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），同时维持供体免疫细胞的移植物抗白血病作用，提高同种异体干细胞移植后患者的生存率。BMT CTN 0201临床试验的临床数据显示，白血病或MDS的移植受者随机接受骨髓移植和g - csf动员的造血干细胞同种异体移植，两种移植来源的总生存率相同，骨髓移植受者的慢性GvHD较少。在同种异体骨髓移植受体中，与接受较少供体细胞的患者相比，接受大量浆细胞样树突状细胞（pDC）和naïve t细胞的患者生存率更高。令人惊讶的是，在含有更多naïve供体t细胞的骨髓异体移植物受体中，严重急性GvHD的发生率较低（但没有复发）。我们最近发表的数据表明，1)高纯度的供体pDC通过干扰素-γ和ido依赖的供体naïve t细胞信号传导促进供体调节性t细胞（Treg）的扩增，从而限制小鼠BMT中严重的GvHD；2)可动员造血干细胞的CXCR4拮抗剂plerixafor也可有效动员pDC和naïve t细胞。我们的总体假设是，造血干细胞移植物中的供体pDC有利于调节供体t细胞激活位点和供体t细胞免疫极化。这种方法的临床翻译受到对供体pDC和t细胞如何相互作用以调节GvHD的理解差距的限制。首先，增强pDC抑制严重GvHD能力的最佳移植物来源或动员策略是什么？其次，供体pDC与naïve t细胞之间的相互作用导致Treg活性增加的本质是什么？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？三个目标将检验我们的总体假设：1。确定优化供体pDC和naïve t细胞含量及免疫活性的造血干细胞采集方法。2. 测试供体干细胞移植物及其后代体内pDC前体如何调节同种异体造血干细胞受体中效应t细胞和调节性t细胞的归巢和同种异体反应性。3. 定义移植后免疫重建的健康供者移植物中pDC含量与naïve t细胞之间的关系，包括GvL和GvHD活性。根据总体假设，在移植排斥和/或GvHD风险较高的同种异体移植受者中，通过增加未成熟供体pDC的含量，可以降低GvHD，维持GvL，并改善移植结果。通过研究Treg诱导和供体t细胞和pDC的体内迁移，小鼠的机制实验和plerixato在人体内动员的创新临床试验将验证这一假设。从该项目中获得的知识将改善接受同种异体干细胞移植的患者的预后，并将在癌症免疫治疗和器官移植中得到应用。

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.