Microbiota-focused strategies to mitigate GVHD

 描述（由申请人提供）：对于白血病、淋巴瘤和其他相关癌症等恶性血液病患者来说，异基因血液/骨髓移植（allo BMT）是一种至关重要的疗法，可以在单独化疗无法治愈的情况下治愈。全世界每年有超过25，000名患者接受异体BMT。异体骨髓移植的一个主要风险仍然是移植物抗宿主病（GVHD），这是由于供体免疫系统将移植受体的器官识别为异物，导致危及生命的炎症。 开发减少GVHD但保持整体免疫功能完整的策略应该会为患者带来重大益处。我们开发的一种有希望的方法是针对居住在我们肠道内的复杂微生物群落，统称为肠道微生物群。虽然微生物与GVHD之间的关系多年来一直受到怀疑，但它仍然不完全理解。在一些但不是所有的中心都使用抗生素进行肠道净化，并且关于抗生素覆盖范围的理想选择没有达成共识。 本申请中的初步数据提出了一个新的发现：属于布劳特氏菌属的细菌的丰度，通常在人类肠道中发现，预测在同种异体BMT患者中保护免于危及生命的GVHD。此外，在鼠模型中引入鼠来源的布劳特氏菌属物种或布劳特氏菌属和人来源的相关细菌的混合物降低了GVHD严重性。一种可能的机制似乎是产生短链脂肪酸（SCFA），诱导供体调节性T细胞，并通过供体同种异体反应性T细胞调节炎症。 额外的初步数据表明，各种以微生物群为重点的策略似乎可以减轻小鼠中的GVHD。策略包括向小鼠施用SCFA、乙酸盐、选择使专性厌氧菌不受影响的抗生素，以及有针对性地引入由布劳特氏菌发酵的糖。 我们的研究结果已经确定了微生物群作为一个有效的盟友，可以招募显着减少GVHD。该项目旨在研究肠道植物群组成对GVHD的影响，评估治疗微生物群损伤和GVHD的策略，并制定预防同种异体BMT患者微生物群损伤的策略。总体目标是为多管齐下的方法奠定基础，将这些发现临床转化为针对同种异体BMT患者的个性化治疗，这些治疗是针对他们特定的微生物群状态而定制的。

 DESCRIPTION (provided by applicant): For patients with hematologic malignancies such as leukemias, lymphomas and other related cancers, allogeneic blood/marrow transplantation (allo BMT) is a critically important therapy that can produce cures when chemotherapy alone cannot. More than 25,000 patients undergo allo BMT world-wide each year. A major risk of allo BMT 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 have developed is targeting the complex community of microbes that reside within our intestinal tracts, collectively termed the intestinal microbiota. While a relationship between the microbiota and GVHD has been suspected for many years, it remains imperfectly understood. Gut decontamination with antibiotics is practiced at some but not all centers, and there is no consensus regarding ideal choice of antibiotic coverage. The preliminary data in this application present a novel finding: the abundance of bacteria belonging to the genus Blautia, commonly found in the intestinal tract of humans, predicts for protection from life-threatening GVHD in allo BMT patients. Furthermore, introducing in murine models a species of Blautia of murine origin, or a mixture of Blautia and related bacteria of human origin reduces GVHD severity. A possible mechanism appears to be generation of short-chain fatty acids (SCFA), inducing donor regulatory T cells, and modulating inflammation by donor alloreactive T cells. Additional preliminary data demonstrate that a variety of microbiota-focused strategies appear to alleviate GVHD in mice. Strategies include administration to mice of a SCFA, acetate, selecting antibiotics that spare obligate anaerobes, and targeted introduction of a sugar that is fermented by Blautia. Our results have identified the microbiota as a potent ally that can be recruited to significantly redue GVHD. The project aims to study the effects of intestinal flora composition on GVHD, to evaluate strategies to treat microbiota injury and GVHD, and to develop strategies to prevent microbiota injury in allo BMT patients. The overarching goal is to lay the foundation for a multi-pronged approach to clinically translate these findings into personalized therapies for allo BMT patients that are tailored to their particular microbiota status.