PATHOGENESIS OF THE TOXIC SHOCK SYNDROME - T-CELL MEDIATED LETHAL SHOCK CAUSED BY THE SUPERANTIGEN TSST-1

The pathogenesis of the toxic shock syndrome (TSS) is only incompletel y understood. We now present evidence that TSS toxin-I (TSST-1), one o f the superantigens produced by Staphylococcus aureus, induces lethal shock in D-galactosamine sensitized mice. In this model TSS is depende nt on T cells, since cyclosporin A (CsA) completely blocked developmen t of shock, and since T cell-deficient SCID mice did not show signs of disease upon injection with TSST-1. However, SCID mice repopulated wi th T cells succumbed to lethal shock. The disease is characterized by a burst of lymphokines like interleukin-2 (IL-2) and tumor necrosis fa ctor (TNF) released into the sera of TSST-1-treated animals. Already 1 -2 h after TSST-1 application TNF serum levels peaked and IL-2 levels peaked around 4 h after treatment. TNF appears as key mediator of TSS, because anti-TNF monoclonal antibodies protected TSST-1-challenged mi ce. Interestingly, the burst of TNF in serum was noted well in advance of detectable markers of T cell activation. Thus, about 5% of all per ipheral T cells started to express the IL-2 receptors as late as 4 h a fter treatment. Comparing TSST-1- and endotoxin-induced shock we concl ude that TNF effects shock in both diseases. However, the type of cell s involved appears distinct in that T cells cause TSS triggered by the exotosin TSST-1 while macrophages mediate the shock induced by endoto xins.