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

摘要： 异基因造血干细胞移植是一种潜在的治愈性疗法， 恶性疾病，其适用性已被其最严重的发展所阻碍， 严重并发症，移植物抗宿主病（GVHD）。移植物抗宿主病是由于 由许多免疫细胞和炎性细胞因子引起的对宿主上皮细胞的靶向。 虽然在理解各种免疫系统的复杂作用方面取得了重大进展， 尽管靶细胞在引起GVHD中起着重要作用，但对靶组织本身在GVHD中所起的作用知之甚少。 调节疾病的严重程度。具体地，诱导宿主肠上皮细胞（IEC） 同种异体反应性供体T细胞和炎性细胞因子引起的细胞凋亡引起胃肠道疾病， (GI)GVHD;然而，宿主IEC对同种免疫T细胞介导的固有抗性机制 损伤，对这些抗性机制至关重要的表观遗传机制及其 从未探索过由组织驻留微生物群落产生的代谢物的调节。IEC 体内平衡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，如组蛋白乙酰化。我们有 证明了通过全身给予组蛋白脱乙酰酶的表观遗传调节 抑制剂（HDACi）调节实验性GVHD，并成功地将这一概念转化为一种新的治疗方法。 用于预防临床GVHD的原理性人体试验的证明。生成的初步数据 证明微生物代谢产物产生的底物发生了显著变化 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）中丁酸盐和色氨酸代谢产物吲哚-3-乙醛（I-3-A）水平 在同种异体骨髓移植后初步数据还显示（a）丁酸盐，一种已知的HDACi，增强 组蛋白乙酰化，调节IEC对损伤的抗性并调节GVHD（B）表达 芳香烃受体（AhR）（色氨酸代谢产物吲哚-3-乙醛的传感器） 减轻GVHD严重程度。但是感知的途径和潜在的机制 丁酸和色氨酸代谢产物吲哚-3-乙醛介导的GVHD作用仍然存在 未知因此，在本提案中，我们将建立在这些令人兴奋和新颖的初步 观察，并将微生物群，代谢组学，组织 生物能量学和表观遗传学，探索微生物代谢产物及其 在减少GI GVHD中对IEC的表观基因组改变的影响。具体来说，我们将测试 核心前提是内源性肠上皮细胞调节靶组织（IEC）阻力 微生物代谢产物丁酸和色氨酸代谢产物吲哚-3-乙醛，改变 乙酰化依赖性表观基因组的IEC和负调节GI GVHD。

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.