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

项目摘要/摘要 对于白血病、淋巴瘤和其他相关癌症等恶性血液病患者， 异基因造血细胞移植(Allo Hct)是一种非常重要的治疗方法。 当其他治疗方法不能的时候。全球每年约有2万名患者接受allo BMT。重大风险 移植物抗宿主病(GVHD)是供者免疫系统引起的移植物抗宿主病 识别移植受者的器官是异物，导致危及生命的炎症。发展中 减少GVHD但保持全球免疫功能不变的策略应该会对 病人。我们提出的一种有希望的测试方法是针对肠道共生的子集 能够消耗和降解粘蛋白的细菌，粘蛋白在维持 肠上皮屏障与免疫内稳态。 在这份提案中，我们提供了初步数据，确定了在allo hct期间的两种常见情况 过程：1)由于GVHD的条件或发展而导致的口服膳食摄入不足，以及2)给药 广谱抗生素。这两种情况通常都会导致粘液溶解细菌的增加。此外，我们还拥有 确定了抑制粘液菌活性的抗生素和代谢策略。我们将应用这些 指导在两种小鼠模型和粪便生物样本中以粘液为重点的GVHD评估的见解 收集自allo hct患者。 我们和其他人已经确认微生物区系是急性移植物抗宿主病严重程度的有力调节器。这 Project建议利用一种机械的洞察力来了解这一点是如何发生的，并具有明确的翻译潜力。

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.