Protecting colonic mucus to mitigate acute intestinal graft-versus-host disease

保护结肠粘液减轻急性肠道移植物抗宿主病

基本信息

批准号：
10441324
负责人：
Robert Jenq
金额：
$ 80.75万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441324
关键词：
Acute Acute Graft Versus Host Disease Acute leukemia Allogeneic Bone Marrow Transplantation Allogenic Anaerobic Bacteria Antibiotics Azithromycin Bacteria Biological Assay Biometry Carbapenems Cells Clinical Consumption Coupled Data Development Diet Monitoring Dietary intake Evaluation Feces Fever Functional disorder Gene Expression Gnotobiotic Hematologic Neoplasms Hematological Disease Hematopoietic Neoplasms Homeostasis Immune Immune Targeting Immune system Immunologics Immunosuppression Inflammation Infusion procedures Intestinal Graft Versus Host Disease Intestines Large Intestine Lead Life Link Malignant Neoplasms Mediating Melphalan Metabolic Mucins Mucolytics Mucous body substance Mus Oral Pathology Patients Play Prevalence Process Propionates Radiation therapy Retrospective Studies Risk Risk Factors Role Sampling Severity of illness Source Specimen Symptoms Technical Expertise Testing Time Tissues Toxic effect Transplant Recipients Work chemotherapy chronic leukemia clinical translation commensal bacteria conditioning dietary dietary restriction experimental study graft vs host disease gut inflammation gut microbiome hematopoietic cell transplantation immune function insight intestinal epithelium leukemia/lymphoma metabolomics microbial microbiome microbiota mouse model novel strategies nutrition organ transplant recipient prebiotics prophylactic prospective stool sample sugar systemic inflammatory response translational potential

项目摘要

PROJECT SUMMARY/ABSTRACT For patients with hematologic malignancies such as leukemias, lymphomas and other related cancers, allogeneic hematopoietic cell transplantation (allo HCT) is a critically important therapy that can produce cures when other treatments cannot. Roughly 20,000 patients undergo allo BMT world-wide each year. A major risk of allo HCT continues to be graft-versus-host disease (GVHD), which results from the donor immune system recognizing the transplant recipient’s organs as foreign, leading to life-threatening inflammation. Developing strategies that reduce GVHD but leave global immune function intact should produce a major benefit for patients. One promising approach that we propose testing is targeting the subset of intestinal commensal bacteria that are capable of consuming and degrading mucins, which play a critical role in maintaining the intestinal epithelial barrier and immunological homeostasis. In this proposal, we present preliminary data identifying two common scenarios during the allo HCT process: 1) poor oral dietary intake due to conditioning or development of GVHD, and 2) administration of broad-spectrum antibiotics. Both of these often lead to increases in mucolytic bacteria. Further, we have identified antibiotic and metabolic strategies to suppress mucolytic bacteria activity. We will apply these insights to guide a mucus-focused evaluation of GVHD, in both mouse models and in stool biospecimens collected from allo HCT patients. We and others have identified the microbiota as a potent modulator of acute GVHD severity. This project proposes capitalizing on a mechanistic insight into how this can occur, with clear translational potential.

项目概要/摘要对于患有白血病、淋巴瘤和其他相关癌症等血液系统恶性肿瘤的患者，异基因造血细胞移植（allo HCT）是一种极其重要的疗法，可以治愈疾病全世界每年约有 20,000 名患者接受异体 BMT，这是一个主要风险。同种异体 HCT 仍然是移植物抗宿主病 (GVHD)，这是由供体免疫系统引起的将移植接受者的器官视为外来器官，导致危及生命的炎症。减少 GVHD 但保持整体免疫功能完好的策略应该会产生重大益处我们建议测试的一种有前途的方法是针对肠道共生菌的子集。能够消耗和降解粘蛋白的细菌，粘蛋白在维持粘蛋白方面发挥着关键作用肠上皮屏障和免疫稳态。在本提案中，我们提供了初步数据，确定了 allo HCT 期间的两种常见情况过程：1) 由于条件反射或 GVHD 的发生而导致口服饮食摄入不足，以及 2) 此外，这两种抗生素通常都会导致粘液溶解细菌的增加。我们将应用这些确定的抗生素和代谢策略来抑制粘液溶解细菌的活性。指导小鼠模型和粪便生物样本中以粘液为中心的 GVHD 评估的见解从异基因 HCT 患者中收集。我们和其他人已经确定微生物群是急性 GVHD 严重程度的有效调节剂。该项目建议利用对如何发生这种情况的机械洞察力，并具有明确的转化潜力。