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（申请人摘要）：脓肿形成是典型的宿主 人类对细菌感染的反应。脓肿的发展 与患者腹内败血症相关，导致严重的发病率 可能是致命的。然而，这种疾病过程的免疫发病机制尚不清楚。 定义的。虽然 T 细胞与脓肿的形成有关， 一直缺乏关于其作用的明确证据，而且其根本原因 T 细胞参与的机制尚未阐明。它一直 证明来自细菌病原体（例如芽孢杆菌）的荚膜多糖。 脆弱菌和金黄色葡萄球菌，通常从临床中分离出来 脓肿病例，可以在动物模型中诱导这种宿主反应 腹腔内败血症。此活动绝对依赖于以下人员的存在： 与其重复单元相关的带正电和负电的基团 结构。最近，我们已经证明这些聚合物以及其他 具有这种两性离子电荷基序的结构不同的多糖是 体外 CD4+ T 细胞的有效激活剂。此外，T 细胞在 体外通过两性离子多糖（Zps）可以诱导腹内 当转移到大鼠腹膜时出现脓肿。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 T 细胞的机制 激活及其在脓肿诱导中的作用。自第一次提交以来 在这个提案中，我们已经证明 Zps 以某种方式激活 T 细胞 与细菌超抗原类似。根据这些数据，我们假设 一种新型 T 细胞介导的 Zps 免疫反应启动 导致脓肿形成的炎症反应。这样做的目的 应用是表征超抗原样 T 细胞对 Zps 的反应和 它在引发导致脓肿的炎症过程中的作用 形成。据信，T 细胞响应的特征 Zps 将导致新的免疫学范式的发展 多糖与 T 细胞相互作用的机制 细胞介导的免疫反应。这种洞察力还应该导致 开发预防脓肿的新治疗剂 与人类腹内败血症有关。