Research Project
6644676
DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is a continuing health threat both in the United States and the rest of the world with an estimated two billion people currently infected worldwide. Antibiotic regimens requiring lengthy direct observation of patients and the emergence of drug resistant strains create a pressing need for novel therapies. One such novel therapy is the use of heat shock protein to adjuvant a tuberculosis peptide vaccine for optimal generation of cell-mediated immune response. Heat shock protein-peptide complexes are recognized by HSP receptors on antigen presenting cells. Peptides chaperoned by HSP are then re-presented by MHC Class I and II molecules leading to cell mediated immunity including stimulation of antigen-specific CD4+ and CD8+ T cells. Cell mediated immunity is an important major protective mechanism in tuberculosis. The ability of heat shock protein-peptide complexes to elicit T cell responses may address a shortcoming of traditional tuberculosis vaccines that primarily elicit antibody responses. The proposed product will consist of Mycobacterium tuberculosis antigens complexed in vitro to mammalian heat shock protein 70. Total cytosolic and culture filtrate fractions from M tuberculosis will be obtained and subjected to proteolysis with highly selective proteases to generate a large array of peptides containing T cell epitopes. Murine heat shock protein 70 will be complexed to the TB peptide extract and utilized as a vaccine. The product will be evaluated in mice for induction of cellular immune responses, assessed by antigen-specific cytotoxicity, cytokine response, and proliferation. The ultimate purpose of the research funded by this grant is to ascertain whether it will be possible to utilize the heat shock protein technology to generate a novel and efficacious therapeutic vaccine.
