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: 6419739
• 负责人: ARTHUR O TZIANABOS
• 金额: $ 31.38万
• 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/6419739
• 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.

与腹部和妇科手术程序相关的粘连的发展会导致严重的发病率，可能是致命的。 这些结构还与女性不孕症和慢性骨盆疼痛有关。 手术粘附形成所引起的并发症的治疗代表了美国医疗体系的重大负担，估计每年耗资约10-2亿美元。目前，可用的治疗选择有限，以防止其开发。 粘附形成的免疫发病发生知之甚少，关于导致其发育的细胞宿主反应，相对较少。 据信，这些结构是由于分子事件之间的平衡而导致的，导致纤维蛋白在正常腹膜伤口愈合反应中的沉积与恢复间皮组织完整性的纤维蛋白水解途径。 我们实验室的初步研究表明，在该宿主反应的两个不同动物模型中，CD4+ T细胞对于腹部手术粘连的发病机理至关重要。 这些数据是该细胞类型在粘附发生中的明确作用的第一个数据。 基于这项工作，我们假设通过释放T细胞衍生的细胞因子和趋化因子，T细胞在策划炎症过程中具有核心作用，从而导致手术粘连的发展。 我们建议通过确定：1）控制形成粘附的特定T细胞子集； 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，关于T细胞在粘附形成中的作用鲜为人知。 这些研究的结果将定义一个新的范式，以理解手术粘附形成的发病机理，并确定可用于预防的化合物开发的新细胞靶标。