Plerixafor for allogeneic hematopoietic stem cell transplantation

描述(由申请人提供)：造血细胞移植(HCT)为多种疾病提供了一种潜在的治愈方法。然而，移植相关死亡率、移植物衰竭和移植物抗宿主病(GvHD)的高发生率使HCT变得复杂。基质衍生因子-1(SDF-1)与CXCR4趋化因子受体的相互作用在造血干细胞归巢和植入过程中起着不可或缺的作用。我们推测，阻断SDF-1/CXCR4与特定CXCR4拮抗剂的相互作用将选择性地促进异基因HCT中供体细胞的重建。Plerixafor是一种高度特异性和可逆性的CXCR4拮抗剂，将用于本研究。我们最近在小鼠同基因移植模型中的研究表明，移植后给予Plerixa可显著提高动物存活率，并选择性地增强供体细胞的植入。这种对供体细胞重建的选择性增强是普利沙福动员残留的受体干细胞和供体干细胞的选择性存活优势共同作用的结果。这项建议的目标是进行关键的翻译研究，以使我们的研究在该奖项结束时进入I/II期临床试验，并进一步剖析plerixafor的机制和CXCR4信号的调节。我们有两个具体目标。我们的目标1是研究plerixafor在几种与临床应用直接相关的同种异体小鼠移植模型中促进供体细胞植入的有效性。我们的目标2是进一步剖析plerixafor促进供体细胞重建的机制，并了解CXCR4信号的调节。这些目标的成功实现将对HCT产生重要影响，并将使HCT患者受益。此外，我们的研究将为CXCR4在造血干细胞归巢、动员和扩增中的作用以及CXCR4信号的调控提供新的线索。

DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) provides a potentially curative treatment for a wide variety of diseases. HCT, however, is complicated by high incidence of transplant-related mortality, graft failure and graft versus host disease (GvHD). The interaction of stromal derived factor-1 (SDF-1) with CXCR4 chemokine receptor plays an indispensable role in hematopoietic stem cell homing and engraftment. We hypothesize that blocking the SDF-1/CXCR4 interaction with a specific CXCR4 antagonist would selectively enhance donor cell reconstitution in allogeneic HCT. Plerixafor is a highly specific and reversible antagonist of CXCR4 and will be used in the current study. Our recent studies in a congeneic mouse transplant model demonstrated that post-transplant administration of plerixafor significantly improved animal survival and selectively enhanced donor cell engraftment. This selective enhancement of donor cell reconstitution results from combined effects of mobilization of residual recipient stem cells by plerixafor and selective survival advantage of donor stem cells. The objectives of this proposal are to perform pivotal translational studies to move our study into a phase I/II clinical trial at the end of this award and to further dissect the mechanisms of plerixafor and the regulation of CXCR4 signaling. We have 2 specific aims. Our Aim 1 is to investigate the efficacy of plerixafor in enhancing donor cell engraftment in several allogeneic mouse transplant models that are directly relevant to clinical applications. Our Aim 2 is to further dissect the mechanisms through which plerixafor enhances donor cell reconstitution and to understand the regulation of CXCR4 signaling. Successful accomplishment of these aims will have important implications in HCT and will benefit patients with HCT. Furthermore, our study will shed new lights into the role of CXCR4 in hematopoietic stem cell homing, mobilization and expansion, as well as the regulation of CXCR4 signaling.