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后发生移植物抗宿主病(GVHD)。具体地说，封锁 到目前为止，趋化因子受体CCR5已经在几个临床试验中进行了检测，并出现了临床结果 前景看好，显示急性移植物抗宿主病发生率低，复发风险或感染性并发症没有增加。 然而，在一些患者中仍然发生了预防失败，人类和小鼠的数据表明 通过CXCR3的信号转导是一种抗性机制。双重CCR5/CXCR3封锁是潜在的 策略，但对趋化因子受体信号在同种异体反应性T细胞迁移中的详细理解是 首先需要的是。 我们建议研究CCR5和CXCR3在T细胞迁移到靶器官中的单独作用以及 潜在拦截策略的影响。这一提议的中心假设是CCR5和CXCR3是 同种异体反应性T细胞迁移的互补途径以及两种受体的联合阻断将 与单一受体阻断相比，对GvHD的保护作用更强。为了支持这一假设， 我们展示了初步的数据，显示了CCR5和CXCR3表达的T- GvHD中的细胞，CXCR3作为CCR5阻断的抵抗机制的证据和证据 CCR5和CXCR3配体通过STAT3激活T细胞，而不依赖于它们对T细胞导航的影响。 为了验证这一假设，我们将使用小鼠模型、临床数据和167名患者的生物标本。 纳入3项临床试验，以检验CCR5和CXCR3在GvHD中的关系。在目标1中，我们将 确定异基因造血干细胞移植受者对CCR5阻断的抵抗机制并确定其新的作用 调节趋化因子受体在移植物抗宿主病中作用的调节剂。在目标2中，我们将确定 CCR5和CXCR3在组织浸润性同种异体反应性T细胞中的互补作用 在老鼠和人类身上的方法学。这项技术将使我们能够评估额外的 趋化因子受体和归巢分子。AIM 3将研究双重CCR5/CXCR3封锁的影响 小鼠模型移植物抗宿主和移植物抗白血病反应的探讨。此翻译 研究将促进我们对GvHD中T细胞迁移的机制的理解，并使 人类的联合受体阻断策略。

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.