Microbiota mechanisms and biomarkers in GVHD

项目摘要 异基因造血细胞移植（allo-HCT）是血液病的重要治疗方法， 恶性肿瘤。肠道微生物群由居住在肠道中的各种微生物组成 并且对于宿主发育、体内平衡和免疫调节至关重要。在人体分析和动物实验中 实验，我们和其他人已经表明，肠道微生物群有助于所有的病理生理学， allo-HCT的三大并发症：感染、GVHD和复发。接下来使用16 S核糖体RNA- 在第二代测序中，我们检查了allo-HCT患者的肠道微生物群，发现移植后 “微生物群损伤”。这种生态失调可能是由于（a）广谱抗生素的联合作用， 移植后发热性中性粒细胞减少症的治疗，和（B）移植后发热性中性粒细胞减少症患者经历的深刻的营养改变， 这些病人。我们发现异基因造血干细胞移植后布劳特氏菌的丢失与GVHD呈反比关系 mortality.我们观察到靶向厌氧藻类植物群的广谱抗生素， 特别是与GVHD相关死亡率的增加有关，事实上，在我们的研究中， 动物模型我们和其他人已经观察到肠球菌与肠球菌病的发展之间的联系。 最后，我们发现淤泥真杆菌与移植物抗宿主病之间存在关联。 allo-HCT后的肿瘤活性。因此，我们假设肠道微生物群可以调节 同种异体反应性我们在目的1中提出鉴定allo-HCT患者中GVHD的微生物群生物标志物， 开发一个临床上有用的多参数，快速周转的生物标志物面板。在目标2中，我们将使用鼠标 研究微生物群成员影响同种异体反应性的机制的模型，包括 GVHD和移植物抗肿瘤活性。除了阐明肠道微生物群在肠道中的相互作用外， GVHD的发展，这项工作将形成临床试验的基础，以减少GVHD和移植相关的 mortality. 在奖励期间，候选人将在纪念斯隆凯特琳癌症进行研究 中心在马塞尔货车登布林克博士和一个咨询委员会的指导下。他将获得关键的 他需要具备成为一名终身教授的物理学家兼科学家的技能，经营自己的学术实验室， 竞争独立的NIH基金。他将获得详细和全面的知识鼠标 微生物群模型，生物标志物开发中的统计方法，以及计算生物学方法， 分析高维微生物组测序数据。

Project Summary Allogeneic hematopoietic-cell transplantation (allo-HCT) is an important treatment for hematological malignancies. The intestinal microbiota consists of a community of diverse microbes that reside in the intestine and are critical for host development, homeostasis, and immune regulation. In human analyses and animal experiments, we and others have shown that the intestinal microbiota contribute to the pathophysiology of all three major complications of allo-HCT: infections, GVHD, and relapse. Using 16S ribosomal RNA next- generation sequencing, we examined the intestinal microbiota of allo-HCT patients and found a post-transplant “microbiota injury”. This dysbiosis is likely due to the combined effects of (a) broad-spectrum antibiotics for the treatment of post-transplant febrile neutropenia and (b) the profound nutritional alterations experienced by these patients. We found an inverse relationship between a loss of the genus Blautia after allo-HCT and GVHD mortality. We observed that broad-spectrum antibiotics that target the anaerobic commensal flora are particularly associated with increases in GVHD-related mortality and in fact worsened intestinal GVHD in our animal model. We and others have observed an association between Enterococcus and the development of GVHD in mouse and man. Finally, we have found an association between Eubacterium limosum and graft-vs- tumor activity after allo-HCT. Therefore, we hypothesize that the intestinal microbiota can modulate alloreactivity. We propose in Aim 1 to identify microbiota biomarkers of GVHD in allo-HCT patients and to develop a clinically useful multi-parameter, rapid-turnaround biomarker panel. In Aim 2, we will use mouse models to study the mechanisms by which members of the microbiota affect alloreactivity, including both GVHD and graft-vs-tumor activity. In addition to elucidating the interactions of the intestinal microbiota in the development of GVHD, this work will form the basis of clinical trials to reduce GVHD and transplant-related mortality. During the award period, the candidate will conduct research at Memorial Sloan Kettering Cancer Center under the mentorship of Dr. Marcel van den Brink and an Advisory Committee. He will obtain the critical skills he needs to become a tenure-track physician-scientist who runs his own academic laboratory and competes for independent NIH funding. He will acquire detailed and comprehensive knowledge of mouse microbiota models, statistical methods in biomarker development, and computational-biology approaches to the analysis of high-dimensional microbiome sequencing data.