Cytokine Regulation in Sepsis/Inflammation

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DESCRIPTION (provided by applicant): Sepsis or the systemic inflammatory response to a microbial infection produces a myriad of host changes in adaptive and innate immunity. Although previous research has been focused primarily on the role of cytokines and inflammatory mediators in the pathogenesis of sepsis, therapies based on these approaches have been generally unsuccessful. During the past funding period, research has been directed towards the intercellular interactions between the innate and adaptive immune responses, targeting the cellular processes that determine an adverse outcome. These studies suggest that the innate and adaptive immune systems are inextricably linked, and sepsis is associated with defects in both, resulting in reduced antimicrobial processes and poor outcome. This application examines the intercellular communication between cells of the innate immune system (conventional dendritic cells (DCs)) and CD4+ effector T cells in their response to a murine model of generalized peritonitis. The proposal aims to answer the following two questions: 1) what role(s) do DCs play in the CD4+ effector T cell apoptosis and dysfunction that accompanies sepsis, and does the sepsis-induced loss of DCs contribute to the CD4+ T cell apoptosis and e. Most experimental approaches have focused solely on the contribution of individual mediators or cells to the sepsis response. Only through a more thorough exploration of the cellular interactions between the innate and the adaptive immune systems will a better understanding of sepsis pathogenesis lead to new therapeutic options. This application will focus on how dendritic cells of the innate immune system communicate with CD4+ effector T cells of the adaptive immune system to regulate the function of each. Targeting the interactions between the innate and adaptive immune system represents a more integrated and comprehensive approach to the treatment of sepsis than simply current approaches at blocking or augmenting individual mediators.