T CELL COSTIMULATION IN INTRAABDOMINAL SEPSIS

Brigham And Women'S Hospital, Boston MA

Investigators

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Abstract

Description (applicant's abstract): Abscess formation is a classic host response to bacterial infection in humans. The development of abscesses associated with intraabdominal sepsis in patients causes severe morbidity and can be fatal. However, the immunopathogenesis of this disease process is poorly defined. While T cells have been implicated in the development of abscesses, definitive evidence of their role has been lacking and the underlying mechanisms of T cell involvement have not been elucidated. It has been demonstrated that capsular polysaccharides from bacterial pathogens such as B. fragilis and Staphylococcus aureus, which are commonly isolated from clinical cases of abscesses, can induce this host response in animal models of intraabdominal sepsis. This activity is absolutely dependent on the presence of positively and negatively charged groups associated with their repeating unit structures. Recently, we have shown that these polymers, as well as other structurally distinct polysaccharides with this zwitterionic charge motif, are potent activators of CD4+ T cells in vitro. Moreover, T cells activated in vitro by zwitterionic polysaccharides (Zps) can induce intraabdominal abscesses when transferred to the peritonea of rats. These are the first studies to demonstrate that purified bacterial polysaccharides can stimulate T cell proliferation and prompted our investigation of the mechanisms of T cell activation and its role in abscess induction. Since the first submission of this proposal, we have demonstrated that Zps activate T cells in a manner similar to that of bacterial superantigens. Based on these data, we hypothesize that a novel type of T cell-mediated immune response to Zps initiates the inflammatory response that leads to abscess formation. The purpose of this application is to characterize the superantigen-like T cell response to Zps and its role in the initiation of the inflammatory process leading to abscess formation. It is believed that the characterization of the T cell response to Zps will lead to the development of new immunologic paradigms concerning the mechanism by which polysaccharides interact with T cells to elicit cell-mediated immune responses. This insight should also lead to the development of new therapeutic agents for the prevention of abscesses associated with intraabdominal sepsis in humans.