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

The kinetics of the gamma delta T-cell response was analysed in the context of the overall haematological response in subjects experimentally infected with sporozoites of Plasmodium falciparum. Numbers of gamma delta and alpha beta T cells and NK cells declined markedly during infection to reach minimum values 12-13 days post-infection when the patients were ill. This decline commenced from the beginning of the erythrocytic cycle and well before parasites could be detected microscopically and clinical symptoms developed. Platelet numbers also declined. In vivo activation of gamma delta T cells was evident with sequential up-regulation of the activation markers CD69 and HLA-DR. gamma delta T cell numbers were highest after treatment with the majority being CD4-CD8-, HLA-DR+ and showing reduced CD45RA expression. Contrary to some published observations gamma delta T-cell percentages remained within the normal range. Little evidence of upregulation of activation or memory markers was observed in the alpha beta T-cell population. In vitro proliferative responses to malaria antigen which involve gamma delta T cells were lost as the infection progressed and the lymphocyte count declined but these could be restored with the addition of exogenous IL-2 to cultures. The authors findings are consistent with a protective and/or immunomodulatory role for gamma delta T cells in malaria.
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PMID:Experimental human Plasmodium falciparum infections: longitudinal analysis of lymphocyte responses with particular reference to gamma delta T cells. 863 2

Malaria infection induces the production of serum antibodies to a variety of malaria antigens but the prevalence of antibodies to any particular antigen is typically much less than 100%. It has been assumed that non-responsiveness to defined antigens in malaria immune subjects is due to HLS-mediated restriction of the immune response. In this study we have investigated the role of HLA and non-HLA genes in the antibody response to two merozoite surface antigens (MSP1 and MSP2) and a sexual stage antigen (Ps260/230) of Plasmodium falciparum, and conclude that host genotype is not a major determinant of responsiveness. Although antibody levels vary in accordance with seasonal variations in malaria transmission in semi-immune children, antibody levels remain stable in clinically immune adults. Antigen recognition is selective with individual donors showing consistent high titre responses to some antigens/epitopes whilst consistently failing to recognize adjacent regions/epitopes of the same protein. An alternative explanation, consistent with the data presented here, is that selective antibody responses to malaria antigens in immune individuals result from a process akin to clonal imprinting (original antigenic sin).
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PMID:Selective recognition of malaria antigens by human serum antibodies is not genetically determined but demonstrates some features of clonal imprinting. 867 80

The various stages of Plasmodium falciparum (sporozoites and liver stages, asexual blood stages and gametocytes) each interact in a particular way with the human immune system. Specific immunity against the liver stages is achieved through a coordinated action of CD8 T cells and specific antibodies, the latter in collaboration with NK cells and macrophages. In this reaction, interferon-gamma plays an essential role. A non-specific "concomitant" immunity against sporozoites is based on a cytokine reaction, elicited by the blood stages. In practice, the high variability in the immunogenic structures of the sporozoite precludes completely protection against recurrent infections. The spleen macrophages have a pivotal role in the immune defense against the asexual blood stages. The elimination of merozoites and parasitized red blood cells (RBC) is facilitated by specific antibodies, produced under the control of CD4 T cells. There are, however, multiple mechanisms of immune deviation, suppression and evolutionary adaptation, which inhibit a sterilizing immunity against the blood stages. Nevertheless, symptoms may be absent in exposed adults, even when parasitemia persists. This clinical resistance, however, is relatively short-lived, once exposition is interrupted. The observation that HIV infection has no adverse effect on malaria also is a remarkable but consistent finding. All these data indicate that a strong T cell-mediated immune memory is absent in human P. falciparum infections. Cerebral malaria and some other serious complications are the consequence of insufficient elimination of parasitized erythrocytes by the spleen, presumably in combination with parasite factors (particular variant surface structures) and with human host genetics (HLA type, blood group etc.). Parasitized RBC massively stick to the endothelium of the micro-vessels and non-parasitized RBC roset around the parasitized ones. Eventually, serious problems in the micro-perfusion and in the local metabolism occur and organ failure may finally ensue. The immune reaction against the surface-antigens of the sexual stage is limited and insufficient, most probably for similar reasons as in the asexual stages. Internal structures of the gametocytes, however, are highly immunogenic, but, unfortunately. Normally cannot be reached by the immune system. Based on these fundamental data, some of the perspectives of vaccination and new therapeutic tools are critically discussed.
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PMID:[Immunology of human Plasmodium falciparum malaria]. 884 94

Major histocompatibility complex (MHC) molecules bind peptides bearing an appropriate 'sequence motif' for MHC binding. The use of phage display libraries exploits the ability of MHC class II molecules to exchange peptides in solution and thus select out peptide sequences with high-affinity binding from a large array of random peptides. We have analysed the peptide binding motifs of HLA-DRB1*1301 and *1302 using affinity purified HLA-DR13 molecules to purify sequentially HLA-DR13-binding peptides from a large random library of M13 phage containing nonamer inserts in the pIII coat protein. These DR13 alleles differ only at position 86 of the HLA-DR beta chain, where they contain valine and glycine residues respectively. These alleles were chosen because of their association with protection from severe malaria and chronic hepatitis B virus infection in West Africa. Analysis of the phage bound to these DR molecules suggests binding motifs. We compare the results derived from the use of the phage display library with results obtained from analysis of eluted peptides and peptide-binding studies. This analysis shows that although there is a common theme to motifs derived using different methods, there are also subtle variations between them.
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PMID:Analysis of peptide-binding motifs for two disease associated HLA-DR13 alleles using an M13 phage display library. 888 46

In animal models, CD8+ T cells are a critical effector mechanism in the protective immunity against malaria. Conventional approaches to the development of many vaccines, including those against malaria, have however proved inadequate. In particular, an alternative approach is needed for the development of vaccines designed to induce a cellular immune response mediated by CD8+ T cells. Advances in the field of molecular immunology during the past decade have provided an insight into the presentation of peptides by MHC class I molecules and their recognition by CD8+ T cells. These studies have provided a conceptual basis for the development of efficacious parasitic and viral vaccines. By a combination of immunochemical and cellular immunologic analyses based on specific peptide binding motifs, a subunit malaria vaccine that includes CD8+ T cell epitopes restricted by the most common class I HLA alleles, including HLA-A2, can now be constructed.
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PMID:Class I HLA-restricted cytotoxic T lymphocyte responses against malaria--elucidation on the basis of HLA peptide binding motifs. 898 96

Some individuals living in malaria-endemic areas have CTL to Plasmodium falciparum liver stage Ags. We have quantified these CTL responses using limiting dilution analysis studies on the peripheral blood cells of naturally exposed Gambian donors. CTL precursor frequencies were determined to a wide range of epitopes derived from different liver stage Ags (liver stage protein 1, circumsporozoite protein, thrombospondin-related anonymous protein, and sporozoite threonine/asparagine-rich protein) restricted through common HLA alleles present in this population (HLA-A2.1, -A2.2, -B7, -B8, -B35, and B53). Precursor frequencies were between 17 and 98/million PBMC and correlated with the levels of specific lysis in parallel bulk cultures. The quantitative nature of limiting dilution assay analysis revealed varying degrees of immunodominance in the CTL responses to different epitopes within single proteins (thrombospondin related anonymous protein: tr42, tr43, tr26, tr29, and tr39; circumsporozoite protein: cp6, cp26, and cp29) and within individual donors. The temporal stability of some of these CTL responses was determined over a 4-yr period. This is the first quantitative study of CTL specific for any plasmodial species or nonviral pathogen in humans and provides a basis for a multiepitope approach to malaria vaccination.
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PMID:Precursor frequency analysis of cytotoxic T lymphocytes to pre-erythrocytic antigens of Plasmodium falciparum in West Africa. 905 21

The efficacy of a malaria peptide vaccine would be enhanced by the inclusion of a parasite-derived universal T cell epitope to ensure that all vaccinees develop parasite-specific cellular and humoral immunity. Two circumsporozoite (CS) protein T cell epitopes, previously identified by CD4+ T cell clones derived from Plasmodium falciparum sporozoite-immunized volunteers, were studied to determine their HLA class II binding potential. One epitope, located in amino acid (aa) 326-345 of the P. falciparum (NF54 strain) CS protein, was "universal" in that it could bind to multiple DR and DQ molecules in vitro. In contrast, the second epitope, T1, which is located in the CS repeat region, was recognized by T cells in the context of DQ6 (DQB1*0603) and did not bind with high affinity to any of the class II molecules tested in the peptide binding assays. The in vitro patterns of peptide/HLA interactions correlated with immunogenicity in vivo. A multiple antigen peptide (MAP) containing the aa 326-345 epitope elicited responses in eight inbred strains (H-2(a,b,d,k,p,q,r,s)), while the T1 MAP was recognized by only a single haplotype, H-2b. The combination of the universal aa 326-345 T cell epitope and the T1 repeat in a di-epitope MAP overcame the genetic restriction to the P. falciparum CS repeat region and elicited antisporozoite Ab responses in all of the MAP-immunized mice. Synthetic peptide malaria vaccines containing the aa 326-345 universal T cell epitope would be expected to elicit parasite-specific immune responses in both sporozoite-primed and naive individuals of diverse genetic backgrounds.
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PMID:Binding of malaria T cell epitopes to DR and DQ molecules in vitro correlates with immunogenicity in vivo: identification of a universal T cell epitope in the Plasmodium falciparum circumsporozoite protein. 923 33

Genetically determined differences in immune responses to environmental agents may underlie susceptibility to many autoimmune and infectious diseases. Leprosy provides an example of a polarity in the type of immune response made to an infectious agent, and there is evidence that the major histocompatibility complex is genetically linked to leprosy type. It was found that HLA-DR2 is associated with both tuberculoid and lepromatous types of leprosy; however, a variant at position -308 of the promoter of the neighboring tumor necrosis factor (TNF) gene was increased in frequency in lepromatous (odds ratio = 3.0, P = .02) but not tuberculoid leprosy. Some studies have found higher serum levels of TNF in lepromatous than tuberculoid leprosy, and high TNF levels are found in malaria and leishmaniasis, which are also associated with this TNF allele. It is speculated that this association reflects genetic variability in cytokine production, which influences the immune response to and clinical outcome of leprosy.
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PMID:Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. 923 25

Vgamma9Vdelta2-encoded T cell receptors (TCR) expressed by most human peripheral blood gammadelta T cells mediate the recognition of nonpeptidic phosphoantigens from various pathogens without any known requirement for HLA molecules. Functionally mature Vgamma9Vdelta2 T cells display a potent natural killer (NK)-like cytotoxic activity, share with NK cells the expression of inhibitory receptors for HLA class I molecules, and release a plethora of cytokines, most notably interferon-gamma and tumor necrosis factor alpha. Hence, through local activation, the early recruitment and stimulation of Vgamma9Vdelta2 T cells may promote efficient anti-infectious immunity. However, a chronic overactivation of this T cell subset may result in immunopathology. The meeting held in St. Vincent, Val d'Aosta, Italy (symposium on gammadelta T cells in natural immunity to infections: a rationale for vaccine development organized by the World Foundation for AIDS Research and Prevention, the UNESCO, and the Italian National Research Council, December 2-4, 1996) focused on the importance of gammadelta T cell activation and anergy for the pathogenesis of tuberculosis, malaria, and HIV infections.
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PMID:Gammadelta T cell activation or anergy during infections: the role of nonpeptidic TCR ligands and HLA class I molecules. 930 66

Merozoite surface protein 2 (MSP2) is a malaria vaccine candidate currently undergoing clinical trials. We analyzed the peripheral blood mononuclear cell (PBMC) response to synthetic peptides corresponding to conserved and variant regions of the FCQ-27 allelic form of MSP2 in Ghanaian individuals from an area of hyperendemic malaria transmission and in Danes without exposure to malaria. PBMC from 20-39% of Ghanaians responded to each of the peptides by proliferation and 29-36% had PBMC which produced interferon-gamma (IFN-gamma) in response to peptide stimulation. In Danes, there was no proliferation to two of the peptides and only PBMC from 5% of the individuals proliferated to the other three peptides. IFN-gamma production was not detected to any peptide. In both Danes and Ghanaians in only a few instances was IL-4 detected in the PBMC cultures. Overall PBMC from 79% of the Ghanaians responded by proliferation and/or cytokine secretion to at least one of three peptides tested, whereas responses were only observed in 14% of Danes (P = 0.002). These data suggest that the Ghanaians had expanded peripheral blood T-cell populations recognizing the peptides as a result of natural infection. The findings are encouraging for the development of a vaccine based on these T-epitope containing regions of MSP2, as the peptides were broadly recognized suggesting that they can bind to diverse HLA alleles and also because they include conserved MSP2 sequences. Immunisation with a vaccine construct incorporating the sequences present in these peptides could thus be expected to be immunogenic in a high percentage of individuals and lead to the establishment of memory T-cells, which can be boosted through natural infection.
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PMID:Human T-cell recognition of synthetic peptides representing conserved and variant sequences from the merozoite surface protein 2 of Plasmodium falciparum. 943 61


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