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

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 异基因造血干细胞移植（alloHSCT）后的GvHD。具体而言， 趋化因子受体CCR 5迄今已在几项临床试验中进行了检测， 有希望的，显示急性GvHD的低发生率，而不增加复发风险或感染并发症。 然而，在一些患者中仍然发生预防失败，并且人类和小鼠的数据表明， 通过CXCR 3的信号传导充当抗性机制。双重CCR 5/CXCR 3阻断是一种潜在的 战略，但在同种异体反应性T细胞迁移趋化因子受体信号的详细了解， 首先需要。 我们建议研究CCR 5和CXCR 3在T细胞迁移到靶器官中的各自作用，以及CCR 5和CXCR 3在T细胞迁移到靶器官中的作用。 潜在封锁策略的影响。该提议的中心假设是CCR 5和CXCR 3是 同种异体反应性T细胞迁移中的互补途径，并且两种受体的联合阻断将 与单受体阻断剂相比，导致更大的抗GvHD保护。为了支持这一假设， 我们显示了初步的数据，表明表达CCR 5和CXCR 3的T细胞具有不同的功能特性。 GvHD中的细胞，CXCR 3作为对CCR 5阻断的抗性机制起作用的证据， CCR 5和CXCR 3配体通过STAT 3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和临床数据和167例患者的生物标本 参加了3项临床试验，以检查GvHD中CCR 5和CXCR 3之间的关系。在目标1中，我们 确定alloHSCT受者对CCR 5阻断的耐药机制，并确定CCR 5阻断的新作用。 调节剂调节趋化因子受体在GvHD中的作用。在目标2中，我们将确定 CCR 5和CXCR 3在组织浸润同种异体反应性T细胞中的互补作用 在小鼠和人类中的方法学。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CCR 5/CXCR 3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。这种平移 这项研究将推动我们对GvHD中T细胞迁移的机制的理解，并使我们能够开发一种 联合受体阻滞剂的策略。

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.