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

Lymphocytes obtained from forty individuals living in a malaria endemic area of West Africa were tested for in vitro proliferative responses to peptides representing variant regions of the immunodominant T cell domain of the circumsporozoite protein (amino acids 326 to 345, referred to as Th2R, and 361 to 380, referred to as Th3R) from three distinct strains of Plasmodium falciparum. A total of 83% of the individuals responded to at least one of the six peptides tested, confirming that these epitopes are immunodominant. A much greater number of individuals than expected by chance (32% of the responders to Th2R and 27% of the responders to Th3R) reacted to all three of the variant peptides for that epitope, indicating interdependency of the T cell responses, suggestive of cross-reactivity. Nevertheless, some subjects' T cells were clearly able to distinguish each variant peptide from the others. Using EBV transformed B cells, lymphocytes from 10 of the individuals were HLA typed. In this small group, HLA DRw13 was associated with a positive response to any of the peptides, whereas there was a negative association between DQw3 and response to any of the peptides. These results, although limited by the small sample size, suggest that recognition of T epitopes may be Ir gene linked. Our findings suggest that it may be possible to broaden the immunogenicity of an anti-sporozoite malaria vaccine.
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PMID:Human T cell recognition of polymorphic epitopes from malaria circumsporozoite protein. 246 29

HLA-A,B,C and DR types were determined for 46 adults living in the Madang area of Papua New Guinea. Sera from these individuals were tested by ELISA for antibodies against: (i) sonicated schizont extract of Plasmodium falciparum; (ii) circumsporozoite repeat regions of P. falciparum and P. vivax; and (iii) epitopes on the 230 and 48/45 kD gametocyte antigens of P. falciparum. All sera were from highly immune individuals and reacted strongly to the schizont antigen. The proportions responding to circumsporozoite repeat regions were 60.7% and 23.9% for P. falciparum and P. vivax, respectively. Between 32.6 and 47.8% of adults responded to each gametocyte epitope as assessed by inhibition of monoclonal antibodies. The limited number of alleles present at each HLA locus which is characteristic of coastal Papua New Guinea was observed. Five HLA-DR alleles were detected, of which only three (HLA-DR2, 4 and w5) were present at frequencies over 0.12. All individuals possessed at least one DR2,4 or w5 allele, and 96% of individuals possessed DR2, or 4 or both. There was no evidence for association between HLA type and antibody response to circumsporozoite repeat regions or the gametocyte epitopes. Homozygotes for DR2 and 4 were able to respond to each antigen. These results imply that either there is no HLA restriction of the response to these antigens or that each DR type is responding to a different variant of the T-epitope. Even in the latter case the results are encouraging for the prospects of inclusion of an HLA-restricted T-epitope in a malaria vaccine for Papua New Guinea since a limited number of versions would be required to cover a population with an HLA profile similar to that in Madang.
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PMID:Association between HLA type and antibody response to malaria sporozoite and gametocyte epitopes is not evident in immune Papua New Guineans. 248 46

Synthetic subunit vaccines to sporozoites, merozoites, and gametes are being developed for malaria. The vaccine strategy assumes that the population to be immunized will respond favorably to these vaccine antigens. Using sera of 35 adults and 50 children from the The Gambia, West Africa, where Plasmodium falciparum is highly endemic, we examined the humoral immune response to candidate malaria vaccine antigens from sporozoites, merozoites, and gametes. We observed widespread restricted immunogenicity to defined parasite antigens in children and adults. HLA typing of adult lymphocytes demonstrated a marked diversity in HLA haplotypes in this population. Our results and those from our studies in mice suggest that genetic factors may partly explain the immunological non-responsiveness. This may necessitate re-evaluation of the malaria vaccine strategy.
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PMID:Differential non-responsiveness in humans of candidate Plasmodium falciparum vaccine antigens. 267 34

Hyperreactive malarious splenomegaly (HMS) represents an abnormal immune response to recurrent malaria, characterized by excessive production of both IgM and IgG antibodies. It has both a racial and a familial distribution in various parts of the world. Immune responses to many foreign antigens, including those of malaria, are under genetic control of the major histocompatibility locus (MHC), through the influence of HLA antigens on regulatory T-lymphocyte activity. It is therefore likely that this region also contains the genetic determinants for HMS, which would be reflected in associations between HMS and particular HLA antigens or haplotypes. Genetic studies of the Watut people of Papua New Guinea have not shown any association between HMS and a wide range of red cell and serum polymorphisms. However, HMS in this group is associated with the class II HLA antigen DR2, and with high levels of HLA heterozygosity. Formal genetic analysis of family data also points to a sex-linked gene as a further determinant of overresponsiveness to malaria in the Anga. These findings suggest that more than one genetic system may be involved in the development of HMS, and that the combined effects of several genetic determinants may be responsible for the extraordinarily high frequency of HMS found in the Upper Watut Valley.
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PMID:The genetic basis of hyperreactive malarious splenomegaly. 269 22

Malaria infection has been shown to induce alterations in immune reactivity. This report describes the effect of serum obtained from Plasmodium falciparum infected patients on in vitro proliferation of human blood mononuclear cells (BMNC) isolated from healthy individuals. Serum obtained before initiation of treatment suppressed the in vitro lymphocyte proliferative response to both Plasmodium-derived antigens and an unrelated antigen (PPD-tuberculin). The suppressive effect was lost if the serum was incubated at 56 degrees C for 30 min, and the effect was not HLA-restricted since the inhibition was seen on both autologous and heterologous BMNC. The degree of suppression was not correlated to the duration of the disease, the degree of parasitemia, or the use of chemoprophylaxis. Sera from 7 patients before and from 3 patients 30 days after initiation of treatment were pooled and fractionated. It was found that the strongest suppressive activity was in the serum fraction containing molecules from 30-100 kD.
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PMID:Inhibition of human lymphocyte proliferative response by serum from Plasmodium falciparum infected patients. 332 60

We applied the microlymphocytotoxicity method to the detection of lymphocytotoxic antibodies in case of 37 patients with acute malaria or 61 patients who sojourned in endemic malaria area and presented antibodies against plasmodial antigens (indirect immunofluorescence test greater than or equal to 1/20). Lymphocytotoxic antibodies were found in 16 patients of the first group and their occurrence may explain the lymphopenia and to a lesser extent the neutropenia and thrombopenia observed in some cases. In the second group lymphocytotoxic antibodies were present in 9 cases. In all samples no anti-HLA specificity was evidenced. Four patients were submitted to auto-cross-match test and 3 were found positive suggesting that among these antibodies some are auto-antibodies with anti-lymphocyte specificity.
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PMID:[Lymphocytotoxic antibodies in malaria]. 636 21

Eighty-five patients with thalassemia and all available immediate family members were typed for HLA-A,B, C, and DR antigens, and the patients were tested for clinical diabetes and white cell antibodies in response to multiple blood transfusions. The antigen Bw35 was increased among both patients and their parents. This finding is consistent with previous data suggesting that this antigen may offer an independent selective advantage in populations at risk for both thalassemia and malaria. No association of the HLA system to the development of diabetes was noted. A wide variation was observed in the degree of white cell antibody response to transfusions: 25 of the 84 patients tested had significant levels of white cell antibodies while the majority (49) of the patients had essentially no antibodies. The frequency of the antigen DR2 was significantly increased in the high-response group, while the antigens Bw35 and DR7 were significantly increased in the low-response group. This finding suggests that an HLA-linked immune response or immune suppression factor or an HLA-linked susceptibility to iron toxicity may play a role in the development of these antibody responses.
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PMID:HLA-A, B, C, and DR antigen frequencies in relation to development of diabetes and variations in white cell antibody formation in highly transfused thalassemia patients. 695 55

Recent studies have identified genes involved in resistance to intracellular pathogens. Such genes include the murine MHC class I gene, Ld (toxoplasmosis), HLA-BW53, HLA DRB1* 1302-DQ B10s01 and TNF2 (malaria), murine Nramp (toxoplasmosis, leishmaniasis and tuberculosis), gene(s) modulating the T-helper type 1 and type 2 dichotomy (leishmaniasis, leprosy and HIV infection) and the natural killer cell complex (cytomegalovirus infection). There also have been other advances in immunogenetics that have led to a better understanding of resistance to intracellular pathogens. These include effector mechanisms of immune response genes and factors modulating genetic susceptibility. Identification of genes that determine resistance/susceptibility (and their effector mechanisms) has impacted on vaccine development. Immunogenetics has been important in characterizing roles of TCR genes, superantigens, and host genes that play a role in molecular mimicry in disease pathogenesis. In addition, recent work with gene knockout, recombinant inbred or congenic, mutant, consomic, and transgenic mice, positional cloning, mouse/human gene homologies to identify candidate human resistance genes, and the rapid expansion of the gene transcription maps of the human genome, have been important in analysis of resistance to intracellular pathogens.
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PMID:Immunogenetics in the analysis of resistance to intracellular pathogens. 749 19

Several cellular and humoral mechanisms probably play a role in natural immunity to Plasmodium falciparum malaria, but the development of an effective vaccine has been impeded by uncertainty as to which antigens are targeted by protective immune responses. Experimental models of malaria have shown that cytotoxic T lymphocytes (CTL) which kill parasite-infected hepatocytes can provide complete protective immunity against certain species of Plasmodium in mice, and studies in The Gambia have provided indirect evidence that CTL play a protective role against P falciparum in humans. By using an HLA-based approach, termed reverse immunogenetics, we have previously identified peptide epitopes for CTL in liver-stage antigen-1 and the circumsporozoite protein of P falciparum. We have extended this work to identify CTL epitopes for HLA class I antigens that are found in most individuals from Caucasian and African populations. Most of these epitopes are in conserved regions of P falciparum. CTL peptide epitopes were found in a further two antigens, thrombospondin-related anonymous protein and sporozoite threonine and asparagine rich protein, indicating that a subunit vaccine designed to induce a protective CTL response may need to include parts of several parasite antigens. However, CTL levels in both children with malaria and in semi-immune adults from an endemic area were low suggesting that boosting these low levels by immunisation might provide substantial or even complete protection against infection and disease.
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PMID:Identification of conserved antigenic components for a cytotoxic T lymphocyte-inducing vaccine against malaria. 753 70

CD8+ CTL specific for the Plasmodium yoelii sporozoite surface protein 2 (PySSP2) protect mice against malaria. For this reason, vaccines designed to induce CTL against P. falciparum SSP2 (PfSSP2) are under development. Optimal development of PfSSP2 as a component of human malaria vaccines requires characterization of HLA class I-restricted CTL against this Ag. For this purpose, PBMC from four HLA-A2+ human volunteers immunized with P. falciparum irradiated sporozoites were stimulated with a recombinant vaccinia virus expressing PfSSP2 and with 35 PfSSP2-derived 15-amino acid peptides containing sequences conforming to HLA-A2 binding motifs. Ag-specific, genetically restricted, CD8+ T cell-dependent cytotoxic activity against autologous target cells transfected with the PfSSP2 gene was demonstrated in the four volunteers. Twelve of the 35 peptides sensitized HLA-A2-matched target cells for lysis by peptide-stimulated effectors. Three volunteers had CTL against 9 of the 12 peptides, and one had no peptide-specific CTL. HLA-A*0201 restriction was confirmed by demonstrating that effectors from the three responders could be stimulated with six different peptides to lyse HLA-A*0201+ T2 cells incubated with the homologous peptides. Peptide-specific, genetically restricted, CD8+ T cell-dependent cytotoxic activity was also demonstrated against two peptides using unstimulated PBMC as effectors. Available data indicate that the motif-bearing sequences in 6 of the 12 positive peptides are conserved among P. falciparum isolates and clones. Demonstration of HLA-A2-restricted CTL responses to multiple PfSSP2-derived peptides, and of circulating activated CTL against PfSSP2 in immune volunteers provide important information for optimal design and evaluation of vaccines containing this pre-erythrocytic stage Ag.
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PMID:HLA-A2-restricted cytotoxic T lymphocyte responses to multiple Plasmodium falciparum sporozoite surface protein 2 epitopes in sporozoite-immunized volunteers. 754 24


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