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

项目总结/摘要 对于患有血液恶性肿瘤如白血病、淋巴瘤和其他相关癌症的患者， 异基因造血细胞移植（allo HCT）是一种非常重要的治疗方法， 其他治疗方法不能。每年全球约有20，000名患者接受异体BMT。一个主要危险 移植物抗宿主病（GVHD）仍是同种异体HCT的主要原因，它是由供体免疫系统引起的 将移植受体的器官识别为异物，导致危及生命的炎症。发展中 减少GVHD但保持整体免疫功能完整的策略应该对 患者我们提出的一种有希望的测试方法是针对肠上皮细胞亚群， 能够消耗和降解粘蛋白的细菌，粘蛋白在维持 肠上皮屏障和免疫稳态。 在这项建议中，我们提出了初步的数据，确定两个常见的情况下，在allo HCT 过程：1）由于GVHD的调节或发展而导致的口服饮食摄入不足，以及2） 广谱抗生素这两种情况经常导致粘液溶解细菌的增加。您因前述 确定了抑制粘液溶解细菌活性的抗生素和代谢策略。我们将应用这些 在小鼠模型和粪便生物标本中指导以粘液为中心的GVHD评价的见解 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。这 该项目提出利用对如何发生这种情况的机械见解，具有明确的转化潜力。

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.