© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 1, 13,
January 2, 2002
© 2002 Oxford University Press
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Heat Shock Protein Vaccine: How Does It Work?
Pramod Srivastava, Ph.D., of the University of Connecticut School of Medicine in Farmington, and his colleagues have shown that their vaccine—the heat shock protein–peptide complex from a patients’s tumor—interacts with an antigen-presenting cell (either macrophages or dendritic cells) at the site of injection. The heat shock proteins bind to the CD91 receptor on macrophages and escort the peptides into the cell, where they are presented on the cell surface by MHC class I molecules.
The antigen-presenting cells then travel to the lymph nodes where they activate an immune response by stimulating various immune cells. The researchers have shown that natural killer cells and CD4+ and CD8+ T lymphocytes are involved in the immunization process as well as the release of interleukin 12 and other cytokines by antigen-presenting cells.
Since heat shock proteins are virtually absent from the bloodstream, the CD91 receptor does not normally come into contact with heat shock proteins. They are only released into the blood or lymph under extreme conditions.
The Srivastava group hypothesizes that the reason such a small quantity of the vaccine can elicit an effective immune response is that the vaccine is mimicking the necrotic pathway, an already-existing mechanism for destroying damaged cells. When the immune system detects heat shock proteins in the bloodstream, it sets off an alarm signaling that the cell membrane has ruptured, spilling its contents (containing heat shock proteins) into the blood.
This sets into motion a highly efficient wrecking system to destroy the dying cell, which begins with the binding of the heat shock protein to a macrophage, so the vaccine takes advantage of the built-in power of the immune system.
Vaccines using the heat shock proteins gp96, hsp70, and calreticulin have all been found to be effective, but the vaccine that uses gp96 (called HSPPC-96) is used in most trials.
Although Srivastava is the first to admit that nothing is certain until the randomized clinical trials are completed, identifying a similar mechanism for the immune response in mice and humans is reassuring.
"The mechanism has been worked out for both, and the mechanisms are the same—the heat shock proteins are the same, they bind peptides and tumor antigens in the same manner, they bind macrophages in the same manner, they have the same receptors—all the various steps in the pathway are identical. This tells me that it’s simply a matter of time. I feel very confident today."
John Sogn, Ph.D., deputy director of the National Cancer Institute’s Division of Cancer Biology, ranks the work as the "nicest, best integrated, basic science, and clinical story there is in vaccine research. Whether the most successful vaccines will come out of that remains to be seen. But over more than a decade, Srivastava has developed an incredible science story that beautifully integrates the developments in tumor immunology."
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