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Impact of tissue resident memory T cells on chronic rejection after lung transplantation

组织驻留记忆T细胞对肺移植后慢性排斥反应的影响

基本信息

批准号：
10646332
负责人：
Mark Eugene Snyder
金额：
$ 16.79万
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646332
关键词：
Acute Acute Lung Injury Affect Allografting Biological Assay Biological Response Modifiers Bronchiolitis Obliterans Bronchoalveolar Lavage CD28 gene CD3 Antigens Cell Survival Cells Chronic Clinical Clinical Trials Clonal Expansion Clonality Consent Cox Proportional Hazards Models Critical Care Cytomegalovirus Data Data Analyses Development Flow Cytometry Functional disorder Gene Expression Gene Expression Profile Generations Genomics Goals HLA Antigens Heart Transplantation Human Hypersensitivity Immunology Incidence Individual Infection Infiltration Inflammatory Influenza Laboratories Life Expectancy Lung Lung Transplantation Lung diseases Lung infections Lymphocyte Lymphoid Tissue Mediating Medicine Mentored Patient-Oriented Research Career Development Award Methodology Methods Mixed Lymphocyte Culture Test Morbidity - disease rate Mucous Membrane Natural Immunity Organ Organ Donor Outcome Participant Pathogenesis Patients Peptide Library Phenotype Population Process Productivity Proliferating Publishing Research Research Personnel Research Proposals Respiratory syncytial virus Risk Running Science Solid Specificity Stains Survivors Syndrome T cell clonality T cell receptor repertoire sequencing T memory cell T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissue Donors Transplant Recipients Transplantation Universities Viral Virus Work adaptive immunity airway obstruction analytical tool cohort cross reactivity cytotoxic cytotoxicity design early onset graft dysfunction immunogenic improved inflammatory milieu knowledge base leadership development lung allograft member mortality new therapeutic target pathogen premature professor single-cell RNA sequencing skills therapeutic target tissue resident memory T cell translational immunology transplant survivor trend

项目摘要

Project Summary / Abstract This application is for a Mentored Patient-Oriented Research Career Development Award entitled, “The impact of tissue resident memory T cells on chronic rejection after lung transplantation”, submitted by Dr. Mark Snyder, an Assistant Professor of Medicine and Immunology within the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, and member of the Starzl Transplantation Institute. The short-term goals outlined in this submission are designed to help the applicant achieve his long-term objective of becoming an independent investigator and leader in the field of human lung immunology research. These short-term goals include (1) advancing knowledge base related to both adaptive and innate immunity, (2) expansion of both technical and analytic tools required to effectively perform translational immunology research, and (3) development of leadership skills required to run a productive human immunology laboratory. The central objective of this research proposal is to investigate the impact of allograft tissue resident memory T cell (TRM) persistence and generation on the risk of developing bronchiolitis obliterans syndrome, the major phenotypic presentation of chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of lung transplant survivors by 5 years after transplantation and is associated with early mortality and substantial morbidity. The mechanism of CLAD remains undefined but is believed to be a T cell-mediated process. Antecedent acute cellular rejection (ACR) and infection, both T cell mediated processes, are associated with the ultimate development of CLAD. The applicant’s prior work, recently published in Science Immunology, shows that donor TRM persistence and recipient TRM generation within the lung allograft are associated with both ACR and infections. Furthermore, unpublished preliminary data show a trend towards early development of CLAD in those patients with rapid allograft population of recipient TRM. With this proposal, the applicant expands on this prior work with the following specific aims (1) Define the relationship between recipient TRM generation in the lung allograft and the risk of early CLAD (within 2 years of transplantation), (2) Determine the alloreactive potential and pathogen specificity of recipient-derived allograft TRM, and (3) Identify the relationship between T cell receptor (TCR) clonal diversity and gene expression among recipient allograft TRM and CLAD. The primary hypothesize is that recipient TRM accumulation will be associated with early-onset CLAD and that recipient TRM will be composed of an expanded population of T cells with high allo-reactive potential. To accomplish these aims, the applicant will employ his previously published method of isolating donor and recipient TRM from the bronchoalveolar lavage of lung transplant recipients longitudinally. Cox-proportional hazard model, adjusting for known confounders will be performed to test the exposure (early proportional decline in donor TRM compared to recipient TRM) as it relates to our outcome of early CLAD. Mixed lymphocyte reactions and single-cell TCR sequencing will be performed to determine TRM alloreactivity and clonality.

项目概要/摘要本申请旨在申请一项以患者为导向的研究职业发展奖，题为“影响组织驻留记忆 T 细胞对肺移植后慢性排斥反应的影响”，Mark 博士提交斯奈德（Snyder），肺科、过敏科和免疫学系的医学和免疫学助理教授匹兹堡大学重症监护医学博士，Starzl 移植研究所成员。这本提交中概述的短期目标旨在帮助申请人实现其长期目标成为人类肺免疫学研究领域的独立研究者和领导者。这些短期目标包括 (1) 推进与适应性免疫和先天免疫相关的知识基础，(2) 有效进行转化免疫学所需的技术和分析工具的扩展研究，(3) 发展运行高效的人类免疫学实验室所需的领导技能。本研究计划的中心目标是研究同种异体移植组织驻留记忆 T 的影响细胞（TRM）的持续存在和产生对发生闭塞性细支气管炎综合征的风险的影响，这是主要的慢性肺同种异体移植功能障碍（CLAD）的表型表现。 CLAD 影响高达 50% 的肺部移植后 5 年存活率与早期死亡率和显着相关发病率。 CLAD 的机制尚未明确，但据信是 T 细胞介导的过程。先前的急性细胞排斥（ACR）和感染，这两个 T 细胞介导的过程，都与 CLAD的最终发展。申请人之前的工作最近发表在《科学免疫学》上，表明供体 TRM 持久性和肺同种异体移植物中受体 TRM 的产生与 ACR 和感染。此外，未发表的初步数据显示了早期开发的趋势 CLAD 在接受 TRM 的快速同种异体移植群体的患者中的应用。有了这个提案，申请人扩展了之前的工作，具有以下具体目标 (1) 定义接收者 TRM 之间的关系同种异体肺移植物中的代数和早期 CLAD 的风险（移植后 2 年内），(2) 确定受体来源的同种异体移植物 TRM 的同种反应潜力和病原体特异性，以及 (3) 确定关系受体同种异体移植物 TRM 和 CLAD 中 T 细胞受体 (TCR) 克隆多样性和基因表达之间的关系。主要假设是受体 TRM 积累与早发 CLAD 相关，并且受体 TRM 将由具有高同种异体反应潜力的扩大的 T 细胞群组成。到为了实现这些目标，申请人将采用他之前公布的方法来隔离捐赠者和来自肺移植受者纵向支气管肺泡灌洗的受者TRM。考克斯比例危险模型，将调整已知的混杂因素来测试暴露（早期比例与受者 TRM 相比，供者 TRM 下降），因为这与我们早期 CLAD 的结果有关。混合淋巴细胞将进行反应和单细胞 TCR 测序以确定 TRM 同种异体反应性和克隆性。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of tissue resident memory T cells by glucocorticoids after acute cellular rejection in lung transplantation.

DOI：
10.1084/jem.20212059
发表时间：
2022-04-04
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Snyder ME;Moghbeli K;Bondonese A;Craig A;Popescu I;Fan L;Tabib T;Lafyatis R;Chen K;Trejo Bittar HE;Lendermon E;Pilewski J;Johnson B;Kilaru S;Zhang Y;Sanchez PG;Alder JK;Sims PA;McDyer JF
通讯作者：
McDyer JF

Rate of recipient-derived alveolar macrophage development and major histocompatibility complex cross-decoration after lung transplantation in humans.