Browsing by Author "Houghten, R.A."
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Item Analysis of human T cell clones specific for conserved peptide sequences within malaria proteins: Paucity of clones responsive to intact parasites(Journal of Immunology, 1994) Quakyi, I.A.; Currier, J.; Fell, A.; Taylor, D.W.; Roberts, T.; Houghten, R.A.; Good, M.F.T cells are thought to be of central importance in malaria immunity. Peptides copying malaria protein sequences often stimulate human CD4+ T cells and it was thought that they represented T cell epitopes present in the parasite and may thus have particular relevance to malaria vaccine development. To verify whether synthetic peptides representing highly conserved regions of parasite Ags may contribute to a malaria vaccine, we searched the data bank for conserved regions of Plasmodium falciparum malaria proteins that were not homologous to known self (human) proteins. We synthesized 24 such peptides representing 11 of the cloned and sequenced malaria asexual stage Ags, which were predicted by algorithms to represent T cell epitopes, and 6 peptides not predicted to be T cell epitopes and used these to generate T cell clones from individuals with an extensive previous history of malaria exposure. The T cell clones responded vigorously to many peptides but only a single clone, specific for a peptide within merozoite surface protein-1, 20-39, VTHESYQELVKKLEALEDAV, and not previously defined to be a T cell epitope responded to malaria parasites by proliferation and secretion of IFN-γ. This epitope was not revealed by studying parasite- induced T cell lines and is thus subdominant. The clone was able to significantly inhibit parasite growth in vitro. The final step in the inhibition of parasite growth appears to be nonspecific because other activated clones (not specific for malaria sequences) can inhibit parasite growth. Our data suggest that few conserved peptides within malaria parasites can be processed from the intact parasite. However, such peptides that can be processed from malaria parasites may be expected to stimulate parasite- specific T cells that could inhibit parasite growth and as such may be lead candidates for a vaccine aimed at inducing cellular immunity to malaria.Item Cytotoxic T cells specific for the circumsporozoite protein of plasmodium falciparum(Nature, 1988) Kumar, S.; Miller, L.H.; Quakyi, I.A.; Keister, D.B.; Houghten, R.A.; Maloy, W.L.; Good, M.F.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 parasites1. Vaccination with irradiated sporozoites can provide protective immunity1 and a recent study2 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 immunity3,4. 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.Item Human T-cell recognition of the circumsporozoite protein of plasmodium falciparum: Immunodominant T-cell domains map to the polymorphic regions of the molecule(Proceedings of the National Academy of Sciences of the United States of America, 1988) Good, M.F.; Pombo, D.; Quakyi, I.A.; Riley, E.M.; Houghten, R.A.; Menon, A.; Miller, L.H.The definition of human T-cell antigenic sites is important for subunit vaccine development of a peptide immunogen if the goal is to allow antibody boosting during infection or to stimulate antibody-independent T-cell immunity. To identify such sites on the circumsporozoite (CS) protein of Plasmodium falciparum, 29 overlapping synthetic peptides spanning the entire CS protein were made and tested for their ability to stimulate peripheral blood lymphocytes from 35 adults living in a P. falciparum malaria-endemic region of West Africa. Three immunodominant domains were located outside the repetitive region. These domains, however, occurred in the polymorphic regions of the molecule, suggesting that parasite mutation and selection has occurred in response to immune pressure from T cells. Such polymorphism may impose an obstacle for vaccine development.