Superantigens are extremely potent stimulators of T lymphocytes that produce a myriad of proinflammatory cytokines known to induce vascular injury, collapse of vascular system (toxic shock syndrome), and disseminated intravascular coagulation (DIC). The mechanisms by which superantigens induce cytokine production in T cells and subsequent cytokine-evoked injury of vascular system and DIC remain to be elucidated. This highly focused and integrated research plan evolves from recent advances made by us in studying superantigen-induced vascular injury, DIC, and apoptotic organ damage. We propose a series of interrelated studies focused on the mechanism of superantigen-induced signaling in T cells subsets, Th1 and Natural Killer T cells (NKT cells). Superantigen-induced signaling mediated by NF-kappaB and other stress-responsive transcription factors will be studied in T cells and NKT cells to delineate the mechanisms responsible for their death or survival. Their interaction with endothelial cells that express superantigen-binding MHC Class II molecules will be elucidated. Cytokine-induced expression of genes encoding procoagulant proteins, tissue factor and plasminogen activator inhibitor, and their role in superantigen-induced microvascular thrombosis manifested by DIC will be delineated. Finally, cell-permeable peptides and proteins that affect superantigen-induced signaling will be designed and tested in animal models for their efficiency to ameliorate vascular injury, DIC, and apoptotic organ damage. Based on this overall workscope, this grant application is submitted in response to RFA HL-01-003 entitled """"""""Cardiovascular, Lung, and Blood Immunobiology in Health and Disease"""""""".
