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

项目摘要 博士韦纳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 肠移植（ITx）实践中的领先外科医生-科学家，以及 肠道免疫生物学与独特的专业知识和沉浸在这两个翻译新的科学发现 投入到重大的临床进展中为此，他的短期职业目标是：1）获得肠道疾病的临床专业知识， 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）增加他的免疫反应， 对微生物学，先天免疫防御以及先进的微生物和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。他组织了一个 导师团队的专业知识和经验，以促进在这一领域的职业发展，他有 资源的承诺和保护研究时间从他的系主任和处长。的 他的项目的意义在于ITx是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。该提案探讨了 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。之前 这项工作表明，排斥反应与肠道微生物组的调节和 维持与植物群内环境平衡的宿主防御。也知道排斥与减少 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博士假设， 肠道微生物组和粘膜防御在维持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。如果这是真的，排斥反应可以用新的疗法来治疗， 例如粪便移植。到目前为止，还没有在人类ITx患者中进行的纵向研究 微生物组调节与临床病程、T细胞嵌合体、GVH：HVG反应性T细胞比率的关系 移植和排斥反应因此，这项工作将描述ITx后肠道微生物组的变化 与血液和移植物中嵌合体和GVH：HVG比率降低相关，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.