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存活率。 通过限制移植物抗宿主病(GvHD)同时维持供者的移植物抗白血病效应 免疫细胞。来自骨髓移植CTN 0201临床试验的临床数据，在该试验中，患有白血病的移植受者 或MDS被随机接受BM和G-CSF动员的异基因血液干细胞移植，发现相同 比较两种移植物来源的总体存活率，骨髓移植受者慢性移植物抗宿主病较少。在收件人中 在骨髓移植中，移植大量浆细胞样树突状细胞的受者存活率较高 (PDC)和幼稚T细胞与接受较少这些捐献细胞的患者相比。令人惊讶的是，更低的 严重急性移植物抗宿主病(但不复发)的受者中观察到含有更多幼稚的同种异体骨髓移植 捐献的T细胞。我们最近发表的数据表明：1)高纯度的供体PDC可抑制小鼠严重的GvHD 通过依赖干扰素和IDO促进供体调节性T细胞(Treg)的扩增 与供者的NAVE T细胞进行信号传递；2)Plerixafor，一种动员造血干细胞的CXCR4拮抗剂， 也能有效地动员PDC和NAVE T细胞。我们的总体假设是供体PDC在 造血干细胞移植对供者T细胞活化和供者T细胞的调节作用 免疫极化。这种方法的临床翻译受限于对供体PDC如何 T细胞相互作用，调节GvHD。首先，最佳的移植物来源或动员策略是什么？ 提高PDC限制严重GvHD的能力？第二，捐赠者之间相互作用的性质是什么？ PDC和幼稚T细胞导致Treg活性增加？第三，PDC在移植物中是如何调控后的 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.确定优化内容物含量的造血干细胞采集方法 供体PDC和NAVE T细胞的免疫活性。 2.检测供体干细胞移植物及其子代体内PDC前体细胞对归巢的调节作用 异基因造血干细胞移植受者效应性和调节性T细胞的异体反应性。 3.明确自体移植物中PDC和NA细胞含量的关系 移植后免疫重建的健康供者，包括GVL和GvHD活动。 根据总体假设，GvHD可以减少，GVL可以维持，移植结果 可通过增加异基因造血干细胞移植高危受者未成熟供者PDC的含量来改善 移植物排斥和/或移植物抗宿主病。小鼠的力学实验和普利沙福的创新临床试验 在人类中的动员将通过研究供体T-T细胞的Treg诱导和体内迁移来验证这一假设。 Cells和PDC。从这个项目中获得的知识将改善接受异基因移植的患者的预后 干细胞移植，并将在癌症免疫治疗和器官移植中应用。 好了！

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. !