Infections with common microorganisms like Staphylococcus can lead to a septic shock, a major cause of morbidity and mortality in intensive cre units. Superantigens which are liberated by these microorganisms cause the disease by massive activation of T lymphocytes. Being able to directly bind to T cell receptors (TCR), superantigens like staphylococcal enterotoxin B (SEB) stimulate up to 20% of all T cells in the body. The closer definition of the pathomechanisms involved in the superantigen triggered lethal shock reaction was delayed by an appropriate animal model. Unlike human that are highly susceptible to this disease, mice have been thought to be resistant to it, unless treated additionally with the anti-metabolite and hepatotoxin D- galactosamine. I have identified mouse strains that are susceptible to the SEB-induced lethal shock syndrome without the additional treatment, providing what promises to be a model that closely approximates the human disease. In this project I propose to dissect the critical steps involved in the pathogenesis of the disease.
In Aim 1 I will test the hypothesis that the disease is T-cell mediated and requires a critical number of cells to induce it. Wild type and TCR-transgenic T cells will be used to sensitize T cell-deficient SCID mice, that, void of T cells, are resistant to the disease. The extent of clonal expansion induced by SEB will be tested in wild type and the chimeric mice. Sub-aim 1 focuses on lymphoid tissues, while sub-aim 2, using a technical innovation, studies clonal sizes in the entire organism and in various organ systems.
In Aim 2, I will test the hypothesis that the disease is mediated in a dose dependent fashion by cytokines of T helper 1-type (Th1) CD4+ T cells. In sub-aim 1 the cytokine response induced by SEB will be characterized in wild type mice and chimeras. In sub-aim 2 I will test how biasing of the SEB-induced response towards Th1 or Th2 type affects the disease. In sub-aim 3, disease induction will be studied after grafting of SCID mice with SEB-reactive TH1 or Th2 cells. In sub-aim 4 I will test whether the neutralization of tumor necrosis factor alpha, or interferon gamma, and of nitric oxide prevents the disease, as there molecules are the major pro-inflammatory effectors molecules of the Th1 response. It is hoped that the data generated will help to better define the effector arm involved in the lethal shock reaction, facilitating the development of a therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI001578-05
Application #
6627949
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
1999-02-01
Project End
2003-06-30
Budget Start
2003-02-01
Budget End
2003-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$31,428
Indirect Cost
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106