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.

项目摘要 /摘要该应用程序是针对以患者为导向的研究职业发展奖的，标题为“影响肺移植后慢性排斥的组织居民记忆T细胞”，由Mark博士提交斯奈德（Snyder），肺部，过敏和分区内的医学和免疫学助理教授匹兹堡大学的重症监护医学和Starzl移植研究所的成员。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）推进与适应性和先天免疫相关的知识库，（2）有效执行转化免疫学所需的技术和分析工具的扩展研究，以及（3）运营人类免疫学实验室所需的领导能力。该研究建议的核心目的是研究同种异体移植组织居民记忆的影响细胞（TRM）的持久性和产生有关培养支气管炎抑制剂综合征的风险，主要是慢性肺合物功能障碍（CLAD）的表型表现。外壳影响多达50％的肺移植后5年移植浮雕，与早期死亡率和实质性相关发病率。外壳的机制仍然不确定，但被认为是T细胞介导的过程。急性急性细胞排斥（ACR）和感染，两个T细胞介导的过程与外壳的最终发展。申请人的先前工作，最近发表在科学免疫学上，表明供体TRM持久性和受体TRM在肺同种异体移植物中的生成与 ACR和感染。此外，未发表的初步数据显示了早期发展的趋势受体TRM的同种异体移植群体快速移植患者的外壳。有了这个建议，申请人通过以下特定目的（1）定义收件人TRM之间的关系肺同种异体移植物和早期外壳的风险（在移植后2年内），（2）确定受体衍生的同种异体TRM的同种异体潜力和病原体特异性，（3）确定关系在受体合金TRM和外壳中，T细胞受体（TCR）克隆多样性和基因表达之间。主要假设是接收者TRM积累将与早期发作的外壳相关联，并且受体TRM将由具有高反应性潜力的T细胞的扩大群体组成。到完成这些目标，申请人将采用他先前发表的捐助者和从肺移植受者的支气管肺泡灌洗中进行的受体TRM纵向。考克斯属性危险模型，将对已知混杂因子进行调整以测试暴露（早期比例）与受体TRM相比，供体TRM的下降与我们的早期甲板的结果有关。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.