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; 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.

项目摘要 Weiner博士是移植外科医生和免疫学研究人员。他的长期职业目标是成为 领先的外科医生科学家在肠道移植（ITX）的实践中 肠道免疫生物学具有独特的专业知识和沉浸在两者中，以翻译新颖的科学发现 进入重大临床进展。为此，他的短期职业目标是1）获得肠道临床专业知识 移植，2）基于当前对ITX后拒绝病理生理学的理解，3）增强他的 个人理解微生物学，先天免疫防御以及先进的微生物和T细胞分析 方法和4）发展由R01支持资助的独立研究职业。他已经组织了一个 指导团队拥有专业知识和经验，以促进该领域的职业发展，他有 他的部门主席和部门负责人对资源的承诺和保护时间。这 他的项目的意义是，ITX是一次肠道衰竭患者的唯一治疗选择 肠胃外营养失败。但是，它的使用受到高拒绝率的限制，这需要增加 免疫抑制水平，使患者患有病态副作用。该提议调查了如何 肠道微生物组和宿主粘膜防御之间的关系与ITX之后的排斥相关。事先的 工作表明，拒绝与肠道微生物组和功能障碍的调制有关 托管防御能力，以维持植物群的体内平衡。还知道拒绝与减少有关 相对于宿主 - 疗法（HVG） - 反应受体T 移植物中的细胞。基于这些并发的发现，韦纳博士假设 肠道微生物组和粘膜防御在维持GVH的平衡中起着至关重要的作用：HVG- 移植物中的反应性T细胞，从而调节排斥。如果是真的，则可以通过新颖的疗法来拒绝， 例如粪便移植。到目前为止，尚未研究人类ITX患者的纵向研究 微生物组与临床过程，T细胞嵌合，GVH的关系：HVG反应性T细胞比率 移植物和拒绝。因此，这项工作将表征ITX之后肠道中微生物组的变化 与血液和移植物中的嵌合和GVH：HVG比的降低相关，与之相关，这与 拒绝率更高。