WATERTOWN, Mass., June 28 /PRNewswire-USNewswire/ -- Published in this month's issue of the journal Nature Medicine, a collaborative team of scientists from the University of Illinois, the University of Minnesota Medical School and the Boston Biomedical Research Institute describe engineered proteins that completely neutralize the lethal activity of a bacterial superantigen in animal models. Their work holds great promise for the development of new therapeutics for toxic shock syndrome, a condition that is characterized by high fever and hypotension and can lead to multi-organ failure and death, and for which no treatment is currently available.
The research team, led by David M. Kranz from the University of Illinois and including members of the laboratories of Patrick M. Schlievert at the University of Minnesota Medical School and Eric J. Sundberg at the Boston Biomedical Research Institute, focuses on a class of toxins know as bacterial superantigens, which are secreted from many common bacteria, including Staphylococcus aureus and Streptococcus pyogenes, which cause toxic shock syndrome. These toxins have also been classified as biological weapons.
Superantigens function by interacting with receptor molecules on the surfaces of human immune system cells. These receptor molecules include the T cell receptor on T lymphocytes and major histocompatibility complex molecules on antigen presenting cells that normally carry out the presentation and recognition of antigens that initiate the tightly-controlled adaptive immune response required to clear the body of infection. Superantigen binding to these receptor molecules, however, results in the stimulation of an inordinate fraction of T lymphocytes and a massive release of the signaling molecules called cytokines that recruit other cells of the immune system, a cascade of biological signaling events that can ultimately lead to toxic shock syndrome.
The research team engineered a fragment of the T cell receptor that normally binds to a superantigen relatively weakly to associate with its superantigen target more than a million-fold tighter through a directed evolutionary process called yeast display. These engineered T cell receptor fragments were produced recombinantly in large quantities, shown to inhibit superantigen-mediated T cell activation in cell culture, and subsequently, used to effectively protect rabbits from lethal doses of superantigen.
Despite the intensive research efforts that have been directed at toxic shock syndrome and superantigens, therapeutics capable of neutralizing superantigen-mediated T cell activation in humans have to date been unavailable. The T cell receptor fragments described in this study represent an easily produced potential treatment for diseases mediated by bacterial superantigens.
About the Boston Biomedical Research Institute
Founded in 1968, Boston Biomedical Research Institute is a not-for-profit basic research institute dedicated to the understanding, treatment and prevention of a wide range of human diseases and conditions including cancer, cardiovascular diseases, neural and neuromuscular diseases, and degenerative diseases. For more information visit http://www.bbri.org.
Boston Biomedical Research Institute