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BIOGRAPHY:
Dr. Plebanski received her Ph.D. in immunology from the University of Bristol in 1992. She conducted postdoctoral research until 1997 at the Institute of Molecular Medicine, Oxford University. She currently holds the position of Associate Professor, Department of Life Sciences and Technology at the Victoria University of Technology, as well as the position of Head of the Vaccine Development Department, Vaccine Development and Infectious Diseases Laboratory at the Austin Research Institute in Melbourne, Australia. In 1998 she was named Honorary Professor to the Center for Research and Advanced Studies in Mexico. In her HHMI project she is studying malaria-induced immuno-suppression with the goal of developing counter-suppressive vaccines.
RESEARCH ABSTRACT SUMMARY:
T Cell Epitope Mapping in Endemic Populations: Are We Seeing the
Whole Picture?
Malaria affects approximately 500 million people each year, causing
an estimated 2 million deaths. T cells, particularly those able to
secrete interferon gamma (IFN-gamma) (T1 cells) have been shown to play
a central role in protective immunity against the pre-erythrocytic
stages of infection. However, recent Phase I immunogenicity studies in
Gambia of the recombinant RTS,S vaccine expressing the circumsporozoite
(CS) protein of Plasmodium falciparum emphasized the unusual
conclusion from our other studies that T cells induced by infection
that are restimulated rapidly to secrete IFN-gamma are different from
those that can do so after in vitro expansion with specific peptides.
Naturally induced CS-specific T cell reactivity was low in magnitude
and broad in specificity, with a range of predicted CS T cell epitopes
contributing to responses. Interestingly, another protein of the
pre-erythrocytic stage, thrombospondin-related adhesive protein (TRAP),
showed a similar broad and low T1 reactivity pattern in large-scale
population studies in Kenya. Interestingly, this reactivity was not
associated with protection. Studies of T cell reactivity in naturally
exposed and vaccinated humans, such as those described above, are
important in providing potential epitope targets able to induce
protective immunity when incorporated into vaccines. Are we missing
protective epitopes in mapping studies? Epitope mapping using
overlapping peptides is “assumption free” but expensive.
Our results indicate that using conventional computer algorithms to
predict high-affinity MHC binding peptides is likely to eliminate from
mapping studies a range of potentially protective T cell epitopes.
Thus, three novel families of peptide MHC-binding modalities are noted:
low-affinity (but immunodominant) binding using short anchor residues,
high-affinity binding using a new MHC pocket (previously not known to
anchor peptides), and the use of carbohydrate molecules in
glycopeptides for anchoring to MHC. We suggest that limitations in the
spectrum of T cell activities analyzed and in the ability to predict
MHC binding has hampered the detection of protective T cell
responses.
Photo: Birgit C. An der Lan
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