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.

项目摘要/摘要 该提案提出了一项五年研究职业发展计划，重点是T细胞的研究 造血干细胞移植（HSCT）和移植-VS宿主疾病（GVHD）后的重构 可以通过对微生物群的clonotypic反应来形成。候选人目前是医学教练 华盛顿大学和弗雷德·哈钦森癌症研究中心的研究助理。这 提案通过提供高级培训来建立候选人以前的研究和临床经验 由他的导师团队Geoffrey Hill博士（HSCT中的GVHD）和Philip博士代表的两个专业知识领域 布拉德利（T细胞响应的计算建模）。拟议的实验和教学工作将 向候选人提供一套独特的跨学科技能，使他的过渡到 独立于HSCT中T细胞介导的免疫学的物理科学家。 T细胞在GVHD的发病机理中起着基本作用，这仍然是成功的主要障碍 HSCT应用于各种良性和血液学恶性肿瘤。 GVHD参与 胃肠道（GI）仍然是发病率和死亡率的主要原因。 GI的组成 微生物组与GVHD的发作和严重程度有关，尽管当前对特定方式的理解 微生物物种有助于GVHD发病机理，与机械的有限相关 见解。虽然微生物组是T细胞的同源抗原的主要来源，但对如何如何了解 在这种情况下，抗微生物TCR可能有助于病理。解析困难的一部分 克隆水平上免疫监视的同种异体反应包括αβ的巨大组合多样性 TCR，任何给定供体池中低拷贝数TCR的高流行以及采样限制。这 该提案的基础是基于使用新型计算算法来识别的初步研究 不受捐助者和宿主遗传学限制的扩展供体TCR，但似乎受到影响 通过共生微生物。 这些抗微生物TCR的准确在移植后环境及其生理上可能起作用 与GVHD相关的是该提案开始解决的问题。更具体地说，目的 建议是1）验证在SCRNA SEQ平台中验证计算鉴定的抗微生物CD4+ TCR 定义与隔室定位有关的细胞表型，2）重建计算识别 CD4+ TCR并通过基因组筛选确定抗原特异性，3）剖析功能作用 鉴定出抗菌CD4+ TCR在急性移植-VS宿主病的传播中。科学 该提案的目的是检查同种异体干细胞后clonotypic T细胞扩张的驱动因素 移植和评估GVHD的发病机理与微生物监测的耦合。