Microbiota mechanisms and biomarkers in GVHD

项目摘要 异基因造血细胞移植(allo-hct)是治疗血液病的重要手段 恶性肿瘤。肠道微生物区系由驻留在肠道中的各种微生物群落组成。 对宿主发育、动态平衡和免疫调节至关重要。在人类分析和动物方面 我们和其他人的实验表明，肠道微生物区系对ALL的病理生理学有贡献 Allo-HCT的三个主要并发症：感染、移植物抗宿主病和复发。接下来使用16S核糖体RNA- 世代测序，我们检查了allo-hct患者的肠道微生物区系，发现移植后 “微生物区系损伤”。这种生态失调很可能是由于(A)广谱抗生素对 移植后发热性中性粒细胞减少症的治疗和(B)患者经历的深刻营养变化 这些病人。我们发现异基因血细胞移植后布劳蒂亚属的丧失与移植物抗宿主病成反比。 死亡率。我们观察到，针对厌氧共生菌的广谱抗生素是 尤其是与移植物抗宿主病相关死亡率的增加有关，事实上，在我们的 动物模型。我们和其他人已经观察到肠球菌与肺炎的发展之间的联系 小鼠和人的GVHD。最后，我们发现了利莫氏真细菌和移植物抗病毒之间的联系。 异体血细胞移植后肿瘤活动性。因此，我们假设肠道微生物区系可以调节 同种异体反应。我们在目标1中建议识别allo-HCT患者GVHD的微生物区系生物标记物，并 开发一种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 研究微生物区系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区系之间的相互作用外， GVHD的开发，这项工作将形成减少GVHD和移植相关的临床试验的基础 死亡率。 在获奖期间，候选人将在斯隆·凯特琳癌症纪念医院进行研究 该中心由马塞尔·范登布林克博士和一个咨询委员会指导。他将获得关键的 他需要的技能才能成为一名终身教职医生兼科学家，经营自己的学术实验室，并 竞争独立的NIH资金。将获得详细而全面的鼠标知识 微生物区系模型，生物标记物开发中的统计方法，以及计算生物学方法 高维微生物组测序数据分析。

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.