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

描述（由申请人提供）：本研究的长期目标是通过限制移植物抗宿主病（GvHD），同时维持供体ts免疫细胞的移植物抗白血病效应，提高异基因干细胞移植后患者的生存率。来自BMT CTN 0201临床试验的临床数据，其中移植白血病或MDS患者随机接受BM与G-CSF动员的造血干细胞同种异体移植，发现两种移植物来源的总生存率相同，BM受体中慢性GvHD较少。在骨髓同种异体移植物的接受者中，与接受较少这些供体细胞的患者相比，在大量浆细胞样树突状细胞（pDC）和幼稚T细胞的接受者中观察到更好的存活率。令人惊讶的是，在含有更多幼稚供体T细胞的BM同种异体移植物的受体中观察到较低的严重急性GvHD（但不复发）率。我们最近发表的数据显示：1）高度纯化的供体pDC通过干扰素-γ和IDO依赖性信号传导促进供体调节性T细胞（Treg）扩增，从而限制了小鼠BMT中的重度GvHD; 2）普乐沙福（一种动员造血干细胞的CXCR 4拮抗剂）也有效动员了pDC和幼稚T细胞。我们的总体假设是造血干细胞移植物中的供体pDC有利地调节供体T细胞活化和供体T细胞免疫极化的位点。这种方法的临床转化受到在理解供体pDC和T细胞如何相互作用以调节GvHD方面的差距的限制。第一，增强pDC限制严重GvHD的能力的最佳移植物来源或动员策略是什么？第二，导致Treg活性增加的供体pDC和初始T细胞之间的相互作用的性质是什么？第三，移植物中的pDC如何调节移植后免疫，包括移植物抗白血病GvL？三个目标将测试我们的整体假设：1。确定采集造血干细胞的方法，优化供体pDC和初始T细胞的含量和免疫活性。 2.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allo-HSCT受体中效应和调节性T细胞的归巢和同种异体反应性。 3.确定从具有移植后免疫重建（包括GvL和GvHD活性）的健康供体收集的移植物中pDC和幼稚T细胞的含量之间的关系。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处于移植物排斥和/或GvHD的较高风险的allo-HSCT受体中的未成熟供体pDC的含量来改善。小鼠机制实验和普乐沙福人体动员的创新性临床试验将通过研究Treg诱导和供体T细胞和pDC的体内迁移来验证这一假设。从该项目中获得的知识将改善接受异基因干细胞移植的患者的结果，并将在癌症免疫治疗和器官移植中应用。

DESCRIPTION (provided by applicant): 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 ts immune cells. Clinical data from the BMT CTN 0201 clinical trial, in which transplant recipienw ith 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 naïve 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 naïve 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-γ- and IDO-dependent signaling with donor naïve T-cells; 2) plerixafor, a CXCR4 antagonist that mobilizes hematopoietic stem cells, also efficiently mobilizes pDC and naïve 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 naïve 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 naïve 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 naïve 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 hypothesi 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.