T CELL COSTIMULATION IN INTRAABDOMINAL SEPSIS

腹内脓毒症中的 T 细胞共刺激

• 批准号: 6126565
• 负责人: ARTHUR O TZIANABOS
• 金额: $ 27.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6126565
• 关键词: Bacteroides; T lymphocyte; bacterial polysaccharides; bactericidal immunity; cellular immunity; cytokine; genetically modified animals; inflammation; laboratory mouse; major histocompatibility complex; peritonitis

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.

描述（申请人的摘要）：脓肿形成是经典的主机 对人类细菌感染的反应。脓肿的发展 患者中与腹腔内败血症有关会导致严重的发病率和 可能是致命的。但是，这种疾病过程的免疫发育很差 定义。尽管T细胞与脓肿的发展有关，但 其角色的确切证据一直缺乏和基础 T细胞受累的机制尚未阐明。它一直 证明来自细菌病原体（如B.）的囊囊多糖 金黄色葡萄球菌和金黄色葡萄球菌通常从临床中分离出来 脓肿的病例可以在动物模型中诱导这种宿主反应 腹内败血症。该活动绝对取决于 与重复单元相关的积极和负电荷的组 结构。最近，我们证明了这些聚合物以及其他 具有这种Zwitterionic电荷基序在结构上不同的多糖是 CD4+ T细胞的有效活化剂体外。此外，T细胞激活 Zwitterionic多糖（ZP）的体外可以诱导腹腔内 脓肿转移到大鼠的腹膜时。这些是第一个 研究证明纯化的细菌多糖可以刺激T 细胞增殖并促使我们研究了T细胞机制 激活及其在脓肿诱导中的作用。自第一次提交 该提议，我们已经证明ZP以某种方式激活T细胞 类似于细菌超抗原。基于这些数据，我们假设 T细胞介导的一种新型T细胞介导的免疫反应引发了 炎症反应导致脓肿形成。这个目的 应用是为了表征超抗原的T细胞对ZP和 它在炎症过程的开始中的作用导致脓肿 形成。据认为，T细胞反应的表征 ZPS将导致有关有关该范式的新免疫范式的发展 多糖与T细胞相互作用以引起的机制 细胞介导的免疫反应。这种见解也应导致 开发用于预防脓肿的新治疗剂 与人类腹腔内败血症有关。