Septic shock, a state of profound hemodynamic instability following infection, is a major clinical problem. Septic shock appears to be mediated by bacterial products such as endotoxins for gram (-) organisms and exotoxins for gram (+) organisms. Recently the gram (+) exotoxins Staph, Enterotoxin B (SEB) and Toxic Shock Syndrome Toxin 1 (TSST-1) have received increasing attention because of their ability to act as """"""""superantigens"""""""", activating large numbers of T cells bearing certain T cell receptors. So far a murine model, the standard for immunological research, for this lethal disease has not been available. We have developed such a model identifying both susceptible and resistant mouse strains.
The aim of our study is to clarify the pathomechanisms involved in the lethal SEB induced disease. We will perform systematic studies monitoring various stages of T cell activation after SEB stimulation while also monitoring for the consequences of T cell activation including vascular leakage and the resultant shock. Importantly, we will study these events in susceptible and resistant mouse strains which will elucidate critical factors defining the pathophysiology of the disease. Specifically, we will continue our studies on the activation of T cells that bear SEB specific receptors, focusing on Vbeta8 and Vbeta17 expressing cells. We will determine the extent to which these T cells acquire an activated phenotype in vivo (Aim 1A), and the magnitude of their clonal expansion following SEB challenge (Aim 1.B).
Aim 1. C studies the effector functions of the SEB stimulated T cells, characterizing pattern of induced cytokines. The pathogenic role of Vbeta8 or Vbeta17 cells will be directly tested via adoptive transfers into immunodeficient SCID mice. Finally, we will test the response of the end organ, the vasculature, to the cytokines that the activated T cells release. In all of these experiments, SEB susceptible and resistant mouse strains will be compared, sorting out the critical factors at 3 critical stages of the pathogenic process: the T cell effector functions (cytokines) and the end organ response (vascular leakage).
| Anderson, M R; Tary-Lehmann, M (2001) Staphylococcal enterotoxin-B-induced lethal shock in mice is T-cell-dependent, but disease susceptibility is defined by the non-T-cell compartment. Clin Immunol 98:85-94 |
