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)

Mice can be immunized to Plasmodium vinckei by repeated infections followed by cure. Such immunity is dependent on CD4 T cells and an architecturally modified spleen, but has little requirement for antibody. Thus, athymic mice can be exposed to P. vinckei and cured, but do not develop immunity. They are resistant to challenge with parasites, however, if they are then given spleen cells from euthymic immunized animals. Such immune spleen cells, however, cannot transfer resistance to normal mice which have been exposed to BCG, Salmonella typhimurium, or vaccinia virus, and are only partially effective in transferring resistance to mice which have been previously immunized with heterologous plasmodia, P. yoelii, P. chabaudi and P. berghei. Mice exposed to varying numbers of irradiated P. vinckei-pRBC do not develop immunity and nor are such animals protected following adoptive transfer of immune spleen cells. Cellular immunity to malaria may not only be dependent on a population of immune CD4 T cells, but may require a specifically architecturally modified spleen which may not occur following either exposure to candidate vaccine vectors, heterologous plasmodia or non-viable homologous plasmodia.
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PMID:Inability of Plasmodium vinckei-immune spleen cells to transfer protection to recipient mice exposed to vaccine 'vectors' or heterologous species of plasmodium. 168 80

Oral immunization with an attenuated Salmonella typhimurium recombinant containing the full-length Plasmodium berghei circumsporozoite (CS) gene induces protective immunity against P. berghei sporozoite challenge in the absence of antibody. We found that this immunity was mediated through the induction of specific CD8+ T cells since in vivo elimination of CD8+ cells abrogated protection. In vitro studies revealed that this Salmonella-P. berghei CS recombinant induced class I-restricted CD8+ cytotoxic T cells that are directed against the P. berghei CS peptide epitope spanning amino acids 242-253. This is the same peptide that previously was identified as the target of cytotoxic T lymphocytes (CTL) induced by sporozoite immunization. Salmonella-P. falciparum CS recombinants were constructed that contained either the full-length CS gene or a repeatless gene consisting of CS flanking sequences. Both of these vaccines were able to induce CD8+ CTL directed against P. falciparum CS peptide 371-390, which is identical to the target of CTL induced by sporozoites and vaccinia CS recombinants. These results directly demonstrate the ability of an intracellular bacteria such as Salmonella to induce class I-restricted CD8+ CTL and illustrate the importance of CD8+ CTL in immunity to malaria.
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PMID:Oral Salmonella: malaria circumsporozoite recombinants induce specific CD8+ cytotoxic T cells. 169 8

Immunogenicity of sexual stage antigens and boosting of transmission blocking antibodies following a natural infection are two critical factors in the design of an effective, subunit vaccine to block the transmission of malaria from man to mosquito. Immunogenicity and boosting are both T cell-dependent. Antigens, such as the 230-kDa, the 48/45-kDa, and the 40/10-kDa, expressed early in the extracellular forms of the sexual stage of Plasmodium falciparum, have limited immunogenicity in humans and in mice. In contrast, Pfs25, expressed predominantly in zygotes and ookinetes, has widespread immunogenicity in mice. Pfs25 expressed by a recombinant vaccinia virus (vSIDK) is also widely immunogenic in mice, and induces transmission blocking antibodies following multiple inoculations with vSIDK. The implications of these immunogenicity data are discussed relative to the design of an effective transmission blocking vaccine.
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PMID:Immunogenicity of Plasmodium falciparum sexual stage antigens: implications for the design of a transmission blocking vaccine. 170 52

Cytotoxic T lymphocytes (CTL) against the circumsporozoite (CS) protein of malaria sporozoites protect against malaria in rodents. Although there is interest in developing human vaccines that induce CTL against the Plasmodium falciparum CS protein, humans have never been shown to produce CTL against any Plasmodium species protein or other parasite protein. We report that when peripheral blood mononuclear cells (PBMC) from three of four volunteers immunized with irradiated P. falciparum sporozoites were stimulated in vitro with a recombinant vaccinia virus expressing the P. falciparum CS protein or a peptide including only amino acids 368-390 of the P. falciparum CS protein [CS-(368-390)], the PBMC lysed autologous Epstein-Barr virus-transformed B cells transfected with the P. falciparum CS protein gene or incubated with CS-(368-390) tricosapeptide. Activity was antigen specific, genetically restricted, and dependent on CD8+ T cells. In one volunteer, seven peptides reflecting amino acids 311-400 were tested, and, as in B10.BR mice, CTL activity was only associated with the CS-(368-390) peptide. Development of an assay for studying human CTL against the CS and other malaria proteins and a method for constructing target cells by direct gene transfection provide a foundation for studying the role of CTL in protection against malaria.
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PMID:Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. 170 38

The development of recombinant subunit vaccines against pathogenic organisms requires not only the identification of epitopes eliciting a protective immune response but also suitable carriers with adjuvant function. B- and T-cell epitopes of the malaria vaccine candidate gp190 were selected on the basis of a systematic search along the gp190 molecule and by computer prediction based on the amino acid sequence. Using some of the epitopes identified, we have redesigned the surface of the hepatitis B surface antigen lipoprotein particles by replacing the major antigenic determinants with malaria-specific sequences of up to 61 amino acids in length. Upon expression via vaccinia virus the hybrid particles elicit an anti-gp190 immune response in animals. Monoclonal antibodies derived from such infections recognize the native parasite.
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PMID:Epitopes of the human malaria parasite P. falciparum carried on the surface of HBsAg particles elicit an immune response against the parasite. 171 8

Many candidate antigens of malaria vaccines have limited immunological recognition. One exception is Pfs25, a cysteine-rich, 25-kilodalton sexual stage surface protein of Plasmodium falciparum. Pfs25 is a target of monoclonal antibodies that block transmission of malaria from vertebrate host to mosquito vector. The surface of mammalian cells infected with a recombinant vaccinia virus that expressed Pfs25 specifically bound transmission-blocking monoclonal antibodies. Furthermore, major histocompatibility complex-disparate congenic mouse strains immunized with recombinant Pfs25 elicited transmission-blocking antibodies, demonstrating that the capacity to develop transmission-blocking antibodies is not genetically restricted in mice. Live recombinant viruses may provide an inexpensive, easily administered alternative to subunit vaccines prepared from purified recombinant proteins to block transmission of malaria in developing countries.
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PMID:Induction of Plasmodium falciparum transmission-blocking antibodies by recombinant vaccinia virus. 192 44

Malaria is initiated by the inoculation of a susceptible host with sporozoites from an infected mosquito. The sporozoites enter hepatocytes and develop for a period as exoerythrocyte or hepatic stage parasites. Vaccination with irradiated sporozoites can provide protective immunity and a recent study shows that this can also be conferred by immunization with a recombinant salmonella expressing only the circumsporozoite protein that normally covers the sporozoites. Protection against infection is likely to be mediated by cytotoxic CD8+ cells, as depletion of CD8+ T cells in a sporozoite-immunized animal can completely abrogate immunity. Here we demonstrate directly the existence of CD8+ cytotoxic T lymphocytes (CTL) that recognize the circumsporozoite protein. B10.BR mice immunized with sporozoites or with recombinant vaccinia virus expressing the CS protein of Plasmodium falciparum contain CTL that specifically kill L cell fibroblasts transfected with the gene encoding the same CS protein. The peptide epitope from the CS protein that is recognized by CTL from this strain of mice is from a variant region of the protein.
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PMID:Cytotoxic T cells specific for the circumsporozoite protein of Plasmodium falciparum. 245 67

The circumsporozoite (CS) protein is a candidate vaccine antigen for the sporozoite stage in the life cycle of the malaria parasite. Using CS protein purified from recombinant baculovirus-infected cells and a panel of H-2 congenic mice, we are able to demonstrate that this protein is poorly immunogenic in terms of antibody production as a result of Ir gene control. The immune response to the protein is also restricted following immunization with a CS-recombinant vaccinia virus or with sporozoites. Using a panel of overlapping peptides spanning the entire protein, we are able to show that the high responder mice recognize helper T cell epitopes from the same region of the protein as do humans. This region, however, is the polymorphic segment of the protein, which has implications for vaccine development. However, the close overlap of human and murine T cell epitopes demonstrates that murine models may be very useful in epitope mapping and vaccine development for human pathogens. The T cell antigenic regions of this protein fulfil the predictive requirements for the amphipathic helicity algorithm.
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PMID:Human and murine CD4 T cell epitopes map to the same region of the malaria circumsporozoite protein: limited immunogenicity of sporozoites and circumsporozoite protein. 246 86

T lymphocytes, in contrast to antibodies, appear to recognize primarily a limited number of antigenic sites on any given antigenic protein. We find that a single site can so dominate the T-cell repertoire that the presence or absence of a response to one immunodominant site can make the difference between a high responder and a low responder, even though low responders respond to other sites almost as well as high responders. Besides interaction with major histocompatibility complex (MHC) molecules, the mode by which the antigen is processed into fragments for T-cell recognition also determines which sites are seen. The products of natural processing of the protein appear to be larger than the synthetic peptides and contain structures which hinder binding to certain MHC molecules or to the T-cell receptor. A third factor in immunodominance is the intrinsic structure of the antigenic site. We have shown that amphipathic helices have a higher than random chance of being immunodominant, and have developed a computer program to locate such structures in protein amino acid sequences. We prospectively predicted sites in the malaria circumsporozoite protein and found that the four most widely recognized sites in an endemic area of West Africa were all predicted. Similarly, we identified two helper T-cell sites from the HIV (AIDS virus) envelope, and have now shown that immunization with these elicits enhanced antibody responses to the whole envelope when injected into monkeys. These sites are also recognized by human T cells from volunteers who had been immunized with a recombinant vaccinia virus expressing the HIV envelope. Also, because cytotoxic T lymphocytes (CTLS) may play a critical role in defence against AIDS, we have used a recombinant vaccinia virus and transfectants expressing the HIV envelope gene to induce specific CTLS against the HIV envelope. Using synthetic peptides, we were able to identify the first CTL recognition site in the AIDS virus. These results may contribute to the rational design of vaccines.
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PMID:Structural features of T-cell recognition: applications to vaccine design. 247 71

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


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