Microbiota-focused strategies to mitigate GVHD

以微生物群为重点的减轻 GVHD 的策略

• 批准号: 9269123
• 负责人: Robert Jenq
• 金额: $ 53.85万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269123
• 关键词: Acetates; Allogenic; Ally; Anaerobic Bacteria; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Applications Grants; Area; Asthma; Atherosclerosis; Bacteria; Blood; Bone Marrow Transplantation; Characteristics; Clinical; Communities; Complex; Consensus; Data; Decontamination; Disease Outcome; Foundations; Generations; Goals; Hematologic Neoplasms; Hematopoietic Neoplasms; Hematopoietic System; Human; Hypersensitivity; Immune; Immune system; Immunosuppression; Individual; Infection; Inflammation; Injury; Intestines; Lead; Life; Link; Malignant Neoplasms; Mediating; Microbe; Molecular; Mus; Nutritional; Obesity; Onset of illness; Organ; Organ failure; Outcome; Patients; Pattern; Prevention; Procedures; Process; Recruitment Activity; Reducing Agents; Regulatory T-Lymphocyte; Research Design; Research Personnel; Risk; Risk Factors; Sampling; Sepsis; Series; Severity of illness; T-Lymphocyte; Technology; Testing; Therapeutic; Translating; Transplant Recipients; Volatile Fatty Acids; bacterial genetics; cancer recurrence; chemotherapy; clinical practice; graft vs host disease; gut microbiota; high risk; immune function; improved outcome; interest; leukemia/lymphoma; member; microbiota; mortality; mouse model; novel; nutrition; pathogenic bacteria; personalized medicine; prevent; public health relevance; resilience; sugar

 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.

 描述（由申请人提供）：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来说，同种异体血液/骨髓移植（allo BMT）是一种极其重要的疗法，在单纯化疗无法治愈的情况下，它可以治愈超过 25,000 名患者。每年在世界范围内进行异基因 BMT 的主要风险仍然是移植物抗宿主病 (GVHD)，这是由移植物抗宿主病 (GVHD) 引起的。供体免疫系统将移植受者的器官识别为外来器官，导致危及生命的炎症。 制定减少 GVHD 但保持整体免疫功能完整的策略应该会给患者带来重大益处，我们开发的一种有前景的方法是针对肠道内的复杂微生物群落，这些微生物群统称为肠道微生物群。多年来，人们一直怀疑微生物群和移植物抗宿主病（GVHD），但在一些但并非所有中心都采用抗生素进行肠道净化，对此仍不完全了解，并且对于抗生素覆盖的理想选择尚未达成共识。该申请提出了一项新发现：人类肠道中常见的布劳氏菌属细菌丰富，预示着异基因 BMT 患者可以免受危及生命的 GVHD 的影响。此外，在小鼠模型中引入一种小鼠布劳氏菌。来源，或 Blautia 和人类来源的相关细菌的混合物可降低 GVHD 的严重程度，一种可能的机制是产生短链脂肪酸 (SCFA)，诱导供体调节性 T 细胞，并通过供体调节炎症。其他初步数据表明，多种以微生物群为重点的策略似乎可以减轻小鼠的 GVHD，其中包括给小鼠施用 SCFA、醋酸盐、选择避免专性厌氧菌的抗生素以及有针对性地引入发酵糖。我们的研究结果表明，微生物群是可以显着减轻 GVHD 的有效盟友。该项目旨在研究肠道菌群组成对 GVHD 的影响，以减少 GVHD 的发生。评估治疗微生物群损伤和 GVHD 的策略，并制定预防异基因 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异基因 BMT 患者的个性化治疗。根据其特定的微生物群状况量身定制。