Nov. 6, 2002 Boston (November 5, 2002) -- Listeria and certain strains of E. coli are the scourge of picnics, but researchers at Harvard Medical School and London's Hammersmith Hospital show in the November Gene Therapy that combining bacterial components of these bad bugs can create a powerful vector against melanoma challenged mice.
For the last four decades, researchers have poked and prodded Escherichia coli and Listeria monocytogenes--the basic science trade names of these sometimes deadly bugs--to discover how they interact with the immune system, invade cells, rob them of nutrients, and blossom within other cells to eventually shut down necessary bodily functions. From his work with these pathogens, Darren Higgins, HMS assistant professor of microbiology, has discovered how to create a vector to promote health.
In the published study, researchers infected mice with an especially virulent line of melanoma. Six of the eight mice whose immune system was primed with the E. coli/Listeria vector remained tumor free for more than 90 days post-tumor challenge, and the remaining two mice showed significant delay in tumor growth compared to mice that did not receive the cancer vaccination. The mice in the study's control group did not live past 16 days.
"The results of this study are very positive," says Higgins. "It suggests that we could utilize this killed bacterial formulation to prime the immune system against diseases such as cancer, or other viral and bacterial pathogens."
Using killed E. coli as the main vector, Higgins stripped out the bacteria's virulence components while leaving a framework that remains attractive to macrophages, cells at the front lines of the immune system. Within this shell, his team then added large proteins for delivery to macrophages to generate an immune response (an advantage over other vectors that cannot deliver large molecules). But the key to this vector is the addition of listeriolysin, a component of Listeria. As its name implies, listeriolysin lyses, or dissolves, a primary component of immune cells, the phagosome, a kind of cellular trash can. It is within the phagosome that foreign particles taken up by immune cells ultimately reside. Once the phagosome is lysed, the engulfed protein escapes from the compartment and is taken to the surface of the immune cell, where it can be presented to teach other immune cells what to target.
In this study, researchers injected mice with a strain of melanoma tagged with ovalbumin, a harmless protein known to generate a strong immune response. Ovalbumin had been previously inserted into the vector. When injected into mice, the killed E. coli vectors are quickly digested by patrolling macrophages or dendritic cells, the most important cells in the immune system for priming killer T- and B-cells. Once inside macrophages, the Trojan horse E. coli is taken within the phagosome to be destroyed, generally occurring minutes after uptake.
But unlike normal E. coli, the vector's listeriolysin subsequently lyses the phagosome and explodes its contents into the macrophage interior. Once in the cytosol, the ovalbumin is taken to the surface of the macrophage and serves as an antigen, a sort of red flag that tells T-cells what to search for and eliminate within the body, in this case melanoma cells coded with ovalbumin.
"We are now moving toward insertion of numerous pathogen-specific antigens into the vector to elicit protective responses," says Higgins. The vector is being tested against several additional infectious disease models.
This research was conducted at the Cancer Research UK, Molecular Oncology Unit, ICSM at Hammersmith Hospital, London.
Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 17 affiliated teaching hospitals and research institutes. Those HMS affiliated institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Hospital, Center for Blood Research, Children's Hospital, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, VA Boston Healthcare System.
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