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

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.

项目总结： 移植物抗宿主病(GVHD)是异基因造血术后常见的严重并发症。 细胞移植(AllHCT)，而密切相关的移植物抗白血病/淋巴瘤(GVL)效应至关重要 了解异基因血细胞移植对血癌患者的疗效。β介导的肾上腺素能应激信号转导 肾上腺素能受体激动剂，如去甲肾上腺素，被认为既影响先天的，也影响适应性的 豁免权。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，即 β2-AR介导同种异体红细胞移植期间的应激反应。利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预后有显著影响 异型红细胞压积。特别是，我们的发现显示，β2-AR信号的激动性刺激显著减少 阻断β2-AR信号时，移植物抗宿主病显著增加。此外，操纵内生性 通过将小鼠暴露在生理应激(即轻微的冷应激)中，去甲肾上腺素的水平概括了 通过使用药理学β2-AR激动剂获得的结果。重要的是，我们的发现进一步表明 操纵β2-AR信号可能是一种可行的策略，以缓解移植物抗宿主病而不牺牲所需的 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反应通过调节供体来源的T细胞的功能。在这个项目中，我们将研究异体HCT 患者和小鼠模型追求三个目标。目标1将检测同种异体红细胞移植患者的去甲肾上腺素水平 患者是影响临床结果的一个潜在因素。我们将对大约200名身份不明的患者进行研究 分析β-肾上腺素能信号水平与包括移植物抗宿主病在内的临床结局的关系 发病率、严重程度和癌症复发。AIM 2将评估操纵β-AR的治疗潜力 调节GVH和GVL反应的信号。我们最近建立了一个异种移植系统。 以人源化NSG小鼠为宿主，检测人免疫细胞的GVH和GVL功能。我们会 使用这个新的转换平台来评估操纵β-AR信令对GVH和GVL的影响 人T细胞的活性。Aim 3将探索β2-AR信号影响T细胞依赖的机制 GVH和GVL反应。我们将使用β2-AR缺陷小鼠作为供体来确定β2-AR信号转导途径 影响已知的主要T细胞亚群的功能，这些T细胞亚群决定移植物抗宿主病的发生和严重程度并调节 良好的GVL效应。总而言之，这个项目不仅将提高我们对基础生物学的理解 但这也可能有助于解释为什么患者自然表现出截然不同的应激反应， 在患移植物抗宿主病或癌症缓解方面差异如此之大。此外，这项研究可能会导致 基于对β2-AR信号的操纵来预防高血压的全新治疗原理 GVHD和保存有益的GVL效应。