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病患者的唯一确定性治疗方法。 然而，与其他实体器官移植相比，肺移植后的结果是微不足道的， 中位生存期只有6年肺移植后长期生存的主要限制因素是 慢性肺移植物功能障碍（CLAD）发生率高，这是肺移植物衰竭的一种进展形式 与高发病率和死亡率相关，5年内影响所有移植受者的一半。集 急性细胞排斥反应是一种T细胞介导的同种异体肺移植免疫炎症， 增加CLAD的风险。我们的研究小组先前表明，在急性细胞性肺损伤期间， 排斥反应作为组织驻留记忆T细胞（TRM）在同种异体移植物中持续存在，并且这些TRM迁移到移植物中。 气道，CLAD中的组织病理学部位。本申请的重点是确定肺移植物是否 TRM是同种异体反应的，以及TRM如何与其局部环境相互作用，以促进 CLAD。重要的是，我们的初步数据表明，全身免疫调节剂不影响肺TRM， 就像它们影响循环免疫细胞一样该应用程序计划推进我们对 常用的免疫抑制剂，如阿仑单抗、巴利昔单抗、糖皮质激素和环孢素 与循环T细胞相比，影响肺TRM的表型、功能和持久性。我们的研究旨在 包括：1）确定肺移植受者中同种异体TRM的同种异体反应潜力， 2）确定肺驻留骨髓细胞在维持同种异体反应性受体-- 衍生的肺TRM;和3）确定全身和吸入免疫调节剂对肺TRM的影响 持久性和功能。这些研究的结果探索了同种异体反应性T细胞 有助于CLAD和阐明现有的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.