Tissue resident memory T cells and chronic lung allograft dysfunction

组织驻留记忆 T 细胞与慢性肺同种异体移植功能障碍

基本信息

批准号：
10633775
负责人：
Mark Eugene Snyder
金额：
$ 76.18万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-20 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633775
关键词：
Acute Affect Airway Fibrosis Allografting Anatomy Biological Assay Biopsy Bronchiolitis Bronchiolitis Obliterans CD58 gene Cell Communication Cells Chronic Circulation Clonal Expansion Cyclosporine Data Development Environment Epitopes Failure Flow Cytometry Functional disorder Genetic Transcription Glucocorticoids Human Immune Immunomodulators Immunosuppressive Agents In Vitro Incidence Influenza Inhalation Injury Intervention Investigation Lead Lesion Life Lung Lung Transplantation Lung diseases Lymphocyte Macrophage Maintenance Mediating Modeling Modification Morbidity - disease rate Myelogenous Myeloid Cells Organ Organ Transplantation Outcome Pathologic Pathology Patients Peptides Perfusion Phenotype Pulmonary Fibrosis Pulmonary Inflammation RNA Receptor Signaling Research Research Project Grants Risk Risk Factors Role Site Solid Specificity Structure of parenchyma of lung Syndrome T cell infiltration T cell receptor repertoire sequencing T memory cell T-Cell Receptor T-Lymphocyte Therapeutic Therapeutic immunosuppression Tissues Transplant Recipients Validation Viral airway inflammation alemtuzumab basiliximab cell motility computerized tools cross reactivity experience improved lung allograft migration mortality pathogen programmed cell death ligand 1 recruit retransplantation screening single-cell RNA sequencing tissue resident memory T cell

项目摘要

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.

项目概要肺移植仍然是许多终末期肺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，肺移植后的结果微乎其微，中位生存期仅为 6 年。肺移植后长期生存的主要限制因素是慢性同种异体肺移植功能障碍（CLAD）的发生率很高，这是一种进行性的同种异体肺移植衰竭与高发病率和死亡率相关，5 年内影响一半的移植受者。剧集数急性细胞排斥是一种 T 细胞介导的同种异体肺移植物的同种免疫炎症，与 CLAD 风险增加。我们的小组之前表明，在急性细胞损伤期间，T 细胞被招募到肺部。排斥反应在同种异体移植物中持续存在，作为组织驻留记忆 T 细胞 (TRM)，并且这些 TRM 迁移到气道是 CLAD 的组织病理学部位。该应用的重点是确定肺是否同种异体移植 TRM 具有同种异体反应性，以及 TRM 如何与其当地环境相互作用，以促进 TRM 的发展 CLAD。重要的是，我们的初步数据表明全身免疫调节剂不会影响肺 TRM 它们影响循环免疫细胞的方式相同。该应用程序旨在加深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。我们的研究目标包括： 1) 确定肺移植受者中受者来源的同种异体移植 TRM 的同种反应潜力并且没有 CLAD； 2) 确定肺驻留骨髓细胞在维持同种异体反应受体中的作用- 衍生肺 TRM； 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反应性 T 细胞的机制为 CLAD 做出贡献并阐明现有免疫调节剂如何影响 TRM 表型和功能。