be paired within the twin pairs, indicating a genetic regulation of their B cell responses. Whether or not this regulation reflects MHC class II restriction, or other factors needs to be elucidated.
 ...
PMID:Characterization of regulatory T cell responses to defined immunodominant T cell epitopes of the Plasmodium falciparum antigen Pf155/RESA. 170 42

We have mapped a T cell epitope in the circumsporozoite (CS) protein of the murine malaria parasite, Plasmodium yoelii. A 21-mer synthetic peptide corresponding to the amino acid positions 59-79 (referred to as Py1), induced specific proliferation in BALB/c and C57BL/6 mice, and provided help for the production of antibodies to peptides from the repetitive region, (QGPGAP)n, of the same CS protein, when mice were immunized with the Py1 peptide conjugated to the repetitive peptide. Long-term CD3+CD4+CD8-TCR alpha beta+ T cell lines and clones were derived from both strains of mice. These lines and clones, that proliferated in an MHC-restricted fashion, did not recognize peptides from the homologous region of another murine malaria parasite, P. berghei. About 50% of these clones produced detectable amounts of IFN-gamma and IL-2, whereas the remaining produced IL-4, IL-5, and IL-6. In preliminary experiments, some of these clones specifically inhibited P. yoelii sporozoite development in vitro and conferred protection in vivo in passive transfer experiments. These findings show that heterogenous T cell populations are activated in mice upon immunization with a short peptide from the P. yoelii CS protein and that some of these cells could be active in the effector arm of the immune response against malaria sporozoites.
 ...
PMID:Peptide-primed CD4+ cells and malaria sporozoites. 170 50

We have measured cellular and humoral immune responses to short synthetic peptides representing epitopes of the malaria vaccine candidate antigen Pf155/RESA in a longitudinal, prospective study of clinical immunity to Plasmodium falciparum malaria in a cohort of 354 Gambian children aged 3-8 years. A significant association was observed between presence of antibodies to the 3' repeat region peptide (EENV)6 and resistance to clinical malaria. The prevalence of protective antipeptide antibodies varied significantly between different ethnic groups, suggesting that immune recognition of some Pf155/RESA epitopes may be genetically regulated. There was no obvious association between proliferative or interferon gamma responses to T cell epitopes of Pf155/RESA and resistance to malaria infection or disease. At an individual level, the presence of peptide-binding antibodies was associated with the induction of interleukin 4 messenger ribonucleic acid expression in T cells activated with the overlapping T cell epitope EENVEHDA(EENV)2. This suggests that measurement of interleukin 4 production by T cells may represent a functional assay for T helper activity.
 ...
PMID:Association between immune recognition of the malaria vaccine candidate antigen Pf155/RESA and resistance to clinical disease: a prospective study in a malaria-endemic region of west Africa. 175 42

The expression of selected interleukin receptors by cloned CD4+ T cells specific for the murine malaria parasite Plasmodium chabaudi chabaudi (P. chabaudi) representative of the T-helper (Th) 1 and Th2 subsets was examined. Both sets of clones expressed receptors for those interleukins for which they had a growth factor requirement in vitro. Each Th1 clone expressed receptors for, and was responsive to, interleukin (IL)-2 and IL-4, while each Th2 clone expressed receptors for, and was responsive to, IL-2, IL-4 and IL-1. IL-1 receptor (IL-1R) expression by the Th1 clones was either negligible or could not be detected. The disparity in expression of IL-1R by the Th1 and Th2 clones was more clear-cut than has been previously reported and IL-1R provided a definitive phenotypic marker for clones of the Th2 subset. Should IL-1R expression prove to be a feature of other Th2 cells cultured long-term in vitro, this will be invaluable for investigations involving the phenotyping, depletion or selection of CD4+ T cells of either Th1 or Th2 subset.
 ...
PMID:Expression of the IL-1 receptor discriminates Th2 from Th1 cloned CD4+ T cells specific for Plasmodium chabaudi. 751 28

Infection of mice with the malaria parasite Plasmodium vinckei vinckei is 100% lethal. However, after two infections followed by drug cure, BALB/c mice develop a solid immunity which is antibody independent but mediated by CD4+ T cells. To elucidate the mechanisms of this immunity, spleen cells from immune mice were challenged in vitro with lysates of P. vinckei-infected or uninfected erythrocytes. The parasite antigen induced proliferation of T cells from immune mice but not from nonimmune mice. When gamma interferon production by cells from immune mice was assayed at the single-cell level, 1 to 3 cells per 1,000 cells were found to release this cytokine when exposed to antigen. In contrast, the numbers of interleukin 4 (IL-4)-producing cells from both immune and control mice were < or = 4 per 10(6) cells, regardless of antigen exposure. Investigation in a bioassay showed that P. vinckei antigen induced the release of IL-4 from spleen cells of immune mice but not from those of control mice. Nevertheless, that IL-4 is of minor significance in this system is also suggested by the absence of elevation of immunoglobulin E levels in blood samples from these mice, in contrast to what is seen with P. chabaudi infection, in which IL-4-producing Th2 cells are of major importance for immunity during later phases of infection. Taken together, the present results indicate that immunity to P. vinckei is a Th1 response, with gamma interferon being an important protective factor. Whether or not the Th1 response, through overproduction of tumor necrosis factor alpha, is also responsible for pathology and death in this infection remains to be clarified.
 ...
PMID:Cellular mechanisms in the immune response to malaria in Plasmodium vinckei-infected mice. 755 9

The relevance of the antibody-dependent cellular inhibition (ADCI) of Plasmodium falciparum to clinical protection has been previously established by in vitro studies of material obtained during passive transfer of protection by immunoglobulin G in humans. We here report further in vitro investigations aimed at elucidating the mechanisms underlying this ADCI effect. Results obtained so far suggest that (a) merozoite uptake by monocytes (MN) as well as by polymorphonuclear cells has little influence on the course of parasitemia; (b) the ADCI effect is mediated by a soluble factor released by MN; (c) this or these factors are able to block the division of surrounding intraerythrocytic parasites at the one nucleus stage; (d) the critical triggering antigen(s) targeted by effective Abs would appear to be associated with the surface of merozoites, as opposed to that of infected red blood cells; (e) the MN receptor for Abs effective in ADCI is apparently Fc gamma RII, and not RI; (f) MN function is up- and down-regulated by interferon-gamma and interleukin 4, respectively; and (g) of several potential mediators released by MN, only tumor necrosis factor (TNF) proved of relevance. The involvement of TNF in defense may explain the recently described increased frequency of the TNF-2 high-expression promoter in individuals living in endemic regions despite its compromising role in severe malaria.
 ...
PMID:Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages. 762 3


1 2 3 4 5 6 7 8 9 10 Next >>