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: 10206244
• 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/10206244
• 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; 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/antagonist; 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一种有前途的策略 (GvHD) 异基因造血干细胞移植 (alloHSCT) 后。具体来说，封锁 趋化因子受体CCR5迄今为止已在多项临床试验中进行了检查，并出现了临床结果 前景乐观，表明急性 GvHD 发生率较低，且不会增加复发风险或感染并发症。 然而，一些患者仍然出现预防失败的情况，人类和小鼠的数据表明 通过 CXCR3 的信号传导充当耐药机制。双 CCR5/CXCR3 阻断是一种潜在的 策略，但对同种反应性 T 细胞迁移中趋化因子受体信号传导的详细了解 首先需要。 我们建议研究 CCR5 和 CXCR3 在 T 细胞迁移至靶器官中的各自作用以及 潜在阻止策略的影响。该提案的中心假设是 CCR5 和 CXCR3 是 同种异体反应性 T 细胞迁移中的互补途径以及两种受体的联合阻断将 与单受体阻断相比，可以更好地预防 GvHD。为了支持这一假设， 我们展示了初步数据，证明了表达 CCR5 和 CXCR3 的 T-的不同功能特性 GvHD 中的细胞、CXCR3 作为 CCR5 阻断抵抗机制的证据和证据 CCR5 和 CXCR3 配体通过 STAT3 激活 T 细胞，而与它们对 T 细胞导航的影响无关。 为了验证这一假设，我们将使用小鼠模型以及来自 167 名患者的临床数据和生物样本 参加了 3 项临床试验，以检查 CCR5 和 CXCR3 在 GvHD 中的关系。在目标 1 中，我们将 确定 alloHSCT 受者对 CCR5 阻断的耐药机制，并确定其新作用 调节剂在 GvHD 中调节趋化因子受体的作用。在目标 2 中，我们将确定 使用新型单细胞研究 CCR5 和 CXCR3 在组织浸润同种反应性 T 细胞中的互补作用 小鼠和人类的方法。这项技术将使我们能够评估额外的潜在作用 趋化因子受体和归巢分子。目标 3 将检查 CCR5/CXCR3 双重阻断的影响 小鼠模型中移植物抗宿主和移植物抗白血病反应的方法。这个翻译 这项研究将加深我们对 GvHD 中 T 细胞迁移机制的理解，并促进开发 人类联合受体阻断策略。