Keywords: Tuberculosis; vaccine; cellular immune response; CD8
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.
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.
The aims of this project are:
Firstly, this project expects to find new CTL epitopes. More specifically, it will:
The results obtained in this project can be used in the development of a vaccine against TB.
Technical University of Denmark, Centre for Biological Sequence Analysis
Tel: +45 4525 2425
Fax: +45 4593 1585
|Official Address||Other Information|
|2||Søren Buus||Institute for Medical Microbiology and Immunology Panum 18.3.12 |
DK-2200 Copenhagen N
|Tel: +45 3532 7885 |
Fax: +45 3532 7853
|3||Tom H.M. Ottenhoff||Department Immunohematology and Blood Transfusion|
Leiden University Medical Center
NL-2333 ZA Leiden
+31 71 5265128 (secr);
Fax: +31 71 5216751
|4||Ugur Sahin||Pharmaceuticals AG, Germany|
|Tel: +49 6131 1440100 |
Fax: +49 6131 1440111