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.

项目摘要对于许多末期肺部疾病患者而言，肺移植仍然是唯一的明确治疗方法。然而，与其他固体器官移植相比，肺移植后的结果微不足道中位生存仅6年。肺移植后长期生存的主要限制因素是慢性肺同种异体功能障碍（CLAD）的高发生率，这是一种肺同种异体衰竭的进行性形式与高发病率和死亡率相关，影响了5年的所有移植受者的一半。情节急性细胞排斥反应，一种T细胞介导的肺同种异体移植的同种异体免疫炎症，与外壳风险增加。我们的组以前表明，急性细胞中募集到肺的T细胞作为组织驻留记忆T细胞（TRM），排斥持续存在于同种异体移植中，并且这些TRM迁移到 Airways，外壳中组织病理学的部位。该应用的重点是确定肺同种异体移植是否是否 TRM具有同种异体反应性，TRM如何与当地环境互动，以促进外壳。重要的是，我们的初步数据表明，系统性免疫调节剂不会影响与它们影响循环免疫细胞的方式相同。该申请计划提高我们对通常使用的免疫抑制剂，例如Alemtuzumab，basiliximab，糖皮质激素和环孢菌素与循环T细胞相比，影响肺TRM的表型，功能和持久性。我们的研究目的包括：1）确定肺移植受者中受体衍生的同种异体TRM的同种异体潜力而且没有外壳； 2）确定肺常驻髓样细胞在维持同种异体反应性受体中的作用 - 派生的肺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一种同种异体T细胞的机制有助于外壳并阐明现有的免疫调节剂如何影响TRM表型和功能。