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Content archived on 2024-06-25

Genome- and HLA- wide scanning and validation of cytotoxic CD8 T cell responses against Mycobacterium tuberculosis

Objective

Vaccines against tuberculosis are urgently needed (Jordan Report, 2000). CD4 T cell responses play a major role in the generation of acquired immunity against M.tubercolosis. However, it is increasingly recognised that CD8 cytotoxic T cells (CTL) also con tribute to optimal host defence against mycobacteria. Of the various CTL subsets, it is commonly accepted that the conventional MHC-Ia restricted CD8 T cell subset play a major role. Unfortunately, relatively few CTL responses against TB have been identif ied. The object of this proposal is to perform a complete antigen-and epitope- discovery of relevance for human immune CTL responses against M.tuberculosis. Focusing on HLA class I restricted CTL constitutes the major risk involved in this project. To mee t our global objectives within the limited time and resources available for this project, we will combine several recently established innovative high-throughput methods from immunology and bioinformatics. Two different screening approaches will be used; o ne of "Forward Antigen Discovery", where expression libaries representing the whole M.tuberculosis genome is screened for proteins that are target for CTL repsonses in TB patients, and one of "Reverse Antigen Discovery", where proteins, which are likely to contain CTL epitopes, are predicted using computational methods, pre- validated by binding to relevant HLA molecules, and finally validated using CTL response from TB patients. The strategy will be initially to perform a genome-wide identification of nove l target proteins. Within these proteins we will subsequently perform HLA-wide epitope discovery where epitopes restricted by one of the major HLA supertypes are predicted, pre- validated for HLA binding and tested for CTL responses in TB patients.Our gene ral goal is to generate a European genomics/proteomics based platform for antigen and epitope discovery, and specifically to test it in the development of vaccines and immunotherapy.

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Keywords

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Topic(s)

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Call for proposal

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FP6-2003-LIFESCIHEALTH-3
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Funding Scheme

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STREP - Specific Targeted Research Project

Coordinator

DANMARKS TEKNISKE UNIVERSITET
EU contribution
No data
Total cost

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Participants (3)

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