JERUSALEM - Researchers at the Faculty of Medicine of The Hebrew University of Jerusalem, taking a novel approach, have designed a small peptide antagonist that blocks the deadly action of Staphylococcal and Streptococcal exotoxins at the top of the toxicity cascade, before activation of T cells takes place.
By doing so, they have kept these bacterial superantigen exotoxins from triggering an excessive cellular immune response with massive release of cytokines that trigger toxic shock syndrome.
Mice injected with the peptide antagonist survived up to 100 percent a lethal challenge with different superantigens and, moreover, were rescued from death when given the antagonist even after the process of lethal toxic shock had ensued.
Earlier attempts that aimed at blocking the cytokines (including interleukin-2, interferon-gamma, tumor necrosis factor-beta) produced by Th1 cells following exposure to superantigenic toxins have failed because "the variety and magnitude of these effector molecules proved impossible to control once unleashed," said Raymond Kaempfer, a professor of molecular biology and cancer research, describing his study with co-workers Gila Arad, Revital Levy and Dalia Hillman, published in the April 2000 Nature Medicine. The title, "Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation."
"It took us four years of molecular design and assays in blood cells from hundreds of human donors to develop an effective antagonist peptide," said Arad, a molecular biologist.
The peptide treatment has met the FDA 28-day survival standard for antidotes against toxic shock with no detectable side effects in mice.
"If clinical trials, planned next year in Israel, are successful, antagonist injection could rescue infected people from lethal shock, as was proven in our animal model," Kaempfer said. "As a secondary bonus, once animals survive toxic shock by virtue of our antagonist, they also become rapidly immune against further lethal challenges, even with different superantigenic toxins," Kaempfer told BioWorld International.
Such protective antibodies could be of extraordinary value in preventing resurgence of toxic conditions upon re-infection and could lead to a new vaccination strategy. "Although the mechanism is not clear, this surely warrants further investigation," Kaempfer said.