Defining the relationship between host-microbiome interactions and rejection after intestinal transplantation

定义宿主-微生物组相互作用与肠移植后排斥反应之间的关系

• 批准号: 10406372
• 负责人: Joshua Weiner
• 金额: $ 19.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406372
• 关键词: Alloantigen; Allografting; Antigen-Presenting Cells; Area; Attenuated; Bacteria; Blood; Bone Marrow; Cells; Chimerism; Clinical; Clone Cells; Data; Department chair; Discipline; Equilibrium; Failure; Functional disorder; Funding; Goals; Graft Rejection; Growth; Gut Mucosa; Homeostasis; Host Defense; Human; Immersion; Immune; Immunobiology; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Longitudinal Studies; Malignant Neoplasms; Mentors; Mentorship; Microbe; Microbiology; Mucous Membrane; Parenteral Nutrition; Patients; Play; Research; Research Personnel; Resources; Role; Scientist; Surgeon; T-Lymphocyte; TCF Transcription Factor; Therapeutic; Therapeutic Intervention; Time; Translating; Transplant Recipients; Transplant Surgeon; Transplantation; Transplantation Immunology; Virus; Volatile Fatty Acids; Work; analytical method; antimicrobial peptide; base; career; career development; commensal microbes; cross reactivity; dysbiosis; experience; fecal transplantation; fungus; gastrointestinal transplantation; graft vs host disease; gut inflammation; gut microbes; gut microbiome; host microbiome; microbial; microbiome; microbiome analysis; microorganism antigen; novel; novel marker; novel therapeutics; pathogenic microbe; preservation; programs; residence; response; side effect

PROJECT SUMMARY Dr. Weiner is a transplant surgeon and immunology researcher. His long-term career goal is to become a leading surgeon-scientist in the practice of intestinal transplantation (ITx) and the understudied discipline of intestinal immunobiology with the unique expertise and immersion in both to translate novel scientific findings into major clinical advances. To that end, his short-term career goals are to 1) gain clinical expertise in intestinal transplantation, 2) build on current understanding of the pathophysiology of rejection after ITx, 3) augment his personal understanding of microbiology, innate immune defenses, and advanced microbial and T cell analytic methods, and 4) develop an independent research career that is funded by R01 support. He has organized a mentoring team with the expertise and experience to facilitate career development in this field, and he has the commitment of resources and protected research time from his department chair and division chief. The significance of his project is that ITx is the only therapeutic option for patients with intestinal failure once parenteral nutrition fails. However, its use is limited by high rates of rejection, which necessitates increased immunosuppression levels, predisposing patients to morbid side effects. This proposal investigates how the relationship between the gut microbiome and host mucosal defenses correlates with rejection after ITx. Prior work demonstrates that rejection is associated with both modulations in the gut microbiome and dysfunction of host defenses that maintain homeostasis with flora. It is also known that rejection is associated with decreased ratios of graft-versus-host (GVH)-reactive donor T cells relative to host-versus-graft (HVG)-reactive recipient T cells within the graft. Based on these concurrent findings, Dr. Weiner hypothesizes that homeostasis between the gut microbiome and mucosal defenses plays an essential role in maintaining the balance of GVH:HVG- reactive T cells in the graft, thus regulating rejection. If true, rejection could be targeted with novel therapies, such as fecal transplantation. Thus far, no longitudinal studies in human ITx patients have investigated microbiome modulations in relationship to clinical course, T cell chimerism, GVH:HVG-reactive T cell ratios in the graft, and rejection. Therefore, this work will characterize how changes in the microbiome in the gut after ITx correlate with decreased chimerism and GVH:HVG ratios in the blood and graft, which are associated with higher rates of rejection.

项目概要 Weiner 博士是一名移植外科医生和免疫学研究员。他的长期职业目标是成为一名 肠道移植（ITx）实践和正在研究的学科领域的领先外科医生科学家 肠道免疫生物学具有独特的专业知识和沉浸感，可以转化新颖的科学发现 进入重大临床进展。为此，他的短期职业目标是 1) 获得肠道方面的临床专业知识 移植，2) 建立在目前对 ITx 后排斥反应病理生理学的理解之上，3) 增强他的能力 对微生物学、先天免疫防御以及高级微生物和 T 细胞分析的个人理解 方法，以及 4) 发展由 R01 支持资助的独立研究生涯。他组织了一次 指导团队拥有促进该领域职业发展的专业知识和经验，并且他拥有 系主任和部门负责人承诺提供资源并保护研究时间。这 他的项目的意义在于，ITx 是肠道衰竭患者的唯一治疗选择 肠外营养失败。然而，它的使用受到高拒绝率的限制，这需要增加 免疫抑制水平，使患者容易出现病态副作用。该提案研究了如何 肠道微生物组和宿主粘膜防御之间的关系与 ITx 后的排斥反应相关。事先的 研究表明，排斥反应与肠道微生物组的调节和肠道菌群功能障碍有关。 维持菌群稳态的宿主防御。还已知排斥与减少有关 移植物抗宿主（GVH）反应性供体 T 细胞相对于宿主抗移植物（HVG）反应性受体 T 细胞的比率 移植物内的细胞。基于这些同时发生的发现，Weiner 博士推测， 肠道微生物群和粘膜防御在维持 GVH:HVG- 平衡中发挥着重要作用 移植物中的反应性 T 细胞，从而调节排斥反应。如果属实，新疗法可以针对排斥反应， 比如粪便移植。迄今为止，尚未对人类 ITx 患者进行纵向研究 微生物组调节与临床病程、T 细胞嵌合、GVH:HVG 反应性 T 细胞比率的关系 移植物和排斥反应。因此，这项工作将描述 ITx 后肠道微生物组的变化 与血液和移植物中的嵌合性和 GVH:HVG 比率降低相关，这与 更高的拒绝率。