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.

项目摘要： 移植物抗宿主病（GVHD）是同种异体造血后常见的浆液 细胞移植（AllOHCT），而密切相关的移植物 - 溶血/淋巴瘤（GVL）效应至关重要 对于血液癌患者的有效性。 肾上腺素等肾上腺素受体（AR）激动剂被认为会影响先天和自适应 豁免权。 β2-ar介导的应激反应在allohct期间使用已建立的鼠模型。 β2AR信号传导的药理学或生理操纵对结果具有重大影响 特别是我们的发现表明，β2AR的刺激显着降低 GVHD在阻断β2-AR信号的同时显着增加了GVHD。 去甲肾上腺素的水平，通过出口到生理胁迫（即轻度冷应激）的出口使您 通过使用药理学β2激动剂获得的发现。 操纵β2-ar信号传导可能是减轻GVHD而不牺牲所需的feastegy GVL效应。 通过调节供体衍生的T细胞的功能，我们将研究AlloHCT的响应。 患者和鼠模型追求三个目标。 作为影响临床结果的潜在因素。 分析β-肾上腺素能信号传导水平和包括GVHD在内的临床结果之间的关系 发病率，严重性和癌症复发将评估操纵β-ar的治疗潜力 向模块化GVH和GVL响应的信号。 使用人源化的NSG小鼠检查人类免疫细胞的GVH和GVL功能 使用这些新的翻译平台来评估操纵对GVH和GVL的影响 人类T细胞的活性3将探索β2-ar信号的T细胞端内机制 GVH和GVL反应。我们将使用β2-AR缺乏小鼠作为供体 影响主要T细胞子集的功能已知可以决定otd SevHD并进行中介 总结的GVL效果。 AlloHCT的属性，但它也可能有助于解释为什么自然表现出广泛差异压力反应的患者为什么 此外，在GVHD或癌症缓解的发展方面有很大不同。 基于对β2AR信号的操纵以预防的新型治疗原理 GVHD和有益GVL效应的保存。