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

项目总结 韦纳博士是一名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一名 肠移植实践(ITX)和未被充分研究的学科的领先外科医生和科学家 肠道免疫生物学具有独特的专业知识和沉浸在两者之间，以翻译新的科学发现 转化为重大临床进展。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)建立在目前对ITX后排斥反应病理生理学的理解基础上，3)增强His 对微生物学、先天免疫防御、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事业。他组织了一场 拥有专业知识和经验以促进这一领域的职业发展的指导团队，他拥有 承诺资源和保护研究时间不受他的部门主席和部门负责人的影响。这个 他的项目的意义在于，ITX是一次性肠衰竭患者的唯一治疗选择 肠外营养失败。然而，它的使用受到高排斥率的限制，这就需要增加 免疫抑制水平，使患者容易出现病态副作用。这项提案调查了 肠道微生物群和宿主黏膜防御系统之间的关系与ITX后的排斥反应有关。之前 研究表明，排斥反应与肠道微生物群的调节和机体功能障碍有关。 与菌群保持动态平衡的宿主防御系统。同样众所周知的是，拒绝与减少 移植物抗宿主(GVH)反应性供者T细胞与宿主抗移植物(HVG)反应性受体T细胞的比率 移植物内的细胞。基于这些共同的发现，韦纳博士假设动态平衡 肠道微生物群和粘膜防御在维持GVH：HVG-平衡中起着至关重要的作用。 移植物中的反应性T细胞，从而调节排斥反应。如果是真的，排斥反应可以通过新的治疗方法来治疗， 比如粪便移植。到目前为止，还没有关于人类ITX患者的纵向研究 微生物群调节与临床病程、T细胞嵌合体、GVH/HVG反应性T细胞比率的关系 嫁接和排斥。因此，这项工作将表征ITX后肠道微生物群的变化 与血液和移植物中嵌合体减少和GVH/HVG比率相关，这与 更高的拒绝率。

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.