Development of a Novel Strategy to Prevent Experimental GVHD

预防实验性 GVHD 的新策略的开发

基本信息

批准号：
8247111
负责人：
PAVAN REDDY
金额：
$ 14.97万
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：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8247111
关键词：
Acetylation Acute Graft Versus Host Disease Adverse effects Aftercare Allogeneic Bone Marrow Transplantation Allogenic Animal Model Antigen-Presenting Cells Area Biological Process Biology Bone Marrow Transplantation Cell model Cell physiology Cells ChIP-seq Clinical Clinical Trials Complement Complication Data Dendritic Cells Development Dioxygenases Disease Enzymes Epigenetic Process Evaluation Future Hematopoietic Stem Cell Transplantation Histone Deacetylase Inhibitor Histones Human Human Volunteers Immune response Institution Institutional Review Boards Lead Lysine Malignant - descriptor Malignant Neoplasms Modality Modification Molecular Mus Pathway interactions Patients Play Pre-Clinical Model Prevention Process Protein Acetylation Proteins Publishing Regulation Role STAT protein Sampling Series Technology Testing Therapeutic Translations antitumor agent bench to bedside genetic regulatory protein graft vs host disease improved in vivo indoleamine inhibitor/antagonist insight leukemia macrophage novel novel strategies pre-clinical prevent public health relevance response

项目摘要

ABSTRACT Antigen presenting cells (APCs) play a critical role in the induction of graft-versus-host (GVHD)/ leukemia (GVL) responses after allogeneic bone marrow transplantation (BMT). Therefore agents that regulate the functions of dendritic cells (DCs), the most potent APCs, might have therapeutic potential in GVH processes. Protein lysine deacetylases, traditionally referred to as histone deacetylases (HDAC) play a pivotal role many biological processes. HDAC inhibitors (HDACi) have been developed as anti-tumor agents and they appear to be well tolerated in human clinical trials; but their immuno-modulatory effects have heretofore been largely unrecognized. Data generated by us demonstrate that HDACi regulate experimental acute GVHD partly through induction of the immuno-suppressive enzyme indoleamine 2, 3 dioxygenase (IDO) in host DCs. These exciting pre-clinical experimental data formed the rationale for the development of a proof of concept clinical trial at our institution ((IRB Approval # 2001.0234), which will test the effects of HDAC inhibition in prevention of acute GVHD. However, the precise molecular mechanisms remain unknown. Preliminary data demonstrate that acetylation of non-histone immuno-regulatory protein, STAT-3, in DCs is critical for the DC suppressive effects of HDACi. Data also show that HDAC-1 enzyme interacts with STAT-3 in DCs. In this proposal we will build on our exciting published and unpublished observations from both murine models and cells from healthy human donors. We will test the central hypothesis that acetylation of the non-histone protein, STAT-3, is critical for the negative regulation of DCs and experimental GVHD after treatment with HDACi. The specific aims (SA) are as follows: Specific Aim (SA) 1: To determine the specific HDAC enzyme critical for acetylation of STAT-3 and regulation of DC function by the HDACi. In this specific aim we will test the hypothesis that HDAC enzyme 1 is critical for STAT-3 acetylation and regulation of the innate and allo-stimulatory functions of DCs. Specific Aim (SA) 2: To elucidate the critical role of STAT-3 in regulation of DCs and GVHD by HDACi. In this specific aim we will explore the hypothesis that acetylation of STAT-3 by HDACi is critical for suppression of DCs and experimental GVHD.

抽象的抗原呈递细胞 (APC) 在诱导移植物抗宿主 (GVHD)/白血病中发挥关键作用同种异体骨髓移植（BMT）后（GVL）反应。因此调节剂树突状细胞 (DC) 是最有效的 APC，其功能可能在 GVH 过程中具有治疗潜力。蛋白质赖氨酸脱乙酰酶，传统上称为组蛋白脱乙酰酶 (HDAC)，在许多生物过程。 HDAC 抑制剂 (HDACi) 已被开发为抗肿瘤药物，并且它们似乎在人体临床试验中具有良好的耐受性；但迄今为止，它们的免疫调节作用在很大程度上是不被认可。我们生成的数据表明 HDACi 部分调节实验性急性 GVHD 通过在宿主 DC 中诱导免疫抑制酶吲哚胺 2, 3 双加氧酶 (IDO)。这些令人兴奋的临床前实验数据构成了开发概念验证临床的基本原理在我们机构进行的试验（（IRB 批准号#2001.0234），将测试 HDAC 抑制在预防急性GVHD。然而，确切的分子机制仍然未知。初步数据表明 DC 中非组蛋白免疫调节蛋白 STAT-3 的乙酰化对于 DC 抑制至关重要 HDACi 的影响。数据还显示 HDAC-1 酶与 DC 中的 STAT-3 相互作用。在本提案中，我们将基于我们对小鼠模型和健康细胞的令人兴奋的已发表和未发表的观察结果人类捐赠者。我们将检验中心假设，即非组蛋白 STAT-3 的乙酰化至关重要 HDACi 处理后 DC 和实验性 GVHD 的负调节。具体目标（SA）如下：具体目标 (SA) 1：确定对 STAT-3 乙酰化和调节至关重要的特定 HDAC 酶 HDACi 的 DC 功能。在这个具体目标中，我们将测试 HDAC 酶 1 对于 STAT-3 乙酰化至关重要的假设，并且 DC 的先天和同种刺激功能的调节。具体目标 (SA) 2：阐明 STAT-3 在 HDACi 调节 DC 和 GVHD 中的关键作用。在这个具体目标中，我们将探讨 HDACi 对 STAT-3 的乙酰化对于抑制 DC 和实验性 GVHD。