Microbiota mechanisms and biomarkers in GVHD

GVHD 中的微生物群机制和生物标志物

• 批准号: 10597535
• 负责人: Jonathan Peled
• 金额: $ 17.16万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597535
• 关键词: Advisory Committees; Affect; Allogenic; Animal Experiments; Animal Model; Antibiotic Therapy; Antibiotics; Antibody Therapy; Applications Grants; Award; Bacteremia; Bacteria; Biological Markers; Bone Marrow Transplantation; Cancer Patient; Clinical; Clinical Trials; Colonic Diseases; Communities; Complex; Computational Biology; Data; Development; Disease; Enterococcus; Eubacterium; Feces; Fever; Functional disorder; Funding; Future; Goals; Health; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Homeostasis; Human; Immune system; Immunosuppression; Indican; Individual; Infection; Inflammation; Injury; Intestines; Knowledge; Laboratories; Life; Memorial Sloan-Kettering Cancer Center; Mentorship; Microbe; Modeling; Morbidity - disease rate; Mucolytics; Mucous Membrane; Mucous body substance; Mus; Neutropenia; Nutritional; Organism; Patients; Physicians; Plasma; Pre-Clinical Model; Prevention strategy; Probiotics; Quality of life; RNA, Ribosomal, 16S; Radiation therapy; Recurrent Malignant Neoplasm; Regimen; Relapse; Research; Risk; Role; Running; Safety; Sampling; Scientist; Series; Severity of illness; Statistical Methods; Surface; Therapeutic; Tissues; Toxic effect; Translating; Transplant Recipients; Transplantation; United States National Institutes of Health; Urine; Work; biomarker development; biomarker panel; cancer recurrence; cancer therapy; chemotherapy; clinically actionable; commensal bacteria; commensal microbes; conditioning; dysbiosis; experience; graft vs host disease; gut microbiota; hematopoietic cell transplantation; high dimensionality; high risk; immune function; immunoregulation; improved; infection risk; insight; intestinal barrier; man; member; microbial community; microbiome sequencing; microbiota; microbiota transplantation; mortality; mouse model; next generation sequencing; pathogenic bacteria; post-transplant; prebiotics; precision medicine; precision oncology; precursor cell; prevent; recurrent infection; skills; tenure track; tumor

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.

项目摘要 同种异体造血细胞移植（Allo-HCT）是血液学的重要疗法 恶性肿瘤。肠道微生物群由一个存在于肠道的潜水员微生物组成 对于宿主发展，体内平衡和免疫调节至关重要。在人类分析和动物中 实验，我们和其他人表明，肠道菌群有助于所有人的病理生理 Allo-HCT的三个主要并发症：感染，GVHD和缓解。接下来使用16S核糖体RNA 生成测序，我们检查了Allo-HCT患者的肠菌群，并发现了移植后 “菌群损伤”。这种营养不良可能是由于（a）广谱抗生素对 治疗移植后热中性减少症和（b）经历的深刻营养改变 这些患者。我们发现Allo-HCT和GVHD后Blautia属的丧失之间存在反比关系 死亡。我们观察到针对厌氧共生菌群的广谱抗生素是 特别与GVHD相关死亡率的增加以及实际上使我们的肠道GVHD恶化有关 动物模型。我们和其他人观察到肠球菌与发展 鼠标和人的GVHD。最后，我们发现了limosum菌群与移植物vs-之间的关联 Allo-HCT后的肿瘤活性。因此，我们假设肠菌可以调节 同种异体。我们建议在AIM 1中识别Allo-HCT患者GVHD的微生物群生物标志物，并 开发临床上有用的多参数，快速转变的生物标志物面板。在AIM 2中，我们将使用鼠标 研究微生物群会影响同种异体的机制的模型，包括 GVHD和GRAFT-VS肿瘤活性。除了阐明肠菌在 GVHD的发展，这项工作将构成临床试验的基础，以减少GVHD和移植相关 死亡。 在奖励期间，候选人将在纪念斯隆·克特林（Sloan Kettering Cancer）进行研究 在马塞尔·范·登（Marcel van den Brink）博士的心态和咨询委员会的心态下。他将获得关键 他需要成为终身训练的身体科学家需要的技能，并经营自己的学术实验室和 争夺独立的NIH资金。他将获取鼠标的详细而全面的知识 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 高维微生物组测序数据的分析。

项目成果

Mitigation of gastrointestinal graft-versus-host disease with tocilizumab prophylaxis is accompanied by preservation of microbial diversity and attenuation of enterococcal domination.

• DOI: 10.3324/haematol.2022.281309
• 发表时间: 2023-01-01
• 期刊: HAEMATOLOGICA
• 影响因子: 10.1
• 作者: Chhabra, Saurabh;Szabo, Aniko;Clurman, Annelie;McShane, Katelyn;Waters, Nicholas;Eastwood, Daniel;Samanas, Lisa;Fei, Teng;Armijo, Gabriel;Abedin, Sameen;Longo, Walter;Hari, Parameswara;Hamadani, Mehdi;Shah, Nirav N.;Runaas, Lyndsey;Jerkins, James H.;van den Brink, Marcel;Peled, Jonathan U.;Drobyski, William R.
• 通讯作者: Drobyski, William R.

Pilot Trial of Homebound Hematopoietic Cell Transplantation.

• DOI: 10.1016/j.jtct.2022.09.014
• 发表时间: 2022-12
• 期刊: TRANSPLANTATION AND CELLULAR THERAPY
• 影响因子: 3.2
• 作者: Landau, Heather J.;Orlando, Evelyn;Rodriguez, Elizabeth S.;Applebaum, Allison;Mitchell, Hannah -Rose;Peled, Jonathan U.;Khan, Niloufer;Funnell, Tyler;Chung, David;Scordo, Michael;Shah, Gunjan L.;LeStrange, Nicole J.;Hambright, Katie A.;McElrath, Courtney M.;Cazeau, Naomi;Devlin, Sean M.;Perales, Miguel -Angel;Giralt, Sergio A.
• 通讯作者: Giralt, Sergio A.

Microbiota and Allogeneic Hematopoietic-Cell Transplantation. Reply.

微生物群和同种异体造血细胞移植。

• DOI: 10.1056/nejmc2006694
• 发表时间: 2020
• 期刊: The New England journal of medicine
• 作者: Peled,JonathanU;Gomes,AntonioLC;vandenBrink,MarcelRM
• 通讯作者: vandenBrink,MarcelRM

Update in clinical and mouse microbiota research in allogeneic haematopoietic cell transplantation.

• DOI: 10.1097/moh.0000000000000616
• 发表时间: 2020-11
• 期刊: Current opinion in hematology
• 影响因子: 3.2
• 作者: Lindner S;Peled JU
• 通讯作者: Peled JU

Vitamin D Insufficiency and Clinical Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Large B-cell Lymphoma.

• DOI: 10.1016/j.jtct.2022.08.001
• 发表时间: 2022-11
• 期刊: Transplantation and cellular therapy
• 影响因子: 3.2
• 作者: Nath K;Tomas AA;Flynn J;Fein JA;Alperovich A;Anagnostou T;Batlevi CL;Dahi PB;Fingrut WB;Giralt SA;Lin RJ;Palomba ML;Peled JU;Salles G;Sauter CS;Scordo M;Fraint E;Feuer E;Shah N;Slingerland JB;Devlin S;Shah GL;Gupta G;Perales MA;Shouval R
• 通讯作者: Shouval R