Cytokine Regulation in Sepsis/Inflammation

描述(由申请人提供)：败血症或对微生物感染的全身炎症反应会在适应性和先天免疫中产生无数的宿主变化。虽然以前的研究主要集中在细胞因子和炎症介质在脓毒症发病机制中的作用，但基于这些方法的治疗通常都不成功。在过去的资助期间，研究的重点是先天免疫反应和获得性免疫反应之间的细胞间相互作用，目标是决定不利结果的细胞过程。这些研究表明，先天免疫系统和获得性免疫系统是密不可分的，而败血症与两者的缺陷有关，导致抗菌过程减少和预后不良。这项应用检查了先天免疫系统细胞(常规树突状细胞(DC))和CD4+效应T细胞之间的细胞间通讯，它们对全身性腹膜炎小鼠模型的反应。该建议旨在回答以下两个问题：1)树突状细胞在脓毒症伴发的CD_4+效应T细胞凋亡和功能障碍中起什么作用，以及脓毒症诱导的树突状细胞缺失是否参与了CD_4~+T细胞的凋亡和功能障碍。 大多数实验方法只关注单个介质或细胞对脓毒症反应的贡献。只有通过更彻底地探索先天免疫系统和获得性免疫系统之间的细胞相互作用，才能更好地了解脓毒症的发病机制，才能找到新的治疗方案。这一应用将侧重于先天免疫系统的树突状细胞如何与适应性免疫系统的CD4+效应T细胞进行通信，以调节各自的功能。靶向先天免疫系统和获得性免疫系统之间的相互作用是治疗脓毒症的一种更综合和更全面的方法，而不是目前简单的阻断或增强单个介质的方法。

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.