Surgical Adhesions: Role of T cells in Pathogenesis

手术粘连：T 细胞在发病机制中的作用

• 批准号: 6726769
• 负责人: ARTHUR O TZIANABOS
• 金额: $ 31.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6726769
• 关键词: CD28 molecule; T cell receptor; T lymphocyte; cell type; chemokine; cytokine; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; flow cytometry; gastrointestinal surgery; gene targeting; genetically modified animals; helper T lymphocyte; immunocytochemistry; inflammation; laboratory mouse; laboratory rat; leukocyte activation /transformation; major histocompatibility complex; pathologic process; peritoneal cavity; polymerase chain reaction; postoperative complications; tissue /cell culture; wound healing

The development of adhesions associated with abdominal and gynecologic surgical procedures causes severe morbidity and can be fatal. These structures are also associated with infertility and chronic pelvic pain in women. The treatment of complications stemming from surgical adhesion formation represents a significant burden to the healthcare system in the United States costing an estimated 1-2 billion dollars per year. Currently, there are a limited number of therapeutic options available to prevent their development. The immunopathogenesis of adhesion formation is poorly understood and relatively little is known regarding the cellular host response responsible for their development. It is believed that these structures form as a result of a breakdown in the balance between the molecular events leading to the deposition of fibrin in the normal peritoneal wound healing response and the fibrinolytic pathway that restores the integrity of mesothelial tissue. Preliminary studies from our laboratory have shown that CD4+ T cells are critical to the pathogenesis of abdominal surgical adhesions in two different animal models of this host response. These data are the first to show a definitive role for this cell type in adhesiogenesis. Based on this work, we hypothesize that T cells, through the release of T cell-derived cytokines and chemokines, have a central role in orchestrating the inflammatory process leading to the development of surgical adhesions. We propose to test this hypothesis by determining: 1) the specific T cell subset(s) that govern adhesion formation; 2) the role of T cell activation and costimulation in mediating this response; and 3) the cytokines and chemokines that control adhesion formation. There is currently very little known regarding the role of T cells in adhesion formation. Results from these studies will define a new paradigm for understanding the pathogenesis of surgical adhesion formation and identify new cellular targets for the development of compounds that can be used for their prevention.

与腹部和妇科手术相关的粘连的发展会导致严重的发病率并且可能是致命的。 这些结构还与女性不孕症和慢性盆腔疼痛有关。 手术粘连形成引起的并发症的治疗给美国医疗保健系统带来了沉重负担，每年估计花费 1-20 亿美元。目前，可用于预防其发展的治疗方案数量有限。 人们对粘附形成的免疫发病机制知之甚少，并且对于负责其发展的细胞宿主反应知之甚少。 据信，这些结构的形成是导致正常腹膜伤口愈合反应中纤维蛋白沉积的分子事件与恢复间皮组织完整性的纤溶途径之间平衡破坏的结果。 我们实验室的初步研究表明，在两种不同的宿主反应动物模型中，CD4+ T 细胞对于腹部手术粘连的发病机制至关重要。 这些数据首次显示了这种细胞类型在粘附发生中的明确作用。 基于这项工作，我们假设 T 细胞通过释放 T 细胞衍生的细胞因子和趋化因子，在协调导致手术粘连发展的炎症过程中发挥核心作用。 我们建议通过确定以下内容来检验这一假设：1) 控制粘附形成的特定 T 细胞亚群； 2) T细胞激活和共刺激在介导这种反应中的作用； 3) 控制粘附形成的细胞因子和趋化因子。目前对于 T 细胞在粘附形成中的作用知之甚少。 这些研究的结果将为理解手术粘连形成的发病机制定义一个新的范式，并确定新的细胞靶点来开发可用于预防粘连的化合物。