Microbiota-focused strategies to mitigate GVHD

 描述(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，异基因血液/骨髓移植(Allo BMT)是一种非常重要的治疗方法，在单用化疗无法治愈的情况下可以治愈。全球每年有超过25,000名患者接受allo BMT。异基因骨髓移植的一个主要风险仍然是移植物抗宿主病(GVHD)，这是由于捐赠者的免疫系统识别移植受者的器官是异体器官，导致危及生命的炎症。 开发减少GVHD但保持全球免疫功能不变的策略应该会为患者带来重大好处。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，统称为肠道微生物区系。虽然多年来人们一直在怀疑微生物区系和GVHD之间的关系，但对它的了解仍然不完全。一些中心但不是所有中心都在使用抗生素进行肠道去污染，对于抗生素覆盖范围的理想选择也没有达成共识。这项应用的初步数据提出了一个新的发现：在人类肠道中常见的布鲁氏菌属细菌的丰富，预示着异基因骨髓移植患者可以预防危及生命的移植物抗宿主病。此外，在小鼠模型中引入一种鼠源性的布鲁氏菌，或布鲁氏菌和人类起源的相关细菌的混合物，可以降低GVHD的严重程度。一个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，并调节供体同种异体反应性T细胞的炎症。更多的初步数据表明，各种专注于微生物区系的策略似乎可以缓解小鼠的移植物抗宿主病。策略包括给小鼠服用SCFA，醋酸盐，选择不产生厌氧菌的抗生素，以及有针对性地引入一种由Blautia发酵的糖。我们的结果已经确定微生物区系是一个强大的盟友，可以招募来显著推迟GVHD。该项目旨在研究肠道菌群组成对移植物抗宿主病的影响，评估微生物区系损伤和移植物抗宿主病的治疗策略，并开发预防异基因骨髓移植患者微生物区系损伤的策略。总体目标是为多管齐下的方法奠定基础，以便在临床上将这些发现转化为针对allo BMT患者的个性化治疗，这些治疗是根据他们特定的微生物区系状况量身定做的。

 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.