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

• 批准号: 9103850
• 负责人: Cameron John Turtle
• 金额: $ 52.57万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 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/9103850
• 关键词: Acute Graft Versus Host Disease; Affect; Allogenic; Animal Model; Antibiotics; Asthma; Autoimmune Diseases; Bacteremia; Bacteria; Bacterial Infections; Blood; Bone Marrow Diseases; CD4 Positive T Lymphocytes; CD8B1 gene; Caring; Cells; Characteristics; Clinical; Clinical Data; Data; Data Set; Databases; Dependence; Development; Diabetes Mellitus; Diet Modification; Disease; Exhibits; Feces; 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; Incidence; Individual; Infection; Inflammation; Inflammatory; Injury; Kinetics; Knowledge; Link; Lung diseases; Maintenance; Mediating; Mediator of activation protein; Metabolic Diseases; Modification; Morbidity - disease rate; Non-Malignant; Obesity; Outcome; Patients; Play; Population Heterogeneity; Procedures; Recovery; Recovery of Function; Regulation; Regulatory T-Lymphocyte; Resolution; Risk; Role; Sampling; Surface; T-Lymphocyte; T-Lymphocyte Subsets; Toxic effect; Transplantation; alpha-beta T-Cell Receptor; chemokine receptor; cohort; conditioning; conventional therapy; curative treatments; cytokine; design; functional plasticity; gastrointestinal; graft vs host disease; human disease; improved; improved outcome; innovation; insight; microbial; microbiota; mortality; novel; pathogen; prevent; public health relevance; rRNA Genes; receptor expression; reconstitution; response; success; therapy development

 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（由申请方提供）：异基因造血干细胞移植（HCT）是恶性血液病患者的潜在治疗方法;然而，其成功受到与免疫重建紊乱相关的移植后感染和移植物抗宿主病（GVHD）发病率和死亡率的限制。最近的研究已经证明了人类胃肠道（GI）细菌组成的非凡多样性，并强调了GI微生物群改变先天性免疫缺陷的能力。 和适应性免疫稳态。在HCT之前和期间，抗生素、免疫抑制、饮食改变和粘膜损伤会改变GI微生物群的组成;然而，人类对响应GI微生物群变化的免疫介质以及微生物群可能影响HCT后临床结局的机制知之甚少。最近对T细胞受体（TCR）αβ+ T细胞的非常规亚群（如粘膜相关的不变T细胞、不变NKT细胞、Th 17细胞和Treg细胞）的表征表明，它们与常规T细胞的部分区别在于它们显著依赖于GI微生物群进行分化和维持。这些细菌应答性T细胞亚群表现出功能可塑性，能够实现促炎或抑制功能，这表明GI微生物群组成的改变可能会影响HCT后的重建并改变临床结果。在这个项目中，我们将开发 并询问综合微生物群、免疫学和临床数据集，以确定GI微生物群的扰动是否影响同种异体HCT后非常规T细胞亚群的重建，并建立这些T细胞亚群与细菌感染和GVHD的关联。在这些人体研究中确定胃肠道微生物群组成、非常规T细胞亚群恢复和HCT后临床结局之间的联系将改变范式，并将指导未来研究、预防和治疗HCT后延迟免疫重建和GVHD的创新方法。