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Vaccines4TB
TUBERCULOSIS
Framework programme: 6
Call: 2
Project number:
LSHP-CT-2004-012175
EC contribution: € 1,053,445
Duration: 24 months
Type: STREP
Starting date: 1 January 2005
Graphic element Genome- and HLA- Wide Scanning and Validation of Cytotoxic CD8 T Cell Responses against Mycobacterium Tuberculosis
Keywords: Tuberculosis; vaccine; cellular immune response; CD8

Summary:

Vaccines against tuberculosis are urgently needed. CD4 T cell responses play a major role in the generation of acquired immunity against M. tuberculosis. However, it is increasingly recognised that CD8 cytotoxic T cells (CTL) also contribute to optimal host defence against mycobacteria. Unfortunately, relatively few CTL responses against TB have been identified. The object of this proposal is to perform a complete antigen- and epitope- discovery of relevance for human immune CTL responses against M. tuberculosis. Several recently established innovative high-throughput methods from immunology and bioinformatics will be combined. Two different screening approaches will be used; one of ‘forward antigen discovery’, where expression libraries representing the whole M. tuberculosis genome will be screened for proteins that are targets for CTL responses 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 initially be to perform a genome-wide identification of novel 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.

Background:

Infectious diseases remain the largest cause of death in the world. Among infectious diseases, tuberculosis is responsible for the greatest number of deaths. Each year, 54 million people are infected with Mycobacterium tuberculosis, 6.8 million develop clinical disease and 2.4 million people die of tuberculosis. Tuberculosis is responsible for 5% of all deaths worldwide. There is mounting evidence from animal studies that CD8 T cells are involved in the control of latent M.  tuberculosis infection. However, relatively little has been published on the functional role of mycobacteria-specific CD8 T cells in humans, nor on the actual mycobacterial antigens and epitopes targeted by these killer cells.

Aim:

The aims of this project are:

  1. to evaluate the CD8 cytotoxic T cell response repertoire in the human population
  2. to test if expression libraries representing the whole M. tuberculosis genome can be used for CTL antigen discovery
  3. to test the use of immuno-bioinformatics is a fast and rational approach to CTL epitope identification

Expected results:

Firstly, this project expects to find new CTL epitopes. More specifically, it will:

  1. identify proteins likely to be good antigens, using expression cloning of M. tuberculosis antigens and M. tuberculosis–derived epitopes seen by patient CTL’s
  2. predict which peptides are potential CTL epitopes within all M. tuberculosis proteins for all major human HLA supertypes and select a fraction of these for actual synthesis and test
  3. measure binding to HLA molecules for the predicted peptides
  4. measure CTL responses against predicted epitopes in M. tuberculosis infected persons and BCG vaccinated individuals using either target cells transfected with the M. tuberculosis expression library + relevant HLA molecules, or target cells pulsed with identified peptides.

Potential applications:

The results obtained in this project can be used in the development of a vaccine against TB.

Coordinator:

Ole Lund
Technical University of Denmark, Centre for Biological Sequence Analysis
Building 208
2800 Lyngby
Denmark
Tel: +45 4525 2425
Fax: +45 4593 1585
E-mail: lund@cbs.dtu.dk
Website: http://www.cbs.dtu.dk

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Søren BuusInstitute for Medical Microbiology and ­Immunology Panum 18.3.12
Blegdamsvej 3
DK-2200 Copenhagen N
Denmark
Tel: +45 3532 7885
Fax: +45 3532 7853
E-mail: S.Buus@immi.ku.dk
Website: http://www.immi.ku.dk
3Tom H.M. OttenhoffDepartment Immunohematology and Blood Transfusion
Leiden University Medical Center

Albinusdreef 2,
NL-2333 ZA Leiden
The Netherlands
Tel:
+31 71 5265128 (secr);
5263809 (desk)
Fax: +31 71 5216751
E-mail: t.h.m.ottenhoff@lumc.nl
4Ugur SahinPharmaceuticals AG, Germany

Freiligrathstr. 12
DE-55131 Mainz
Germany
Tel: +49 6131 1440100
Fax: +49 6131 1440111
E-mail:
v.schlueter@ganymed-pharmaceuticals.com

 
 
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