Using donor pDC to optimize GvHD and GvL in allogeneic stem cell transplantation

这项研究的长期目标是提高异基因干细胞移植后患者的生存率 通过限制移植物抗宿主病（GvHD），同时维持供体的移植物抗白血病效应， 免疫细胞来自BMT CTN 0201临床试验的临床数据，在该试验中， 或MDS随机接受BM与G-CSF动员的造血干细胞同种异体移植，发现相同 比较两种移植物来源的总生存率，BM受体中慢性GvHD较少。接种者 在骨髓同种异体移植物中，浆细胞样树突状细胞数量较多的受者存活率更高 (pDC)与接受较少这些供体细胞的患者相比，令人惊讶的是， 在含有更多幼稚细胞的BM同种异体移植物的接受者中，观察到严重急性GvHD的发生率（但没有复发） 捐赠的T细胞我们最近发表的数据显示：1）高度纯化的供体pDC限制了小鼠中严重的GvHD， BMT通过促进供体调节性T细胞（Treg）的扩增，通过干扰素和IDO依赖性 与供体幼稚T细胞的信号传导; 2）普乐沙福，一种动员造血干细胞的CXCR 4拮抗剂， 也有效地动员pDC和幼稚T细胞。我们的总体假设是， 造血干细胞移植物有利地调节供体T细胞活化和供体T细胞增殖的位点。 免疫极化这种方法的临床转化受到在理解供体pDC如何 和T细胞相互作用以调节GvHD。首先，什么是最佳的移植来源或动员策略， 增强pDC限制严重GvHD的能力？第二，捐助者与非捐助者之间的互动性质是什么？ pDC和幼稚T细胞导致Treg活性增加？第三，移植物中的pDC是如何调节移植后 移植免疫包括移植物抗白血病GvL三个目标将检验我们的总体假设： 1.确定优化造血干细胞含量的采集方法， 供体pDC和幼稚T细胞的免疫活性。 2.为了测试供体干细胞移植物及其后代中的pDC前体如何在体内调节归巢， 以及allo-HSCT受体中效应T细胞和调节T细胞的同种异体反应性。 3.为了确定pDC含量和从移植物中收集的幼稚T细胞之间的关系， 具有移植后免疫重建的健康供体，包括GvL和GvHD活性。 根据总体假设，GvHD可以减少，GvL可以维持，并且移植结果 可以通过增加具有更高风险的allo-HSCT受者中未成熟供体pDC的含量来改善， 移植排斥和/或GvHD。普乐沙福的小鼠机制实验和创新性临床试验 在人类中的动员将通过研究Treg诱导和供体T细胞的体内迁移来检验这一假设。 细胞和pDC。从该项目中获得的知识将改善接受同种异体移植的患者的结局。 干细胞移植，并将在癌症免疫治疗和器官移植中应用。 !

The long-term goal of this research is to improve survival for patients after allogeneic stem cell transplantation by limiting graft-versus-host disease (GvHD) while maintaining the graft-versus-leukemia effect of donor immune cells. Clinical data from the BMT CTN 0201 clinical trial, in which transplant recipients with leukemia or MDS were randomized to receive BM versus G-CSF-mobilized blood stem cell allografts, found identical overall survival comparing the two graft sources, with less chronic GvHD in BM recipients. Among recipients of BM allografts, better survival was seen among recipients of larger numbers of plasmacytoid dendritic cells (pDC) and naive T-cells compared with patients who received fewer of these donor cells. Surprisingly, lower rates of severe acute GvHD (but not relapse) were seen in recipients of BM allografts containing more naive donor T-cells. Our recent published data shows that 1) highly purified donor pDC limit severe GvHD in murine BMT by facilitating expansion of donor regulatory T-cells (Treg) through interferon-¿- and IDO-dependent signaling with donor na¿ve T-cells; 2) plerixafor, a CXCR4 antagonist that mobilizes hematopoietic stem cells, also efficiently mobilizes pDC and na¿ve T-cells. Our overall hypothesis is that donor pDC in the hematopoietic stem cell graft favorably regulate the site of donor T-cell activation and donor T-cell immune polarization. Clinical translation of this approach is limited by gaps in understanding how donor pDC and T-cells cells interact to regulate GvHD. First, what is the optimal graft source or mobilization strategy to enhance the ability of pDC to limit severe GvHD? Second, what is the nature of interaction between donor pDC and naive T-cells that leads to increased Treg activity? Third, how do pDC in the graft regulate post- transplant immunity, including graft-versus-leukemia GvL? Three aims will test our overall hypothesis: 1. To determine the method of collecting hematopoietic stem cells that optimizes the content and immunological activity of donor pDC and na¿ve T-cells. 2. To test how pDC precursors in the donor stem cell graft and their progeny in vivo regulate homing and allo-reactivity of effector and regulatory T-cells in allo-HSCT recipients. 3. To define the relationship between the content of pDC and na¿ve T-cells in grafts collected from healthy donors with post-transplant immune reconstitution, including GvL and GvHD activities. According to the overall hypothesis, GvHD can be reduced, GvL can be maintained, and transplant outcomes can be improved by increasing the content of immature donor pDC in allo-HSCT recipients at higher risk for graft rejection and/or GvHD. Mechanistic experiments with mice and an innovative clinical trial of plerixafor mobilization in humans will test this hypothesis by studying Treg induction and in vivo migration of donor T- cells and pDC. Knowledge gained from this project will improve outcomes for patients undergoing allogeneic stem cell transplants and will have applications in cancer immunotherapy and organ transplantation. !