Effector T-cell trafficking in graft-versus-host disease

移植物抗宿主病中的效应 T 细胞运输

• 批准号: 10443805
• 负责人: Ran Reshef
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443805
• 关键词: Acute Graft Versus Host Disease; Affect; Allogenic; Busulfan; CCR5 gene; CXC chemokine receptor 3; CXCR3 gene; Cell Migration Pathway; Cells; Chemotaxis; Clinical; Clinical Data; Clinical Trials; Data; Data Set; Development; Disease; Disease model; Enrollment; Environment; Failure; Gastrointestinal tract structure; Genetic; Genomics; Goals; Hematopoietic Stem Cell Transplantation; Homing; Human; Immune response; Immunologic Memory; Immunologics; In Situ; Individual; Infection; Inflammatory; Investigation; Knock-out; Knowledge; Lead; Ligands; Lymphocyte; Mediating; Melphalan; Memory; Methodology; Modeling; Morbidity - disease rate; Multicenter Trials; Mus; Organ; Outcome; PPBP gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phenotype; Prevention; Prevention strategy; Property; Prophylactic treatment; Receptor Signaling; Recurrent disease; Regimen; Resistance; Role; STAT3 gene; Serum; Shapes; Side; Signal Transduction; Stem cell transplant; T memory cell; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Transplant Recipients; Transplantation; Transplantation Conditioning; antagonist; base; cell motility; chemokine; chemokine receptor; clinically relevant; conditioning; effector T cell; experimental study; genomic data; graft vs host disease; graft vs leukemia effect; inflammatory milieu; inhibitor; migration; mortality; mouse model; novel; novel strategies; pre-clinical; prevent; protective effect; receptor; relapse risk; resistance mechanism; response; single cell analysis; single cell technology; success; therapeutic target; therapy resistant; trafficking; translational approach; translational study

Project Abstract Blockade of lymphocyte chemotaxis is a promising strategy for the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem-cell transplantation (alloHSCT). Specifically, blockade of the chemokine receptor CCR5 has so far been examined in several clinical trials and clinical results appear promising, showing low rates of acute GvHD without an increase in relapse risk or infectious complications. However, prophylaxis failure still occurred in some patients and data in humans and murine suggest that signaling through CXCR3 serves as a resistance mechanism. Dual CCR5/CXCR3 blockade is a potential strategy, but a detailed understanding of chemokine receptor signaling in alloreactive T-cell migration is needed first. We propose to study the individual roles of CCR5 and CXCR3 in T-cell migration into target organs and the impact of potential blocking strategies. The central hypothesis of this proposal is that CCR5 and CXCR3 are complementary pathways in alloreactive T-cell migration and that combined blockade of both receptors will lead to greater protection against GvHD compared to single-receptor blockade. In support of this hypothesis, we show preliminary data that demonstrate distinct functional properties for CCR5-and CXCR3-expressing T- cells in GvHD, evidence for CXCR3 operating as a resistance mechanism to CCR5 blockade and evidence that CCR5 and CXCR3 ligands activate T-cells through STAT3 independent of their effect on T-cell navigation. To test this hypothesis, we will use murine models and clinical data and biospecimens from 167 patients enrolled on 3 clinical trials to examine the relationship between CCR5 and CXCR3 in GvHD. In Aim 1, we will identify the resistance mechanisms to CCR5 blockade in alloHSCT recipients and identify a novel role for conditioning agents in modulating the role of chemokine receptors in GvHD. In Aim 2, we will determine the complementary roles of CCR5 and CXCR3 in tissue-infiltrating alloreactive T-cells using a novel single-cell methodology in mice and humans. This technology will allow us to assess the potential role of additional chemokine receptors and homing molecules. Aim 3 will examine the impact of dual CCR5/CXCR3 blockade approach on the graft-versus-host and graft-versus-leukemia responses in mouse models. This translational study will fuel our mechanistic understanding of T-cell migration in GvHD, and enable the development of a strategy of combined receptor blockade in humans.

项目摘要 阻断淋巴细胞趋化性是预防移植物抗宿主病的有前途的策略 （GVHD）同种异性造血干细胞移植（alloHSCT）。具体而言，封锁 到目前为止，趋化因子受体CCR5已在几项临床试验中进行了检查，并且出现临床结果 有希望的，显示出较低的急性GVHD发生率，而没有增加复发风险或感染并发症。 但是，某些患者仍然发生预防衰竭，人类和鼠的数据表明 通过CXCR3发出信号是一种电阻机制。双CCR5/cxcr3封锁是潜在的 策略，但是对同种异体T细胞迁移中趋化因子受体信号传导的详细理解是 首先需要。 我们建议研究CCR5和CXCR3在T细胞迁移到目标器官以及 潜在阻止策略的影响。该提议的中心假设是CCR5和CXCR3是 同种反应性T细胞迁移中的互补途径和两个受体的结合封锁将 与单受体阻滞相比，对GVHD的保护更大。为了支持这一假设， 我们显示的初步数据显示了表达CCR5和CXCR3的T-的不同功能特性 GVHD中的细胞，CXCR3作为CCR5阻滞和证据的抗性机制的证据 该CCR5和CXCR3配体通过STAT3激活T细胞，独立其对T细胞导航的影响。 为了检验这一假设，我们将使用167名患者的鼠模型和临床数据和生物测量 参加了3项临床试验，以检查GVHD中CCR5和CXCR3之间的关系。在AIM 1中，我们将 识别AlloHSCT受体中CCR5阻断的阻力机制，并确定新的作用 调节剂在调节GVHD中趋化因子受体的作用方面。在AIM 2中，我们将确定 CCR5和CXCR3使用新型的单细胞的互补作用 小鼠和人类的方法论。这项技术将使我们能够评估附加的潜在作用 趋化因子受体和归巢分子。 AIM 3将检查双CCR5/CXCR3封锁的影响 在小鼠模型中的移植物抗宿主和移植物 - 抗逆转录线虫反应上。这种翻译 研究将促进我们对GVHD中T细胞迁移的机械理解，并使A的发展 人类组合受体阻滞的策略。