The colonic microbiota and immunity after hematopoietic stem cell transplantation

造血干细胞移植后的结肠微生物群和免疫

基本信息

批准号：
9904323
负责人：
Cameron John Turtle
金额：
$ 51.64万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904323
关键词：
Acute Graft Versus Host Disease Adaptive Immune System Affect Allogenic Animal Model Antibiotics Asthma Autoimmune Diseases Bacteremia Bacteria Bacterial Infections Biological Response Modifiers Blood Bone Marrow Diseases CD8-Positive T-Lymphocytes Caring Cells Characteristics Clinical Data Data Set Databases Dependence Development Diabetes Mellitus Diet Modification Disease Exhibits Frequencies Future Gastrointestinal tract structure Health Heart Diseases Hematologic Neoplasms Hematological Disease Hematopoietic Stem Cell Transplantation High-Throughput Nucleotide Sequencing Home environment Homeostasis Human Immune Immune response Immune system Immunity Immunologic Deficiency Syndromes Immunologics Immunosuppression Impairment Incidence Individual Infection Inflammation Inflammatory Injury Intervention Studies Kinetics Knowledge Link Lung diseases Maintenance Mediating Metabolic Diseases Modification Morbidity - disease rate Mucous Membrane Non-Malignant Obesity Outcome Patients Play Population Heterogeneity Procedures Recovery Recovery of Function Regulation Regulatory T-Lymphocyte Resolution Risk Role Surface T-Lymphocyte T-Lymphocyte Subsets Toxic effect Transplant Recipients Transplantation alpha-beta T-Cell Receptor chemokine receptor cohort colon microbiota conditioning conventional therapy curative treatments cytokine design functional plasticity gastrointestinal graft vs host disease gut microbiota human disease immune reconstitution improved improved outcome innovation insight microbial microbiota mortality novel pathogen post-transplant prevent public health relevance rRNA Genes receptor expression reconstitution response stool sample success therapy development

项目摘要

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for patients with hematologic malignancies; however, its success has been limited by the morbidity and mortality of post-transplant infection and graft versus host disease (GVHD) associated with perturbed immune reconstitution. Recent studies have demonstrated extraordinary diversity in the bacterial composition of the human gastrointestinal (GI) tract and have highlighted the capacity of the GI microbiota to modify innate and adaptive immune homeostasis. Prior to and during HCT, antibiotics, immune suppression, dietary alteration and mucosal injury alter the composition of the GI microbiota; however, relatively little is known in humans about the immunologic mediators that are responsive to changes in the GI microbiota and the mechanisms by which the microbiota might affect clinical outcomes after HCT. Recent characterization of non-conventional subsets of T cell receptor (TCR) αβ+ T cells, such as mucosal-associated invariant T cells, invariant NKT cells, Th17 cells and Treg cells has shown that they are distinguished in part from conventional T cells by their remarkable dependence on the GI microbiota for differentiation and maintenance. These bacteria-responsive T cell subsets exhibit functional plasticity that enables pro-inflammatory or suppressive function, suggesting that alterations in the composition of the GI microbiota might affect their reconstitution after HCT and alter clinical outcomes. In this project, we will develop and interrogate a comprehensive microbiota, immunologic and clinical dataset to determine whether perturbation of the GI microbiota impacts reconstitution of non-conventional T cell subsets after allogeneic HCT, and establish the association of these T cell subsets with bacterial infection and GVHD. Identification of a link in these human studies between the composition of the GI microbiota, non-conventional T cell subset recovery, and clinical outcomes after HCT will be paradigm changing, and will guide future innovative approaches to investigate, prevent and treat delayed immune reconstitution and GVHD after HCT.

描述（适用提供）：同种异体造血干细胞移植（HCT）是血液学恶性肿瘤患者的潜在现代手术。然而，其成功受到移植后感染以及与扰动免疫缔结相关的宿主疾病（GVHD）（GVHD）的发病和死亡率的限制。最近的研究表明，人类胃肠道（GI）的细菌组成中的多样性非常多样性，并强调了GI微生物群的能力来改变先天和自适应免疫稳态。在HCT之前和期间，抗生素，免疫抑制，饮食改变和粘膜损伤改变了胃肠道菌群的组成。然而，人类在对胃肠道菌群变化以及微生物群可能会影响HCT后临床结果的机制中响应的免疫学介质的知名度相对较少。 T细胞受体（TCR）αβ+ T细胞的非惯性亚群的最新表征，例如粘膜相关的不变T细胞，不变的NKT细胞，TH17细胞和Treg细胞表明它们部分与GI Microbobioba的显着依赖性相对于常规T细胞而言是与GI Microbobiota的显着依赖性所区别的。这些细菌反应性T细胞子集表现出功能性可塑性，可实现促炎或抑制功能，这表明胃肠道菌群组成的改变可能会影响其在HCT后的重建并改变临床结果。在这个项目中，我们将开发并询问一个全面的菌群，免疫学和临床数据集，以确定GI微生物群的扰动是否会影响同种异体HCT后的非惯性T细胞亚群的重构，并建立这些T细胞群与细菌感染和GVHD的关联。在胃肠道菌群组成，非规定的T细胞子集回收与HCT后的临床结果之间的这些联系中鉴定了与人类研究中的联系，并将改变HCT的临床结果，并将指导未来的创新方法，以调查，预防HCT后调查，预防和治疗延迟的免疫重建和GVHD。