Plerixafor for allogeneic hematopoietic stem cell transplantation

描述（由申请人提供）：造血细胞移植（HCT）为多种疾病提供了潜在的治愈性治疗。然而，HCT由于移植相关死亡率、移植物衰竭和移植物抗宿主病（GvHD）的高发生率而变得复杂。基质衍生因子-1（SDF-1）与趋化因子受体CXCR 4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。我们假设，用特异性CXCR 4拮抗剂阻断SDF-1/CXCR 4相互作用将选择性地增强同种异体HCT中供体细胞的重建。普乐沙福是一种高度特异性的可逆性CXCR 4拮抗剂，将用于本研究。我们最近在同种小鼠移植模型中的研究表明，移植后给予普乐沙福可显著改善动物存活率，并选择性增强供体细胞植入。这种供体细胞重建的选择性增强是普乐沙福动员残余受体干细胞和供体干细胞选择性存活优势的综合作用的结果。本提案的目的是进行关键转化研究，以便在本奖项结束时将我们的研究转入I/II期临床试验，并进一步剖析普乐沙福的机制和CXCR 4信号转导的调控。我们有两个具体目标。我们的目的1是研究普乐沙福在几种与临床应用直接相关的同种异体小鼠移植模型中增强供体细胞植入的疗效。我们的目标2是进一步剖析plerixafor增强供体细胞重建的机制，并了解CXCR 4信号转导的调控。这些目标的成功实现将对HCT具有重要意义，并将使HCT患者受益。此外，我们的研究将为CXCR 4在造血干细胞归巢、动员和扩增中的作用以及CXCR 4信号转导的调节提供新的线索。

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.