Tissue resident memory T cells and chronic lung allograft dysfunction

项目摘要 肺移植仍然是许多终末期肺部疾病患者的唯一确定的治疗方法。 然而，与其他实体器官移植相比，肺移植后的结果微不足道。 中位生存期仅为6年。肺移植后长期存活的主要限制因素是 慢性同种异体肺移植功能障碍(CLAD)的高发生率，这是同种异体肺移植失败的进行性形式 与高发病率和高死亡率有关，在5年内影响到一半的移植接受者。剧集： 急性细胞排斥反应是一种T细胞介导的同种异体免疫炎症，与 增加了穿着的风险。我们的研究小组先前发现，T细胞在急性细胞性疾病期间被招募到肺中 排斥反应在同种异体移植物中作为组织驻留记忆T细胞(TRM)持续存在，这些TRM迁移到 航空公司，穿着衣服的组织病理部位。这一应用的重点是确定同种异体肺移植 TRM是同种反应性的，以及TRM如何与当地环境相互作用以促进 衣冠楚楚。重要的是，我们的初步数据表明，全身性免疫调节剂不会影响肺TRM 与它们影响循环免疫细胞的方式相同。这个应用程序计划促进我们对 常用的免疫抑制剂，如阿仑珠单抗、巴利昔单抗、糖皮质激素和环孢素 与循环T细胞相比，对肺TRM的表型、功能和持久性的影响。我们的研究目的是 包括：1)确定受者来源的同种异体肺移植在肺移植受者中的同种异体反应潜力 2)确定肺内常驻髓系细胞在维持同种异体反应性受体中的作用。 确定全身免疫调节剂和吸入免疫调节剂对肺TRM的影响 持久性和功能性。这些研究的结果探索了一种同种异体反应性T细胞 有助于包膜和阐明现有免疫调节剂如何影响TRM表型和功能。

Project Summary Lung transplantation remains the only definitive treatment for many patients with end stage lung disease. However, the outcomes after lung transplant are meager when compared to other solid organ transplants, with a median survival of only 6 years. The major limiting factor to long-term survival after lung transplantation is the high incidence of chronic lung allograft dysfunction (CLAD), a progressive form of a lung allograft failure associated with high morbidity and mortality affecting half of all transplant recipients by 5 years. Episodes of acute cellular rejection, a T cell mediated allo-immune inflammation of the lung allograft, are associated with increased risk of CLAD. Our group previously showed that T cells recruited to the lung during acute cellular rejection persist within the allograft as tissue resident memory T cells (TRM) and that these TRM migrate to the airways, the site of tissue pathology in CLAD. The focus of this application is to identify whether lung allograft TRM are alloreactive and how TRM may interact with their local environment to contribute to the development of CLAD. Importantly, our preliminary data suggests that systemic immune modulators do not impact lung TRM in the same way that they effect circulating immune cells. This application plans to advance our understanding of how commonly used immunosuppressants, like alemtuzumab, basiliximab, glucocorticoids, and cyclosporine impact the phenotype, function, and persistence of lung TRM compared to circulating T cells. Our research aims include: 1) Identify the alloreactive potential of recipient-derived allograft TRM in lung transplant recipients with and without CLAD; 2) Establish the role of lung resident myeloid cells in the maintenance of alloreactive recipient- derived lung TRM; and 3) Determine the impact of systemic and inhaled immune modulators on lung TRM persistence and function. The results of these investigations explore a mechanism where alloreactive T cells contribute to CLAD and elucidate how existing immune modulators impact TRM phenotype and function.