Cellular and molecular mechanisms of target tissue resistance for mitigating GVHD severity

减轻 GVHD 严重程度的靶组织抵抗的细胞和分子机制

• 批准号: 9194674
• 负责人: PAVAN REDDY
• 金额: $ 47.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-25 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194674
• 关键词: Acetaldehyde; Acetylation; Adverse effects; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Amino Acids; Antigen-Antibody Complex; Apoptosis; Aryl Hydrocarbon Receptor; Attention; Autoimmunity; Bioenergetics; Biology; Butyrates; Cell surface; Cells; Chemicals; Clinical; Complex; Complication; Data; Dendritic Cells; Development; Disease; Ecosystem; Epigenetic Process; Epithelial; Epithelial Cells; Essential Amino Acids; Family; Gastrointestinal tract structure; Hematopoietic Stem Cell Transplantation; Histone Acetylation; Histone Deacetylase Inhibitor; Homeostasis; Human; Hypersensitivity; Immune; Immunity; Indoles; Infection; Inflammatory; Intestines; Link; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Metabolic; Microbe; Modality; Modification; Molecular; Pathway interactions; Patients; Pattern recognition receptor; Peripheral; Play; Prevention trial; Proteins; Reaction; Regulation; Research Personnel; Resistance; Role; Severities; Severity of illness; Signal Transduction; Skin; T-Lymphocyte; Testing; Therapeutic; Tissues; Transcriptional Regulation; Translating; Tryptophan; Volatile Fatty Acids; chromatin modification; curative treatments; cytokine; epigenetic regulation; epigenome; epigenomics; gastrointestinal; gastrointestinal epithelium; graft vs host disease; improved; insight; intestinal homeostasis; leukemia; member; metabolic profile; metabolomics; microbial; microbiome; microbiota; novel; public health relevance; receptor; resistance mechanism; response; sensor; solute

ABSTRACT: Allogeneic hematopoietic stem cell transplantation is potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, graft-versus-host disease (GVHD). GVHD results from the damage caused to the host epithelial cell targets by the many immune cells and inflammatory cytokines. While significant progress is being made in understanding the complex role of various immune cells in causing GVHD, little is known about the role played by the target tissues themselves in regulating the severity of disease. Specifically, induction of host intestinal epithelial cell (IEC) apoptosis by the alloreactive donor T cells and inflammatory cytokines causes gastrointestinal (GI) GVHD; however host IEC intrinsic resistance mechanisms to allo-immune T-cell mediated damage, the epigenetic mechanisms that are critical for these resistance mechanisms and its regulation by the tissue resident microflora generated metabolites has never been explored. IEC homeostasis and resistance depends on complex interactions between the metabolic energy substrates (such as short chain fatty acids and amino acid metabolites) and the regulation of transcription and epigenetic chromatin modifications such as histone acetylation. We have demonstrated that epigenetic regulation by systemic administration of histone deacetylase inhibitors (HDACi) regulates experimental GVHD and successfully translated this concept into a proof of principle human trial for prevention of clinical GVHD. Preliminary data generated demonstrate significant alterations in substrates that are derived from microbial metabolites such as essential short chain fatty acids (SCFA) and amino acids metabolites, specifically in butyrate and tryptophan metabolite indole-3-acetaldehyde (I-3-A) levels, in the GI tract (IECs) after allogeneic BMT. Preliminary data also show that (a) butyrate, a known HDACi, enhances histone acetylation, modulates IECs resistance to damage and regulates GVHD (b) expression of aryl hydrocarbon receptor (AhR) (a sensor of tryptophan metabolite indole-3-acetaldehyde) mitigates GVHD severity. But the pathways of sensing and the mechanisms underlying the butyrate and tryptophan metabolite indole-3-acetaldehyde -mediated effects in GVHD remain unknown. Therefore, in this proposal, we will build on these exciting and novel preliminary observations and bring together the diverse fields of microbiota, metabolomics, tissue bioenergetics and epigenetics, to explore the interplay between microbial metabolites and their effects on epigenomic alterations of the IECs in reducing GI GVHD. Specifically, we will test the central premise that regulation of target tissue (IEC) resistance by the endogenous intestinal microbial metabolites butyrate and tryptophan metabolite indole-3-acetaldehyde, alter the acetylation dependent epigenome of IECs and negatively regulates GI GVHD.

抽象的： 同种异体造血干细胞移植是许多用于许多治疗的治疗 其适用性受到最大发展所阻碍的恶性疾病 严重的并发症，移植物与宿主病（GVHD）。 GVHD造成的损坏导致 许多免疫细胞和炎症细胞因子引起宿主上皮细胞靶标。 尽管在理解各种免疫的复杂作用方面正在取得重大进展 引起GVHD的细胞，对于目标组织本身所起的作用知之甚少 调节疾病的严重程度。具体而言，诱导宿主肠上皮细胞（IEC） 同种反应性供体T细胞和炎性细胞因子的凋亡导致胃肠道 （gi）GVHD;但是，宿主的IEC内在电阻机制介导了异源T细胞T细胞介导 破坏，对这些抗性机制至关重要的表观遗传机制及 从未探索过组织驻留的菌群产生的代谢产生的代谢产生的调节。 IEC 稳态和阻力取决于代谢能量之间的复杂相互作用 底物（例如短链脂肪酸和氨基酸代谢产物），并调节 转录和表观遗传染色质修饰，例如组蛋白乙酰化。我们有 证明了系统施用组蛋白脱乙酰基酶的表观遗传调节 抑制剂（HDACI）调节实验性GVHD，并成功地将此概念转化为 预防临床GVHD的主要人类试验证明。生成的初步数据 证明了从微生物代谢物衍生的底物的显着变化 例如必需的短链脂肪酸（SCFA）和氨基酸代谢物，特别是在 在胃肠道（IEC） 同种异体BMT之后。初步数据还表明（a）已知的HDACI丁酸酯增强了 组蛋白乙酰化，调节IEC对损伤的抵抗力并调节GVHD（B）表达 芳基烃受体（AHR）（色氨酸代谢物吲哚-3-乙醛的传感器） 减轻GVHD的严重性。但是感应的途径和依据的机制 丁酸酯和色氨酸代谢物吲哚-3-乙醛介导的GVHD的作用仍然存在 未知。因此，在此提案中，我们将基于这些令人兴奋和新颖的初步 观察并汇集微生物群，代谢组学的各种领域 生物能力和表观遗传学，以探索微生物代谢物及其它们的相互作用 IEC在减少GI GVHD时对IEC的表观基因组改变的影响。具体来说，我们将测试 内源性肠道靶组织（IEC）耐药性调节的中心前提 微生物代谢物丁酸酯和色氨酸代谢物吲哚-3-乙醛，改变 IEC的乙酰化依赖性表观组，并对GIGVHD进行负调节。