Development of a Novel Strategy to Prevent Experimental GVHD

预防实验性 GVHD 的新策略的开发

• 批准号: 8096577
• 负责人: PAVAN REDDY
• 金额: $ 14.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/8096577
• 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; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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, GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality to treat many patients with hematological cancers.

描述（由申请人提供）：抗原呈递细胞（APC）在同种异体骨髓移植（BMT）后诱导移植物抗宿主（GVHD）/白血病（GVL）反应中发挥关键作用。因此，调节树突状细胞 (DC)（最有效的 APC）功能的药物可能在 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)，在许多生物过程中发挥着关键作用。 HDAC 抑制剂 (HDACi) 已被开发为抗肿瘤药物，在人体临床试验中似乎具有良好的耐受性；但迄今为止，它们的免疫调节作用基本上未被认识到。我们生成的数据表明，HDACi 部分通过诱导宿主 DC 中的免疫抑制酶吲哚胺 2, 3 双加氧酶 (IDO) 来调节实验性急性 GVHD。这些令人兴奋的临床前实验数据构成了我们机构开发概念验证临床试验的基本原理（IRB 批准号#2001.0234），该试验将测试 HDAC 抑制在预防急性 GVHD 中的效果。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 HDACi 的 DC 抑制作用至关重要。数据还显示 HDAC-1 酶与 DC 中的 STAT-3 相互作用。在这项提案中，我们将基于我们对小鼠模型和健康人类捐赠者细胞的令人兴奋的已发表和未发表的观察结果。我们将测试中心假设，即非组蛋白 STAT-3 的乙酰化对于 HDACi 治疗后 DC 和实验性 GVHD 的负调节至关重要。具体目标(SA)如下： 具体目标(SA) 1：确定对于STAT-3乙酰化和HDACi调节DC功能至关重要的特定HDAC酶。在这个具体目标中，我们将测试以下假设：HDAC 酶 1 对于 STAT-3 乙酰化以及 DC 的先天和同种异体刺激功能的调节至关重要。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 乙酰化 STAT-3 对于抑制 DC 和实验性 GVHD 至关重要的假设。 公共健康相关性：同种异体造血干细胞移植是许多恶性疾病的潜在治疗方法，但其适用性因其最严重的并发症 GVHD 的发展而受到阻碍。减轻 GVHD 的策略将允许更好地利用这种有效的治疗方式来治疗许多血液癌症患者。