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.

项目概要： 移植物抗宿主病（GVHD）是异基因造血后常见且严重的并发症 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 对血癌患者通过 β- 介导的肾上腺素能应激信号的有效性。 去甲肾上腺素等肾上腺素受体 (AR) 激动剂被认为会影响先天性和适应性 基于我们最近发表的工作，本研究的目标是探索一种关于免疫的新范式。 使用已建立的小鼠模型，我们发现 β2-AR 在 alloHCT 期间介导应激反应。 β2-AR 信号传导的药理学或生理学操作对结果有显着影响 特别是，我们的研究结果表明 β2-AR 信号传导的激动性刺激显着减少。 此外，阻断β2-AR信号传导可显着增加GVHD，此外，操纵内源性也可显着增加GVHD。 通过将小鼠暴露在生理应激（即轻度冷应激）下，去甲肾上腺素水平概括了 通过使用药理学 β2-AR 激动剂获得的结果重要的是，我们的研究结果进一步表明： 操纵β2-AR信号传导可能是减轻GVHD而不牺牲所需效果的可行策略 基于这些发现，我们发现应激诱导的 β2-AR 信号传导可能控制 GVH。 在这个项目中，我们将研究 alloHCT。 目标 1 将检查 alloHCT 中的去甲肾上腺素血液水平。 我们将研究约 200 名身份不明的患者，以了解其作为影响临床结果的潜在因素。 分析 β-肾上腺素能信号水平与临床结果（包括 GVHD）之间的关系 目标 2 将评估操纵 β-AR 的治疗潜力。 我们最近建立了异种移植系统。 我们将使用人源化 NSG 小鼠作为宿主来检查人类免疫细胞的 GVH 和 GVL 功能。 使用这个新的翻译平台来评估操纵 β-AR 信号传导对 GVH 和 GVL 的影响 目标 3 将探索 β2-AR 信号传导影响的 T 细胞依赖性机制。 我们将使用 β2-AR 缺陷小鼠作为供体来确定 β2-AR 信号传导如何。 影响已知决定 GVHD 的发作和严重程度并介导的主要 T 细胞亚群的功能 总而言之，这个项目不仅会提高我们对基础生物学的理解。 alloHCT 的研究，但它也可能有助于解释为什么自然表现出截然不同的应激反应的患者， 它们在 GVHD 或癌症缓解方面的差异如此之大，而且这项研究可能会导致。 基于β2-AR信号传导的全新治疗原理，用于预防 GVHD 和保留有益的 GVL 效应。