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

基本信息

批准号：
9337421
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
项目类别：
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/9337421
关键词：
Acetaldehyde Acetylation Adverse effects Affect Allogeneic Bone Marrow Transplantation Allogenic Alpha Cell 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 Hematologic Neoplasms Hematopoietic Stem Cell Transplantation Histone Acetylation Histone Deacetylase Inhibitor Homeostasis Human Hypersensitivity Immune Immunity Indoles Infection Inflammatory Intestines Link Liver Malignant - descriptor Malignant neoplasm of gastrointestinal tract Mediating Metabolic Microbe Modality Modification Molecular Pathway interactions Patients Pattern Recognition Pattern recognition receptor Peripheral Play Prevention trial Proteins Receptor Signaling Regulation Regulatory T-Lymphocyte Research Personnel Resistance Role Severities Severity of illness Skin T-Lymphocyte Testing Tissues Transcriptional Regulation Translating Treatment Efficacy Tryptophan Volatile Fatty Acids chromatin modification curative treatments cytokine epigenetic regulation epigenome epigenomics gastrointestinal gastrointestinal epithelium graft vs host disease immunoreaction improved insight intestinal homeostasis leukemia member metabolic profile metabolomics microbial microbiome microbiota novel public health relevance receptor resistance mechanism response sensor solute

项目摘要

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人的潜在治疗方法恶性疾病，其适用性因其大多数疾病的发展而受到阻碍严重并发症，移植物抗宿主病（GVHD）。 GVHD 是由损伤引起的由许多免疫细胞和炎症细胞因子对宿主上皮细胞靶标引起的。虽然在理解各种免疫的复杂作用方面正在取得重大进展细胞引起 GVHD 的过程中，人们对靶组织本身在 GVHD 中所起的作用知之甚少。调节疾病的严重程度。具体而言，宿主肠上皮细胞（IEC）的诱导同种异体反应性供体 T 细胞和炎症细胞因子导致胃肠道细胞凋亡 (GI) 移植物抗宿主病；然而，宿主 IEC 对同种免疫 T 细胞介导的内在抵抗机制损伤，对于这些抵抗机制至关重要的表观遗传机制及其组织驻留微生物群产生的代谢物的调节从未被探索过。国际电工委员会稳态和抵抗力取决于代谢能量之间复杂的相互作用底物（如短链脂肪酸和氨基酸代谢物）和调节转录和表观遗传染色质修饰，例如组蛋白乙酰化。我们有证明通过全身施用组蛋白脱乙酰酶进行表观遗传调控抑制剂（HDACi）调节实验性 GVHD 并成功地将这一概念转化为预防临床 GVHD 的原理人体试验证明。生成初步数据证明源自微生物代谢物的底物发生显着变化例如必需短链脂肪酸 (SCFA) 和氨基酸代谢物，特别是在胃肠道 (IEC) 中的丁酸盐和色氨酸代谢物吲哚-3-乙醛 (I-3-A) 水平同种异体 BMT 后。初步数据还表明，(a) 丁酸盐（一种已知的 HDACi）可增强组蛋白乙酰化，调节 IECs 对损伤的抵抗力并调节 GVHD (b) 表达芳烃受体 (AhR)（色氨酸代谢物吲哚-3-乙醛的传感器）减轻 GVHD 的严重程度。但传感途径和潜在机制丁酸和色氨酸代谢物吲哚-3-乙醛介导的 GVHD 效应仍然存在未知。因此，在本提案中，我们将建立在这些令人兴奋且新颖的初步基础上观察并将微生物群、代谢组学、组织等不同领域结合在一起生物能量学和表观遗传学，探索微生物代谢物及其代谢物之间的相互作用 IEC 表观基因组改变对减少 GI GVHD 的影响。具体来说，我们将测试中心前提是内源性肠道调节靶组织（IEC）抵抗力微生物代谢物丁酸和色氨酸代谢物吲哚-3-乙醛，改变 IECs 的乙酰化依赖性表观基因组并负向调节 GI GVHD。