Targeting Beta-Adrenergic Signaling to Control GVH and GVL Responses

靶向 β-肾上腺素能信号传导来控制 GVH 和 GVL 反应

• 批准号: 9315583
• 负责人: Xuefang Cao
• 金额: $ 7.4万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2017-10-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315583
• 关键词: Adrenergic Agents; Adrenergic beta-Agonists; Affect; Agonist; Allogenic; Biological Preservation; Biology; Blood; Cancer Patient; Cancer Relapse; Cancer Remission; Cells; Clinical; Clinical Trials; Complication; Development; Disease remission; Effectiveness; Exhibits; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Neoplasms; Human; Human Activities; Immune; Immune System Diseases; Incidence; Infection; Lead; Measures; Mediating; Mus; Natural Immunity; Neuroimmune; Norepinephrine; Outcome; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Physiological; Plasma; Prevention; Publishing; Receptor Signaling; Research; Severities; Shapes; Signal Pathway; Signal Transduction; Stress; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Work; Xenograft procedure; adaptive immunity; base; beta-2 Adrenergic Receptors; beta-adrenergic receptor; biological adaptation to stress; blood treatment; cancer therapy; clinically relevant; curative treatments; graft vs host disease; hematopoietic cell transplantation; improved; leukemia/lymphoma; mouse model; neoplastic cell; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; response; Adrenergic Agents; Adrenergic beta-Agonists; Affect; Agonist; Allogenic; Biological Preservation; Biology; Blood; Cancer Patient; Cancer Relapse; Cancer Remission; Cells; Clinical; Clinical Trials; Complication; Development; Disease remission; Effectiveness; Exhibits; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Neoplasms; Human; Human Activities; Immune; Immune System Diseases; Incidence; Infection; Lead; Measures; Mediating; Mus; Natural Immunity; Neuroimmune; Norepinephrine; Outcome; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Physiological; Plasma; Prevention; Publishing; Receptor Signaling; Research; Severities; Shapes; Signal Pathway; Signal Transduction; Stress; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Work; Xenograft procedure; adaptive immunity; base; beta-2 Adrenergic Receptors; beta-adrenergic receptor; biological adaptation to stress; blood treatment; cancer therapy; clinically relevant; curative treatments; graft vs host disease; hematopoietic cell transplantation; improved; leukemia/lymphoma; mouse model; neoplastic cell; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; response

Project Summary: Graft-versus-host disease (GVHD) is a common and serious complication after allogeneic hematopoietic cell transplantation (alloHCT), while the closely related graft-versus-leukemia/lymphoma (GVL) effect is crucial for the effectiveness of alloHCT for blood cancer patients. Adrenergic stress signaling mediated through β- adrenergic receptor (AR) agonists such as norepinephrine is recognized to influence both innate and adaptive immunity. Based on our recently published work, the goal of this study is to explore a new paradigm regarding β2-AR mediated stress response during alloHCT. Using established murine models, we have discovered that pharmacologic or physiologic manipulation of β2-AR signaling exhibits a significant impact on the outcome of alloHCT. Specially, our findings show that agonistic stimulation of β2-AR signaling significantly decreased GVHD while blocking of β2-AR signaling significantly increased GVHD. In addition, manipulating endogenous levels of norepinephrine, by exposing mice to a physiological stress (i.e. mild cold stress) recapitulates the findings obtained by using pharmacologic β2-AR agonists. Importantly, our findings further suggest that manipulation of β2-AR signaling may be a feasible strategy to alleviate GVHD without sacrificing the desired GVL effect. Based on these findings, we hypothesize that stress-induced β2-AR signaling may control GVH and GVL responses via regulating the functions of donor-derived T cells. In this project, we will study alloHCT patients and murine models to pursue three aims. Aim 1 will examine norepinephrine blood levels in alloHCT patients as a potential factor influencing clinical outcomes. We will study about 200 de-identified patients to analyze the relationship between β-adrenergic signaling levels and clinical outcomes including GVHD incidence, severity and cancer relapse. Aim 2 will evaluate the therapeutic potential of manipulating β-AR signaling to modulate GVH and GVL responses. We have recently established a xenotransplantation system using humanized NSG mice as hosts to examine the GVH and GVL functions of human immune cells. We will use this new translational platform to evaluate the impact of manipulating β-AR signaling on the GVH and GVL activities of human T cells. Aim 3 will explore T cell-dependent mechanisms by which β2-AR signaling impacts GVH and GVL responses. We will use β2-AR deficient mice as donors to determine how β2-AR signaling affects the functions of major T cell subsets known to dictate the onset and severity of GVHD and to mediate the favorable GVL effect. In summary, this project will not only improve our understanding of the basic biology of alloHCT, but it may also help to explain why patients, who naturally exhibit widely differing stress responses, differ so widely in terms of their development of GVHD or cancer remission. Moreover, this research may lead to a completely new therapeutic rationale based upon manipulation of β2-AR signaling for the prevention of GVHD and preservation of the beneficial GVL effect.

项目摘要： 移植物抗宿主病（GVHD）是同种异体造血后常见而严重的并发症 细胞移植（AllOHCT），而密切相关的移植物 - 白血病/淋巴瘤（GVL）效应至关重要 为了使AllOHCT对血液癌患者的有效性。通过β-介导的肾上腺应激信号传导 肾上腺素等肾上腺激动剂（AR）激动剂被认为会影响先天性和适应性 免疫。基于我们最近发表的工作，这项研究的目的是探索有关的新范式 β2-ar介导的应激反应。使用已建立的鼠模型，我们发现 β2AR信号传导的药理学或生理操纵对结果具有重大影响 allohct。特别是，我们的发现表明β2-AR信号的激动刺激显着降低 GVHD在阻断β2-AR信号传导的同时显着增加了GVHD。另外，操纵内源性 去甲肾上腺素的水平，通过将小鼠暴露于身体压力（即轻度冷应激）概括 通过使用药理学β2-ar激动剂获得的发现。重要的是，我们的发现进一步表明 操纵β2-AR信号传导可能是减轻GVHD而不牺牲所需的可行策略 GVL效应。基于这些发现，我们假设应力诱导的β2-AR信号可能控制GVH 通过调节供体衍生的T细胞功能的GVL响应。在这个项目中，我们将学习allohct 患者和鼠模型追求三个目标。 AIM 1将检查AlloHCT中的去甲肾上腺素血液水平 患者是影响临床结果的潜在因素。我们将研究大约200名被识别的患者 分析β-肾上腺素能信号水平和包括GVHD在内的临床结果之间的关系 发病率，严重性和癌症缓解。 AIM 2将评估操纵β-AR的治疗潜力 信号调节GVH和GVL响应。我们最近建立了一个异种移植系统 使用人源化的NSG小鼠作为宿主检查人类免疫细胞的GVH和GVL功能。我们将 使用这个新的翻译平台评估操纵β-ar信号对GVH和GVL的影响 人类T细胞的活性。 AIM 3将探索T细胞依赖性机制，β2-AR信号传导影响 GVH和GVL响应。我们将使用β2-ar不足小鼠作为供体来确定β2-ar信号如何传导 影响主要T细胞子集的功能，已知可以决定GVHD的发作和严重程度并进行介导 有利的GVL效果。总而言之，该项目不仅会改善我们对基本生物学的理解 AlloHCT的含义，但它也可能有助于解释为什么自然暴露于广泛不同的压力反应的患者为什么 在GVHD或癌症缓解的发展方面，不同的是不同的。而且，这项研究可能会导致 基于对β2AR信号的操纵以预防的全新治疗原理 GVHD和有益GVL效应的保存。