Mucosal Immunity and Microbiota in Intestinal Graft-versus-Host Disease

肠移植物抗宿主病中的粘膜免疫和微生物群

• 批准号: 9086215
• 负责人: Marcel R M van den Brink
• 金额: $ 42.79万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086215
• 关键词: Acute Graft Versus Host Disease; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antibodies; Bacteremia; Bacteria; Bifidobacterium; Blood; Bone Marrow; Cells; Clinic; Clinical Protocols; Clinical Research; Complication; Consensus; Data; Decontamination; Dendritic Cells; Development; Diet; Disease; Endothelium; Enterobacteriaceae; Enterococcus; Environment; Epithelial; Fostering; Functional disorder; Funding; Genes; Genus staphylococcus; Germ-Free; Gnotobiotic; Graft-Versus-Tumor Induction; Hematopoietic; Hematopoietic Stem Cell Transplantation; Homeostasis; Human; Image; Immune; Immune System Diseases; Immune system; Immunity; Incidence; Individual; Inflammatory Bowel Diseases; Integrins; Interleukin-17; Intestinal Graft Versus Host Disease; Intestines; Lactobacillus; Left; Life; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Mucosal Immunity; Mus; Non-Malignant; Outcome; P-Selectin; Patients; Prevention; Prophylactic treatment; Regimen; Reporter; Research Personnel; Role; Source; Streptococcus; System; T-Lymphocyte; Testing; Therapeutic; Translating; Translations; Transplantation; Vendor; aryl hydrocarbon receptor ligand; chemokine receptor; conditioning; gastrointestinal; germ free condition; graft vs host disease; gut microbiota; improved; insight; integrin alpha4beta7; microbial; microbiota; mortality; mouse model; neutralizing antibody; new technology; novel; novel therapeutics; nutrition; preclinical study; prophylactic; research study; success; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Allogeneic bone marrow or hematopoietic stem cell transplantation (allo BMT) is an important therapy with curative potential for a variety of malignant and non-malignant diseases. Despite standard prophylactic regimens, graft-versus-host disease (GVHD) continues to limit the success of outcomes in allo BMT patients. Gastrointestinal (GI) GVHD is the predominant contributor to acute GVHD-related mortality. In the first funding period we hypothesized that T cell trafficking to the intestines represented a therapeutic target that could significantly reduce intestinal and systemic GVHD while sparing graft-versus-tumor and improve overall outcome. Among other results we identified the α4ß7 integrin as an excellent target for the prevention of GI GVHD and we are currently developing a clinical protocol with a neutralizing antibody. In this renewal application, we propose to continue exploring the pathophysiology of intestinal GVHD and focus on the role of the intestinal flora. Early studies in mice and in patients suggested a link between an individual's intestinal microbial flora and his/her propensity for GVHD, but the translation to the clinic (gut decontamination and/or laminar airflow protective environment) remains controversial. The availability of a novel technology, 16s ribosomal RNA (rRNA) gene sequencing, to analyze the composition of the gut flora in much greater detail has resulted in better understanding of the relationship between gut flora and its interaction with intestinal immunity and intestinal epithelil homeostasis. Our preliminary data in mouse models indicate that GVHD is associated with specific changes in the intestinal flora, including a loss of microbial diversity, dysbiosis (imbalance of intestinal flora) and the expansion of Lactobacillus or Enterobacteriaceae, which have opposite effects on GVHD. Moreover, pre-BMT antibiotic use could aggravate GVHD. Our analysis of 66 allo BMT patients shows a) a remarkable loss of microbial diversity in allo-HSCT recipients, which is associated with bacteremia and intestinal domination by Enterococci, Streptococci and Staphylococci, and b) an association between dysbiosis and GVHD. Therefore, we hypothesize that the interactions between intestinal microbiota, allogeneic donor cells, intestinal immunity and intestinal epithelial homeostasis can impact GVHD, and this can be exploited therapeutically to reduce GVHD. We propose in Aim 1 to fully characterize the intestinal microbiota during allo BMT. We will assess the effects of the conditioning and antibiotic regimens and further characterize the GVHD-associated changes (loss of microbial diversity, dysbiosis and expansion of Lactobacillus or Enterobacteriaceae). These experiments are required to define the variables that affect the intestinal flora in allo BMT recipients and provide the necessary background for the experiments in Aim 2, in which we hypothesize that manipulation of the intestinal flora and nutrition can ameliorate intestinal GVHD. We will study the effects of a) introduction of Lactobacillus on GVHD and potential mechanisms of action (suppression of Enterococcus and γδT cells), b) other potentially anti-inflammatory bacteria on GVHD (prioritizing Bifidobacterium), and c) the diet content of aryl hydrocarbon receptor ligands on the intestinal flora and GVHD. In addition, we will explore effects of murine and human intestinal flora on GVHD in germ-free and gnotobiotic mice. The investigators of this proposal are performing similar sequential analyses of the gut flora in allo BMT patients, which fosters a continuing interaction and translatability of the results. Therefore, we expect that these preclinical studies have a high likelihood to improve prophylaxis and treatment of intestinal GVHD as well as overall outcome in allo BMT patients.

描述（由适用提供）：同种异体骨髓或造血干细胞移植（Allo BMT）是一种重要的疗法，具有各种恶性和非恶性疾病的现代潜力。尽管有标准的预防性方案，但移植物与宿主疾病（GVHD）继续限制Allo BMT患者的结果成功。胃肠道（GI）GVHD是急性GVHD相关死亡率的主要因素。在第一个资金期间，我们假设T细胞运输到肠道上代表了一个治疗靶标，可以显着降低肠道和全身GVHD，同时避免移植物抗肿瘤并改善整体结果。除其他结果外，我们将α4ß7整合素确定为预防GI GVHD的绝佳靶标，并且我们目前正在开发具有中和抗体的临床方案。在此续签应用中，我们建议继续探索肠道GVHD的病理生理学，并专注于肠道菌群的作用。对小鼠和患者的早期研究表明，个人的肠道微生物菌群与他/她对GVHD的倾向之间有联系，但是转化为诊所（肠道净化和/或层状气流保护的环境）仍然存在争议。一种新型技术的可用性，即16S核糖体RNA（RRNA）基因测序，可以更详细地分析肠道菌群的组成，从而更好地理解了肠菌群之间的关系以及其与肠道免疫和肠道上皮稳态的相互作用。我们在小鼠模型中的初步数据表明，GVHD与肠道菌群的特定变化有关，包括微生物多样性的丧失，营养不良（肠道菌群的不平衡）以及乳酸杆菌或肠杆菌科的扩展，这对GVHD产生了相反的影响。此外，BMT前抗生素的使用可能会加剧GVHD。我们对66名Allo BMT患者的分析表明，A）在Allo-HSCT受体中显着丧失微生物多样性，这与肠球菌，链球菌和葡萄球菌的细菌和肠道统治有关，以及B）在营养不良和GVHD之间的关联。因此，我们假设肠道菌群，同种异体供体细胞，肠道免疫学和肠上皮稳态之间的相互作用会影响GVHD，并且可以热探索以减少GVHD。我们在AIM 1中提议在Allo BMT期间充分表征肠菌。我们将评估条件和抗生素方案的影响，并进一步表征与GVHD相关的变化（微生物多样性的丧失，乳酸杆菌或肠杆菌科的扩张）。需要这些实验来定义影响Allo BMT受体中肠道菌群的变量，并为AIM 2中的实验提供必要的背景，在这种情况下，我们假设对肠道菌群和营养的操纵可以改善肠道GVHD。我们将研究a）a）引入乳杆菌对GVHD和潜在的作用机制（抑制肠球菌和γδT细胞），b）其他潜在的抗炎细菌对GVHD（优先考虑双歧杆菌的优先级），以及c）在含液体含量的饮食含量。此外，我们将探索鼠和人类肠菌群对无菌和gnotobiotic小鼠GVHD的影响。该提案的研究人员正在对Allo BMT患者进行类似的肠道菌群的顺序分析，这促进了结果的持续相互作用和转换性。因此，我们期望这些临床前研究很有可能改善预防和治疗肠道GVHD以及Allo BMT患者的总体结果。