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

• 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
• 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

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.

项目总结/摘要 该提案提出了一项为期五年的研究职业发展计划，重点是T细胞的研究 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。候选人目前是一名医学讲师， 华盛顿大学和弗雷德哈钦森癌症研究中心的研究助理。这 建议建立在候选人以前的研究和临床经验，提供先进的培训， 他的导师团队Geoffrey Hill博士（HSCT中的GVHD）和Philip博士代表了两个专业领域 布拉德利（T细胞反应的计算建模）。拟议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 在HSCT中T细胞介导的免疫方面作为医生科学家的独立性。 T细胞在GVHD的发病机制中起着重要作用，GVHD仍然是成功治疗的主要障碍。 HSCT用于广泛的良性和恶性血液病。GVHD的参与 胃肠道（GI）仍然是发病和死亡的主要原因。GI的组成 微生物组与GVHD的发生和严重程度相关，尽管目前对GVHD的特异性 导致GVHD发病机制的微生物物种仍然在很大程度上与有限的机制相关， 见解.虽然微生物组是T细胞同源抗原的主要来源，但人们对它如何发挥作用知之甚少。 抗微生物TCR可能导致这种情况下的病理学。解析出 来自克隆水平上免疫监视的同种异体反应性应答包括αβ TCR、任何给定供体库中低拷贝数TCR的高患病率以及抽样限制。的 这项建议的基础是基于初步研究，使用一种新的计算算法，以确定 扩增的供体TCR不受供体和宿主遗传学的限制，但似乎受到 微生物的作用。 这些抗微生物TCR在移植后环境中的确切功能及其生理学意义 与GVHD相关的是本提案开始解决的问题。更具体地说，其目的是 建议是：1）在scRNA seq平台中通过计算机计算鉴定抗微生物CD 4 + TCR， 定义与区室定位相关的细胞表型，2）重建计算鉴定的 CD 4 + TCR并通过基因组筛选确定抗原特异性，以及3）剖析其功能作用。 鉴定的抗微生物CD 4 + TCR对急性移植物抗宿主病传播的影响。科学 这项计划的目的是研究同种异体干细胞移植后克隆型T细胞扩增的驱动因素 移植和评估GVHD的发病机制是如何耦合到微生物监测。