Propagation of graft vs. host disease through CD4+ T-cell cognate recognition of gastrointestinal microbiota

通过 CD4 T 细胞对胃肠道微生物群的同源识别来传播移植物抗宿主病

基本信息

批准号：
10573092
负责人：
Albert Chia-Chun Yeh
金额：
$ 16.24万
依托单位：
FRED HUTCHINSON CANCER CENTER
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：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573092
关键词：
Acute Graft Versus Host Disease Address Allogenic Antigenic Specificity Antigens Benign Binding Biochemical CD4 Antigens CD4 Positive T Lymphocytes Cellular Immunity Clinical Clonal Expansion Cloning Computational algorithm Computer Models Computing Methodologies Coupled Data Data Set Disease Outcome Donor Selection Ecosystem Epithelial Cells Epitopes Face Foundations Fred Hutchinson Cancer Research Center Gastrointestinal tract structure Gene Expression Genetic Genome Genomics Hematologic Neoplasms Hematopoietic Stem Cell Transplantation High Prevalence Homeostasis Hybridomas Immune response Immunologic Surveillance Immunologics Inflammatory Bowel Diseases Injury Ligands Low Prevalence Mediating Medicine Mentors Minor Modeling Molecular Mimicry Morbidity - disease rate Mus Outcome Pathogenesis Pathogenicity Pathology Peptides Phenotype Physicians Physiological Play Postdoctoral Fellow Program Development Proteins Research Resolution Role Sampling Scientist Severities Shapes Shotguns Source Specificity Stem cell transplant System T cell reconstitution T cell response T-Cell Activation T-Lymphocyte TCR Activation Testing Training Transplantation Universities Washington Work alpha-beta T-Cell Receptor antimicrobial career development combinatorial commensal microbes differential expression experience experimental study graft vs host disease gut microbiome gut microbiota improved in vivo insight instructor intestinal epithelium machine learning prediction microbial microbial composition microbiome microbiota microorganism antigen mortality novel post-transplant protein aminoacid sequence response screening sequencing platform single cell sequencing single-cell RNA sequencing skills transcriptomics transplant model whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal presents a five-year research career development program focused on the study of T-cell reconstitution following hematopoietic stem cell transplantation (HSCT) and how graft-vs-host disease (GVHD) can be shaped by clonotypic response to microbiota. The candidate is currently an Instructor of Medicine at the University of Washington and Research Associate at the Fred Hutchinson Cancer Research Center. This proposal builds on the candidate’s previous research and clinical experience by providing advanced training in two domains of expertise represented by his mentor team of Dr. Geoffrey Hill (GVHD in HSCT) and Dr. Philip Bradley (computational modeling of the T-cell response). The proposed experiments and didactic work will provide the candidate with a unique set of cross-disciplinary skills that will enable his transition to independence as a physician scientist in T cell mediated immunity in HSCT. T-cells play a fundamental role in the pathogenesis of GVHD which remains a major barrier for the successful application of HSCT for a wide range of benign and hematologic malignancies. GVHD involvement of the gastrointestinal (GI) tract remains a major cause of morbidity and mortality. The composition of the GI microbiome is associated with onset and severity of GVHD, though current understanding of how specific microbial species contribute to GVHD pathogenesis remains largely correlative with limited mechanistic insights. While the microbiome acts as a major source of cognate antigen for T cells, little is known about how anti-microbial TCRs may contribute to pathology in this setting. Part of the difficulty in parsing out the alloreactive response from immune surveillance on a clonal level includes the vast combinatorial diversity of αβ TCRs, the high prevalence of low copy number TCRs in any given donor pool, and sampling limitations. The foundation of this proposal is based on preliminary studies using a novel computational algorithm to identify expanded donor TCRs that are not constrained by donor and host genetics, but rather appear to be influenced by commensal microbes. How exactly these anti-microbial TCRs might function in the post-transplant context and its physiological relevance to GVHD are questions that this proposal begins to address. More specifically, the aims of this proposal are to 1) Validate computationally identified anti-microbial CD4+ TCRs in an scRNA seq platform and define cellular phenotypes in relation to compartment localization, 2) Reconstruct computationally identified CD4+ TCRs and determine antigenic specificity through genomic screening, and 3) Dissect the functional role of identified anti-microbial CD4+ TCRs on the propagation of acute graft-vs-host disease. The scientific objective of this proposal is to examine the drivers of clonotypic T-cell expansion following allogeneic stem cell transplant and assess how the pathogenesis of GVHD is coupled to microbial surveillance.

项目概要/摘要该提案提出了一个专注于 T 细胞研究的五年研究职业发展计划造血干细胞移植 (HSCT) 后的重建以及移植物抗宿主病 (GVHD) 可以通过对微生物群的克隆型反应来塑造该候选人目前是该大学的医学讲师。华盛顿大学和 Fred Hutchinson 癌症研究中心的研究员。提案建立在候选人之前的研究和临床经验的基础上，提供高级培训由 Geoffrey Hill 博士（HSCT 中的 GVHD）和 Philip 博士组成的导师团队代表了两个专业领域 Bradley（T 细胞反应的计算模型）提出的实验和教学工作将。为候选人提供一套独特的跨学科技能，使他能够过渡到作为一名医师科学家，在 HSCT 中 T 细胞介导的免疫方面具有独立性。 T 细胞在 GVHD 的发病机制中发挥着重要作用，这仍然是成功的主要障碍 HSCT 在涉及多种良性和血液系统恶性肿瘤的治疗中的应用。胃肠道 (GI) 仍然是发病和死亡的主要原因胃肠道的组成。微生物组与 GVHD 的发生和严重程度相关，尽管目前对具体情况的了解导致 GVHD 发病机制的微生物种类在很大程度上与有限的机制相关虽然微生物组是 T 细胞同源抗原的主要来源，但人们对其如何发挥作用却知之甚少。在这种情况下，抗微生物 TCR 可能会导致病理学的部分困难。克隆水平上免疫监视的同种反应反应包括 αβ 的巨大组合多样性 TCR、任何给定供体池中低拷贝数 TCR 的高流行率以及采样限制。该提案的基础是基于使用一种新颖的计算算法来识别的初步研究扩大的供体TCR不受供体和宿主遗传学的限制，但似乎受到影响通过共生微生物。这些抗微生物 TCR 在移植后环境及其生理学中到底如何发挥作用与 GVHD 的相关性是本提案开始解决的问题，更具体地说，是本提案的目标。建议 1) 在 scRNA seq 平台中验证计算识别的抗微生物 CD4+ TCR，以及定义与区室定位相关的细胞表型，2) 重建计算确定的 CD4+ TCR 并通过基因组筛选确定抗原特异性，以及 3) 剖析功能作用已鉴定的抗微生物 CD4+ TCR 对急性移植物抗宿主病传播的影响。该提案的目的是检查同种异体干细胞后克隆型 T 细胞扩增的驱动因素移植并评估 GVHD 的发病机制如何与微生物监测相结合。