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

Immune responses in major histocompatibility complex (MHC)-disparate congenic mouse strains immunized with sexual stage malaria parasites or purified recombinant protein were adjuvant dependent. Whereas mice exhibited a limited antibody response to immunization with newly emerged Plasmodium falciparum gametes in Freund's adjuvant, all five congenic mouse strains responded to several transmission-blocking vaccine candidate antigens, when parasites were emulsified in a monophosphoryl lipid A (MPL) and trehalose dimycolate (TDM) adjuvant. The humoral response in those animals immunized with the antigen in a MPL/TDM adjuvant was helper T cell dependent, as evident by boosting of the antibody response after a second immunization. If the immunogen consisted of purified recombinant protein, then the immune response was not MHC class II limited in mice immunized with either complete Freund's adjuvant or TDM/MPL. The potential role of adjuvants in overcoming apparent immune nonresponsiveness and the implications for development of a malaria transmission-blocking vaccine are discussed.
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PMID:Adjuvant-dependent immune response to malarial transmission-blocking vaccine candidate antigens. 138 89

A Plasmodium falciparum schizont lysate has been previously described as being a powerful inducer of proliferation for human peripheral T lymphocytes. In this report we study the phenotype of cycling T cells from unexposed donors and examine how the P. falciparum lysate compares with the conventional T cell mitogen phytohemagglutinin (PHA), a known superantigen staphylococcal enterotoxin B (SEB), and a classical antigen pure protein derivative (PPD). We show that for this lymphoproliferative activity interaction with the MHC class II molecule is required and that in the presence of P. falciparum the great majority of the cycling cells at day 6 are gamma delta T cells, all of them bearing V gamma 9 V delta 2. Our results suggest that P. falciparum induces a T cell proliferative response that resembles a response of human peripheral blood gamma delta T cells to superantigen. This observation is in agreement with the elevated level of peripheral gamma delta lymphocytes observed during and after malaria acute infection.
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PMID:Preferential expansion of V gamma 9 V delta 2 T cells following stimulation of peripheral blood lymphocytes with extracts of Plasmodium falciparum. 153 50

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.
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PMID:Characterization of regulatory T cell responses to defined immunodominant T cell epitopes of the Plasmodium falciparum antigen Pf155/RESA. 170 42

We have examined T cell recognition of a recombinant polypeptide (190L), corresponding to a 175-amino-acid-long conserved region of the major surface antigen (p190) of Plasmodium falciparum merozoites. We show that 190L contains a variety of T cell epitopes, and can be recognized in association with many different MHC class II molecules, including HLA-DR, DP, and DQ antigens. Most of the epitope-containing peptides are able to bind to more than one DR, and a single DR molecule can bind to different peptides. These findings, together with the fact that humans are generally heterozygous at the DR, DQ, and DP beta chain loci, suggest that MHC restriction should not be a major constraint in the development of malaria subunit vaccines.
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PMID:HLA polymorphism and T cell recognition of a conserved region of p190, a malaria vaccine candidate. 171 5

The anamnestic antibody response to synthetic peptide antimalarial vaccines is under Ir gene control. It has therefore been inferred that the development of antibody responses to the native repetitive Ag of malaria parasites also requires linkage of T and B cell epitopes, presentation of Ag in the context of MHC class II components, and cognate T cell help for antibody production. In this study, we sought to test this assumption, by utilizing classical protocols to determine whether the antibody response to the repetitive surface Ag of malaria sporozoites, the circumsporozoite (CS) protein, is under Ir gene control. In contrast to vaccine constructs, such as recombinant proteins or synthetic peptides, secondary responses to the repetitive oligomeric domains of the native CS protein of intact malaria sporozoites do not require the presence of Ag-specific Th cells. Conferral of CS-specific Th cells does not appear to influence the magnitude of this thymus-independent response to sporozoites. In further contrast to synthetic CS analogs, exposure to the parasite appears to be associated with low levels of Ag-specific Th cell sensitization. These observations suggest a functional role in immune evasion for the immunodominant repetitive domains found within protein Ag of malaria and other parasites.
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PMID:Lack of Ir gene control in the immune response to malaria. I. A thymus-independent antibody response to the repetitive surface protein of sporozoites. 213 52

In the case of the malaria CS protein we have shown that there is at least one T cell determinant which is able to bind to and be recognized by most human MHC class II molecules, while for the 190L polypeptide, derived from a conserved region of the p190 merozoite surface protein, we have identified several epitopes recognized by T cell clones in association with different HLA-class II isotypes and alleles. In addition, binding analysis of these epitopes indicated that most of the peptides are able to bind to multiple allelic forms of class II molecules. Although there are important obstacles to malaria vaccine development we believe that, in the light of these results, unresponsiveness in humans, caused by MHC restriction, might not be a major constraint in development of a subunit vaccine.
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PMID:Malaria antigens and MHC restriction. 228 57

An ideal vaccine should elicit a long lasting immune response against the natural parasite, both at the T- and B-cell level. The immune response should occur in all individuals and be directed against determinants that do not vary in the natural parasite population. A major problem in designing synthetic peptide vaccines is that T cells generally recognize peptide antigens only in association with one or a few of the many variants of major histocompatibility complex (MHC) antigens. During the characterization of epitopes of the malaria parasite Plasmodium falciparum that are recognized by human T cells, we analysed a sequence of the circumsporozoite protein, and found that synthetic peptides corresponding to this sequence are recognized by T cells in association with many different MHC class II molecules, both in mouse and in man. This region of the circumsporozoite protein is invariant in different parasite isolates. Peptides derived from this region should be capable of inducing T-cell responses in individuals of most HLA-DR types, and may represent good candidates for inclusion in an effective anti-malaria peptide vaccine.
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PMID:A malaria T-cell epitope recognized in association with most mouse and human MHC class II molecules. 246 73

The immune response to three peptides corresponding to the repeat regions of the malaria candidate vaccine ring infected E surface Ag (RESA) were studied. Both antibody responses and lymphocyte stimulation in mice injected with these peptides without carrier were found to be restricted to certain MHC class II haplotypes. Mice bearing IAk were strong responders to all three peptides. Mice bearing IAd were strong responders only to the 3' repeat peptides, the octamer and tetramer. Mice bearing Is or Iq did not respond to any repeat peptides. Remarkably, the pattern of genetic restriction of the antibody response to the entire RESA as expressed in vaccinia indicated that there were no other epitopes besides the three repeats. Because only one class II haplotype (i.e., k) out of five tested responded strongly to this peptide and only two out of five (i.e., k and d) responded to the octamer or tetramer, it may be difficult to achieve a good immune response against RESA in most or all humans.
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PMID:Class II restriction in mice to the malaria candidate vaccine ring infected erythrocyte surface antigen (RESA) as synthetic peptides or as expressed in recombinant vaccinia. 271 42

In an individual experiencing the first attack of malaria, symptoms of disease can occur at very low parasitemia. T cells and cytokines have been implicated in the etiology of disease symptoms, and others and ourselves have shown that T cells from non-exposed individuals can be stimulated by malaria parasites. Here, we show that nine from 11 blood samples, naturally infected with malaria parasites, could stimulate proliferation of a malaria-specific T cell clone derived from a non-exposed donor. T cells were able to respond to infected blood at a parasitaemia as low as 0.000003% (comparable to the level at which individuals can first experience symptoms of malaria) and secrete cytokines implicated in pathology. Antigens capable of stimulating T cells are expressed throughout the blood stage, but are specifically released at the time of schizont rupture. While most TCR V beta genes are expressed during the T cell response of naive donors to malaria parasites, processing of parasite antigens is blocked by chloroquine and monensin, and activation of 36 of 41 malaria-specific clones tested was restricted by defined MHC class II allelic antigens, strongly suggesting that parasites do not act as mitogens nor as superantigens. The clones react to various commonly encountered pathogenic and non-pathogenic microbes. These data support the concept that activation of cross-reactive memory T cells by malaria parasites contributes to disease symptoms in individuals experiencing their first attack of malaria.
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PMID:Antigens released at schizont burst stimulate Plasmodium falciparum-specific CD4+ T cells from non-exposed donors: potential for cross-reactive memory T cells to cause disease. 754 8

Liposomes have been proposed as vehicles for vaccines against parasitic and viral illnesses. Experimental vaccines against malaria, HIV, hepatitis A, and influenza virus have been shown to be safe and highly immunogenic in several human trials. Analysis of the intracellular trafficking patterns of liposomal antigen reveals that after being phagocytosed by macrophages, liposomal antigen readily escapes from endosomes into the cytoplasm of the macrophages. It is proposed that liposomal peptide antigen can enter either the Golgi apparatus or the endoplasmic reticulum and thereby interact with MHC class II or class I molecules. The intracellular cytoplasmic trafficking patterns of liposomal antigens raise the possibility that liposomes may have utility in human vaccines for induction of either humoral immunity or cytotoxic T lymphocytes.
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PMID:Liposomal vaccines: clinical status and immunological presentation for humoral and cellular immunity. 762 48


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