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: 9178850
• 负责人: Xuefang Cao
• 金额: $ 24.59万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178850
• 关键词: Adrenergic Agents; Adrenergic Agonists; Affect; Allogenic; Biological Preservation; Biology; Blood; Cancer Patient; Cancer Relapse; Cancer Remission; Cells; Clinical; Clinical Trials; Complication; Development; Effectiveness; Exhibits; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Neoplasms; Human; Human Activities; Immune; Immune System Diseases; Incidence; Infection; Lead; Measures; Mediating; Mus; Natural Immunity; Norepinephrine; Outcome; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; 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; 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）是异基因造血干细胞移植后常见而严重的并发症 细胞移植（alloHCT），而密切相关的移植物抗白血病/淋巴瘤（GVL）效应至关重要 alloHCT对血癌患者的有效性。β-肾上腺素介导的肾上腺素能应激信号传导 肾上腺素能受体（AR）激动剂如去甲肾上腺素被认为影响先天性和适应性两者 免疫力基于我们最近发表的工作，本研究的目标是探索一种新的范式， β2-AR介导alloHCT的应激反应。使用已建立的小鼠模型，我们发现， β2-AR信号的药理学或生理学操作对治疗结果有显著影响， alloHCT。特别地，我们的研究结果表明，激动性刺激β2-AR信号显著降低 阻断β2-AR信号可显著增加GVHD。此外，操纵内源性 通过将小鼠暴露于生理应激（即轻度冷应激）， 通过使用药理学β2-AR激动剂获得的结果。重要的是，我们的研究结果进一步表明， 操纵β2-AR信号可能是一种可行的策略，以减轻GVHD，而不牺牲所需的 GVL效应。基于这些发现，我们推测应激诱导的β2-AR信号可能控制GVH 和GVL应答。在本项目中，我们将研究alloHCT， 患者和小鼠模型追求三个目标。目的1将检查alloHCT中的去甲肾上腺素血液水平 患者是影响临床结局的潜在因素。我们将研究约200名去身份化患者， 分析β-肾上腺素能信号水平与包括GVHD在内的临床结局之间的关系 发病率、严重程度和癌症复发。目的2：探讨β-AR的治疗潜力 信号传导以调节GVH和GVL应答。我们最近建立了一个异种移植系统 使用人源化NSG小鼠作为宿主来检测人免疫细胞的GVH和GVL功能。我们将 使用这个新的翻译平台来评估操纵β-AR信号对GVH和GVL的影响， 人T细胞的活性。目的3将探讨β2-AR信号影响T细胞依赖性机制 GVH和GVL应答。我们将使用β2-AR缺陷小鼠作为供体，以确定β2-AR信号传导如何影响小鼠的免疫功能。 影响主要T细胞亚群的功能，已知其决定GVHD的发作和严重程度，并介导 有利的GVL效应。总之，这个项目不仅会提高我们对基础生物学的理解， 但它也可能有助于解释为什么自然表现出广泛不同应激反应的患者， 在GVHD或癌症缓解的发展方面差异如此之大。此外，这项研究可能会导致 一个全新的治疗原理，基于β2-AR信号的操纵，用于预防 GVHD和有益GVL效应的保留。